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Guo YX, Yan X, Liu XC, Liu YX, Liu C. Artificial intelligence-driven strategies for managing renal and urinary complications in inflammatory bowel disease. World J Nephrol 2025; 14:100825. [DOI: 10.5527/wjn.v14.i1.100825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/29/2024] [Accepted: 12/27/2024] [Indexed: 01/20/2025] Open
Abstract
In this editorial, we discuss the article by Singh et al published in World Journal of Nephrology, stating the need for timely adjustments in inflammatory bowel disease (IBD) patients' long-term management plans. IBD is chronic and lifelong, with recurrence and remission cycles, including ulcerative colitis and Crohn's disease. It's exact etiology is unknown but likely multifactorial. Related to gut flora and immune issues. Besides intestinal symptoms, IBD can also affect various extraintestinal manifestations such as those involving the skin, joints, eyes and urinary system. The anatomical proximity of urinary system waste disposal to that of the alimentary canal makes early detection and the differentiation of such symptoms very difficult. Various studies show that IBD and it's first-line drugs have nephrotoxicity, impacting the patients' life quality. Existing guidelines give very few references for kidney lesion monitoring. Singh et al's plan aims to improve treatment management for IBD patients with glomerular filtration rate decline, specifically those at risk. Most of IBD patients are young and they need lifelong therapy. So early therapy cessation, taking into account drug side effects, can be helpful. Artificial intelligence-driven diagnosis and treatment has a big potential for management improvements in IBD and other chronic diseases.
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Affiliation(s)
- Ya-Xiong Guo
- Surgical Unit 1, Shanxi Combined Traditional Chinese and Western Medicine Hospital, Taiyuan 030072, Shanxi Province, China
- No. 1 Clinical Medical School, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Xiong Yan
- No. 1 Clinical Medical School, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Xu-Chang Liu
- No. 1 Clinical Medical School, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Yu-Xiang Liu
- Department of Nephrology, Shanxi Provincial People’s Hospital, Taiyuan 030012, Shanxi Province, China
| | - Chun Liu
- No. 1 Clinical Medical School, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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2
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Julius M, Lavsky HS, Kalfon L, Kfir NC, Herskovits M, Wiesmann I, Zaccai TCF. Primary hyperoxaluria type 3: from infancy to adulthood in a genetically unique cohort. Pediatr Nephrol 2025; 40:731-741. [PMID: 39476025 PMCID: PMC11753311 DOI: 10.1007/s00467-024-06536-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 01/21/2025]
Abstract
BACKGROUND Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder caused by bi-allelic genetic variants in the 4 hydroxy-2 oxoglutarate aldolase (HOGA-1) gene. We report the natural history of PH3 in a 16-patient cohort, 15 from a unique genetically isolated population. METHODS This retrospective single-center study followed PH3 patients between 2003 and 2023 with demographic, clinical, radiographic, genetic, and biochemical parameters. Genetic population screening was performed in four villages to determine carrier frequency and identify couples at risk in a genetically isolated population. RESULTS Sixteen patients with biallelic (or homozygous) pathogenic variants (PV) in HOGA-1 (c.944_946 del, c.119C > A, c.208C > T) were included in the study, 15 Druze and one Jewish, aged 0-63 years at diagnosis (4 adults and 12 pediatric patients). All symptomatic patients had clinical or imaging signs of nephrolithiasis. One developed chronic kidney disease (CKD) stage 5; biopsy showed focal mesangial sclerosis and chronic tubulo-interstitial changes with few oxalate deposits. Two other patients had CKD stage 2 (eGFR 87 and 74 mL/min/1.73 m2) upon their last visit. The remaining cohort showed preserved kidney function until the latest follow-up. Of 1167 healthy individuals screened, 90 carriers were found, a rate of 1:13 in the genetically unique cohort screened. CONCLUSIONS A high prevalence of PH3 patients was found among a unique cohort, but probably still underdiagnosed due to relatively mild disease course. The carrier rate is high. There is no specific therapy for PH3, but early diagnosis can prevent redundant diagnostic efforts and provide early treatment for kidney stone disease. Even in our homogeneous cohort, kidney stone disease severity and CKD degree were variable, supporting a suspected contribution of yet unknown genetic or environmental factors.
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MESH Headings
- Humans
- Hyperoxaluria, Primary/genetics
- Hyperoxaluria, Primary/diagnosis
- Hyperoxaluria, Primary/complications
- Hyperoxaluria, Primary/epidemiology
- Male
- Female
- Retrospective Studies
- Adult
- Adolescent
- Child
- Young Adult
- Child, Preschool
- Infant
- Oxo-Acid-Lyases/genetics
- Middle Aged
- Infant, Newborn
- Mutation
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/diagnosis
- Renal Insufficiency, Chronic/etiology
- Renal Insufficiency, Chronic/epidemiology
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Affiliation(s)
- Michal Julius
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Hadas Shasha Lavsky
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Pediatric Nephrology Unit, Galilee Medical Center, Nahariya, Israel
| | - Limor Kalfon
- Galilee Medical Center, Institute of Human Genetics, Nahariya, Israel
| | - Nehama Cohen Kfir
- Galilee Medical Center, Institute of Human Genetics, Nahariya, Israel
| | | | - Irith Wiesmann
- Pediatric Nephrology Unit, Galilee Medical Center, Nahariya, Israel
| | - Tzipora C Falik Zaccai
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
- Galilee Medical Center, Institute of Human Genetics, Nahariya, Israel.
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Mukherjee SD, Batagello CA, Adler A, Agudelo J, Zampini A, Suryavanshi M, Nguyen A, Orr T, Dearing D, Monga M, Miller AW. Complex system modelling reveals oxalate homeostasis is driven by diverse oxalate-degrading bacteria. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.10.28.620613. [PMID: 39553961 PMCID: PMC11565779 DOI: 10.1101/2024.10.28.620613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Decades of research have made clear that host-associated microbiomes touch all facets of health. However, effective therapies that target the microbiome have been elusive given its inherent complexity. Here, we experimentally examined diet-microbe-host interactions through a complex systems framework, centered on dietary oxalate. Using multiple, independent molecular, animal, and in vitro experimental models, we found that microbiome composition influenced multiple oxalate-microbe-host interfaces. Importantly, administration of the oxalate-degrading specialist, Oxalobacter formigenes, was only effective against a poor oxalate-degrading microbiota background and gives critical new insights into why clinical intervention trials with this species exhibit variable outcomes. Data suggest that, while heterogeneity in the microbiome impacts multiple diet-host-microbe interfaces, metabolic redundancy among diverse microorganisms in specific diet-microbe axes is a critical variable that may impact the efficacy of bacteriotherapies, which can help guide patient and probiotic selection criteria in probiotic clinical trials.
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4
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Saffe S, Doerry K, Büscher AK, Hansen M, Rohmann M, Kanzelmeyer N, Latta K, Kemper MJ, Loos S. Variable treatment response to lumasiran in pediatric patients with primary hyperoxaluria type 1. Pediatr Nephrol 2025:10.1007/s00467-025-06665-w. [PMID: 39869204 DOI: 10.1007/s00467-025-06665-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 12/13/2024] [Accepted: 12/27/2024] [Indexed: 01/28/2025]
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH 1) is a rare genetic condition due to mutations in the AGXT gene. This leads to an overproduction of oxalate in the liver. Hyperoxaluria often causes kidney stones, nephrocalcinosis, and chronic kidney disease. Lumasiran is a recently approved drug that reduces the hepatic oxalate production by mRNA interference. METHODS In this multicenter study, we evaluated the response to lumasiran treatment in PH 1 patients (n = 8) with a median age of 10.9 years (range 1.2-17.9 years), including two patients on hemodialysis. We retrospectively analyzed the reduction of urinary and plasma oxalate levels as well as changes in kidney stone events, nephrocalcinosis, and kidney function. RESULTS In patients without kidney failure, the median reduction of urinary oxalate was 64% (range 10-80%) and 71% (61-86%) at 6 and 12 months, respectively. However, only one patient reached urinary oxalate levels within the age-specific normal range. Two patients did not respond to lumasiran and treatment was stopped. In one of the two patients on hemodialysis, the frequency of sessions could be reduced. The only notable side effects were injection site reactions. CONCLUSION There was a variable response to lumasiran in PH 1. Despite a reduction of hyperoxaluria in many patients with PH 1, only one patient reached normal values and 2 of 8 patients did not respond. Regular monitoring of urinary oxalate values and registry data collection seems mandatory to monitor the efficacy and the long-term outcome of PH 1 treated with lumasiran.
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Affiliation(s)
- Sina Saffe
- Department of Pediatrics, Asklepios Klinik Nord Heidberg, Hamburg, Germany
| | - Katja Doerry
- University Medical Center Hamburg-Eppendorf, University Children's Hospital, Martinistrasse 52, Hamburg, 20246, Germany
| | - Anja K Büscher
- Pediatric Nephrology, Children's Hospital, University of Essen, Essen, Germany
| | - Matthias Hansen
- Department of Pediatric Nephrology, KfH-Nierenzentrum Für Kinder Und Jugendliche Beim Clementine Kinderhospital, Frankfurt, Germany
| | - Melanie Rohmann
- Department of Pediatric Nephrology, Universitätsklinikum Jena, Jena, Germany
| | - Nele Kanzelmeyer
- Department of Pediatric Nephrology, Medizinische Hochschule Hannover, Kinderklinik, Hannover, Germany
| | - Kay Latta
- Department of Pediatric Nephrology, Clementine Kinderhospital, Frankfurt, Germany
| | - Markus J Kemper
- Department of Pediatrics, Asklepios Klinik Nord Heidberg, Hamburg, Germany
| | - Sebastian Loos
- University Medical Center Hamburg-Eppendorf, University Children's Hospital, Martinistrasse 52, Hamburg, 20246, Germany.
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Mariscal de Gante L, Salanova L, Valdivia Mazeyra M, Serrano Pardo R, Quiroga B. Secondary hyperoxaluria: Cause and consequence of chronic kidney disease. Nefrologia 2025; 45:5-14. [PMID: 39800598 DOI: 10.1016/j.nefroe.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/08/2024] [Indexed: 02/01/2025] Open
Abstract
Secondary hyperoxaluria is a metabolic disorder characterized by an increase in urinary oxalate excretion. The etiology may arise from an increase in the intake of oxalate or its precursors, decreased elimination at the digestive level, or heightened renal excretion. Recently, the role of the SLC26A6 transporter in the etiopathogenesis of this disease has been identified. This transporter is active at both the intestinal and renal levels, and its mechanism of action is disrupted during systemic inflammation and metabolic syndrome, which could explain the rising incidence of secondary hyperoxaluria in recent decades. Treatment includes hygienic dietary measures, and medications aimed at reducing intestinal absorption by increasing fecal excretion. Different immunomodulatory drugs, microbiome modifiers and SGLT2 inhibitors could constitute new therapeutic targets. Currently, specific treatments for secondary hyperoxaluria are lacking, making early diagnosis and preventive measures against kidney failure the main therapeutic strategies.
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Affiliation(s)
| | - Laura Salanova
- Servicio de Nefrología, Hospital Universitario de la Princesa, Madrid, Spain
| | | | - Rosario Serrano Pardo
- Servicio de Anatomía Patológica, Hospital Universitario de la Princesa, Madrid, Spain
| | - Borja Quiroga
- Servicio de Nefrología, Hospital Universitario de la Princesa, Madrid, Spain.
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Siener R, Ernsten C, Welchowski T, Hesse A. Metabolic Profile of Calcium Oxalate Stone Patients with Enteric Hyperoxaluria and Impact of Dietary Intervention. Nutrients 2024; 16:2688. [PMID: 39203825 PMCID: PMC11357492 DOI: 10.3390/nu16162688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 08/03/2024] [Accepted: 08/08/2024] [Indexed: 09/03/2024] Open
Abstract
This study investigated the risk profile and the impact of dietary intervention in calcium oxalate stone formers with enteric hyperoxaluria under controlled, standardized conditions. Thirty-seven patients were included in the study. Dietary and 24-h urinary parameters were obtained on the self-selected diet and a balanced, standardized diet. Tests for [13C2]oxalate absorption, calcium- and ammonium chloride-loading were performed. Mean [13C2]oxalate absorption was 18.8%. A significant positive association was observed between urinary oxalate excretion and intestinal oxalate absorption. In addition, urinary oxalate excretion was significantly correlated with dietary oxalate intake. Mean urinary oxalate excretion decreased from 0.841 mmol/24 h on the usual diet to 0.662 mmol/24 h on the balanced diet, corresponding to a reduction of 21.3%. Besides hyperoxaluria, hypocitraturia and hypomagnesuria were the most common urinary abnormalities at baseline, being present in 83.8% and 81.1% of patients, respectively. Urinary citrate increased by 50.9% and magnesium excretion increased by 25.2% on the balanced diet. As a result, the relative supersaturation of calcium oxalate declined significantly (by 36.2%) on the balanced diet. Since 41% of patients on the balanced diet still had a urine volume of less than 2.0 L/24 h, efforts should be made to increase urine volume by increasing fluid intake and reducing intestinal fluid losses. Dietary intervention proved to be effective in reducing urinary oxalate excretion and should be a cornerstone of the treatment of patients with enteric hyperoxaluria.
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Affiliation(s)
- Roswitha Siener
- University Stone Center, Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (C.E.); (A.H.)
| | - Charlotte Ernsten
- University Stone Center, Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (C.E.); (A.H.)
| | - Thomas Welchowski
- Department of Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, 53127 Bonn, Germany;
| | - Albrecht Hesse
- University Stone Center, Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (C.E.); (A.H.)
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Post Hospers G, Visser WJ, Verhoeven JGHP, Laging M, Baart SJ, Mertens zur Borg IRAM, Hesselink DA, de Mik-van Egmond AME, Betjes MGH, van Agteren M, Severs D, van de Wetering J, Zietse R, Vos MJ, Kema IP, Kho MML, Reinders MEJ, Roodnat JI. Delayed Graft Function After Kidney Transplantation: The Role of Residual Diuresis and Waste Products, as Oxalic Acid and Its Precursors. Transpl Int 2024; 37:13218. [PMID: 39100754 PMCID: PMC11294083 DOI: 10.3389/ti.2024.13218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 07/01/2024] [Indexed: 08/06/2024]
Abstract
Delayed graft function (DGF) after kidney transplantation heralds a worse prognosis. In patients with hyperoxaluria, the incidence of DGF is high. Oxalic acid is a waste product that accumulates when kidney function decreases. We hypothesize that residual diuresis and accumulated waste products influence the DGF incidence. Patients transplanted between 2018-2022 participated in the prospective cohort study. Pre-transplant concentrations of oxalic acid and its precursors were determined. Data on residual diuresis and other recipient, donor or transplant related variables were collected. 496 patients were included, 154 were not on dialysis. Oxalic acid, and glyoxylic acid, were above upper normal concentrations in 98.8%, and 100% of patients. Residual diuresis was ≤150 mL/min in 24% of patients. DGF occurred in 157 patients. Multivariable binary logistic regression analysis demonstrated a significant influence of dialysis type, recipient BMI, donor type, age, and serum creatinine on the DGF risk. Residual diuresis and glycolic acid concentration were inversely proportionally related to this risk, glyoxylic acid directly proportionally. Results in the dialysis population showed the same results, but glyoxylic acid lacked significance. In conclusion, low residual diuresis is associated with increased DGF incidence. Possibly accumulated waste products also play a role. Pre-emptive transplantation may decrease the incidence of DGF.
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Affiliation(s)
- Gideon Post Hospers
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Wesley J. Visser
- Department of Internal Medicine, Division of Dietetics, Erasmus MC, Rotterdam, Netherlands
| | - Jeroen G. H. P. Verhoeven
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Mirjam Laging
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Sara J. Baart
- Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, Netherlands
| | | | - Dennis A. Hesselink
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | | | - Michiel G. H. Betjes
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Madelon van Agteren
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - David Severs
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Jacqueline van de Wetering
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Robert Zietse
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Michel J. Vos
- Department of Clinical Chemistry Metabolic Diseases, University Medical Center, Groningen, Netherlands
| | - Ido P. Kema
- Department of Clinical Chemistry Metabolic Diseases, University Medical Center, Groningen, Netherlands
| | - Marcia M. L. Kho
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Marlies E. J. Reinders
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Joke I. Roodnat
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
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Hawkins-van der Cingel G, Walsh SB, Eckardt KU, Knauf F. Oxalate Metabolism: From Kidney Stones to Cardiovascular Disease. Mayo Clin Proc 2024; 99:1149-1161. [PMID: 38762815 DOI: 10.1016/j.mayocp.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/24/2024] [Accepted: 02/09/2024] [Indexed: 05/20/2024]
Abstract
Oxalate kidney stones are common and exert a huge burden of morbidity worldwide. However, circulating or excreted concentrations of oxalate are rarely measured. We argue that oxalate and its metabolism are important above and beyond kidney stone formation. There is emerging evidence that increased concentrations of oxalate could be a driver of chronic kidney disease progression. Furthermore, oxalate has been implicated in cardiovascular disease. Thus, the reduction of elevated plasma oxalate concentrations may represent a novel cardioprotective and nephroprotective strategy.
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Affiliation(s)
- Gerlineke Hawkins-van der Cingel
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany; UCL Department of Renal Medicine, University College London, London, United Kingdom.
| | - Stephen B Walsh
- UCL Department of Renal Medicine, University College London, London, United Kingdom
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Felix Knauf
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
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9
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Zaidan N, Wang C, Chen Z, Lieske JC, Milliner D, Seide B, Ho M, Li H, Ruggles KV, Modersitzki F, Goldfarb DS, Blaser M, Nazzal L. Multiomics Assessment of the Gut Microbiome in Rare Hyperoxaluric Conditions. Kidney Int Rep 2024; 9:1836-1848. [PMID: 38899198 PMCID: PMC11184406 DOI: 10.1016/j.ekir.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/14/2024] [Accepted: 03/04/2024] [Indexed: 06/21/2024] Open
Abstract
Introduction Hyperoxaluria is a risk factor for kidney stone formation and chronic kidney disease progression. The microbiome is an important protective factor against oxalate accumulation through the activity of its oxalate-degrading enzymes (ODEs). In this cross-sectional study, we leverage multiomics to characterize the microbial community of participants with primary and enteric hyperoxaluria, as well as idiopathic calcium oxalate kidney stone (CKS) formers, focusing on the relationship between oxalate degrading functions of the microbiome. Methods Patients diagnosed with type 1 primary hyperoxaluria (PH), enteric hyperoxaluria (EH), and CKS were screened for inclusion in the study. Participants completed a food frequency questionnaire recording their dietary oxalate content while fecal oxalate levels were ascertained. DNA and RNA were extracted from stool samples and sequenced. Metagenomic (MTG) and metatranscriptomic (MTT) data were processed through our bioinformatics pipelines, and microbiome diversity, differential abundance, and networks were subject to statistical analysis in relationship with oxalate levels. Results A total of 38 subjects were recruited, including 13 healthy participants, 12 patients with recurrent CKS, 8 with PH, and 5 with EH. Urinary and fecal oxalate were significantly higher in the PH and the EH population compared to healthy controls. At the community level, alpha-diversity and beta-diversity indices were similar across all populations. The respective contributions of single bacterial species to the total oxalate degradative potential were similar in healthy and PH subjects. MTT-based network analysis identified the most interactive bacterial network in patients with PH. Patients with EH had a decreased abundance of multiple major oxalate degraders. Conclusion The composition and inferred activity of oxalate-degrading microbiota were differentially associated with host clinical conditions. Identifying these changes improves our understanding of the relationships between dietary constituents, microbiota, and oxalate homeostasis, and suggests new therapeutic approaches protecting against hyperoxaluria.
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Affiliation(s)
- Nadim Zaidan
- Department of Medicine, Division of Nephrology, NYU Langone Medical Center, New York, New York, USA
| | - Chan Wang
- Department of Population Health, New York University School of Medicine, NYU Langone Health, New York, New York, USA
| | - Ze Chen
- Department of Population Health, New York University School of Medicine, NYU Langone Health, New York, New York, USA
| | - John C. Lieske
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Dawn Milliner
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Barbara Seide
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Melody Ho
- Department of Medicine, Division of Nephrology, NYU Langone Medical Center, New York, New York, USA
| | - Huilin Li
- Department of Population Health, New York University School of Medicine, NYU Langone Health, New York, New York, USA
| | - Kelly V. Ruggles
- Department of Medicine, Division of Precision Medicine, New York University School of Medicine, NYU Langone Health, New York, New York, USA
| | - Frank Modersitzki
- Department of Medicine, Division of Nephrology, NYU Langone Medical Center, New York, New York, USA
| | - David S. Goldfarb
- Department of Medicine, Division of Nephrology, NYU Langone Medical Center, New York, New York, USA
| | - Martin Blaser
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, USA
| | - Lama Nazzal
- Department of Medicine, Division of Nephrology, NYU Langone Medical Center, New York, New York, USA
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Ahmadi M, de Souza Goncalves L, Verkman AS, Cil O, Anderson MO. Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria. RSC Med Chem 2024; 15:1731-1736. [PMID: 38784456 PMCID: PMC11110725 DOI: 10.1039/d3md00644a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 02/27/2024] [Indexed: 05/25/2024] Open
Abstract
SLC26A3, also known as downregulated in adenoma (DRA), is an anion (Cl-, HCO3- and oxalate) exchanger in the luminal membrane of intestinal epithelial cells. Loss of DRA function in mice and humans causes congenital chloride-losing diarrhea and reduces urinary excretion of oxalate, a major constituent of kidney stones. Thus, inhibition of DRA is a potential treatment approach for constipation and calcium oxalate kidney stones. High-throughput screening previously identified 4,8-dimethylcoumarins (4a-4c) as DRA inhibitors, with lead candidate 4b having an IC50 of 40-50 nM for DRA inhibition. Here, we explored the effects of varying substituents at the 8-position, and replacing 8-methyl by 5-methyl (4e-4h). A focused library of 17 substituted compounds (4d-4t) was synthesized with good yield and purity. Compounds were tested for DRA inhibition potency using Fischer rat thyroid cells stably expressing DRA and a halide-sensitive YFP. Structure-activity analysis revealed that 8-bromo- (4m-4p) and 8-fluoro-coumarins (4q-4t) were slightly less potent than the corresponding 8-chloro analogs, demonstrating that the size of methyl or chloro substituents at the coumarin 8 position affects the potency. An analog containing 8-chlorocoumarin (4k) had ∼2-fold improved potency (IC50 25 nM) compared with the original lead candidate 4b. 5,8-Dimethylcoumarins were active against DRA, but with much lower potency than 4,8-disubstituted coumarins. In mice, orally administered 4k at 10 mg kg-1 reduced constipation and normalized stool water content in a loperamide-induced constipation model with comparable efficacy to 4b. Pharmacokinetic analysis of orally administered 4k at 10 mg kg-1 in mice indicated serum levels of >10 μM for at least six hours after single dose. This study expands SAR knowledge of 4,8-disubstituted coumarin inhibitors of DRA as novel drug candidates for constipation and kidney stones.
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Affiliation(s)
- Maria Ahmadi
- Department of Chemistry and Biochemistry, San Francisco State University San Francisco CA USA
| | | | - Alan S Verkman
- Department of Medicine, University of California, San Francisco San Francisco CA USA
| | - Onur Cil
- Department of Pediatrics, University of California, San Francisco San Francisco CA USA
| | - Marc O Anderson
- Department of Chemistry and Biochemistry, San Francisco State University San Francisco CA USA
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Brösecke F, Pfau A, Ermer T, Dein Terra Mota Ribeiro AB, Rubenbauer L, Rao VS, Burlein S, Genser B, Reichel M, Aronson PS, Coca S, Knauf F. Interleukin-16 is increased in dialysis patients but is not a cardiovascular risk factor. Sci Rep 2024; 14:11323. [PMID: 38760468 PMCID: PMC11101424 DOI: 10.1038/s41598-024-61808-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 05/09/2024] [Indexed: 05/19/2024] Open
Abstract
Oxalate, a uremic toxin that accumulates in dialysis patients, is associated with cardiovascular disease. As oxalate crystals can activate immune cells, we tested the hypothesis that plasma oxalate would be associated with cytokine concentrations and cardiovascular outcomes in dialysis patients. In a cohort of 104 US patients with kidney failure requiring dialysis (cohort 1), we measured 21 inflammatory markers. As IL-16 was the only cytokine to correlate with oxalate, we focused further investigations on IL-16. We searched for associations between concentrations of IL-16 and mortality and cardiovascular events in the 4D cohort (1255 patients, cohort 2) and assessed further associations of IL-16 with other uremic toxins in this cohort. IL-16 levels were positively correlated with pOx concentrations (ρ = 0.39 in cohort 1, r = 0.35 in cohort 2) and were elevated in dialysis patients when compared to healthy individuals. No significant association could be found between IL-16 levels and cardiovascular events or mortality in the 4D cohort. We conclude that the cytokine IL-16 correlates with plasma oxalate concentrations and is substantially increased in patients with kidney failure on dialysis. However, no association could be detected between IL-16 concentrations and cardiovascular disease in the 4D cohort.
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Affiliation(s)
- Frederic Brösecke
- Department of Nephrology and Medical Intensive Care, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Anja Pfau
- Department of Nephrology and Medical Intensive Care, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117, Berlin, Germany
- MVZ Dialysezentrum (Dialysis Center), Schweinfurt, Germany
| | - Theresa Ermer
- Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA
| | - Ana Beatriz Dein Terra Mota Ribeiro
- Department of Nephrology and Medical Intensive Care, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Lisa Rubenbauer
- Department of Nephrology and Medical Intensive Care, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Veena S Rao
- Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Sarah Burlein
- Department of Nephrology and Medical Intensive Care, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Bernd Genser
- Department of General Medicine, Centre for Preventive Medicine and Digital Health Baden Württemberg, Ruprecht Karls University, Heidelberg, Germany
- High5Data GmbH, Heidelberg, Germany
| | - Martin Reichel
- Department of Nephrology and Medical Intensive Care, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Peter S Aronson
- Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA
| | - Steven Coca
- Mount Sinai School of Medicine, Mt. Sinai Hospital, New York, NY, USA
| | - Felix Knauf
- Department of Nephrology and Medical Intensive Care, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117, Berlin, Germany.
- Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA.
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12
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Puurunen M, Kurtz C, Wheeler A, Mulder K, Wood K, Swenson A, Curhan G. Twenty-four-hour urine oxalate and risk of chronic kidney disease. Nephrol Dial Transplant 2024; 39:788-794. [PMID: 37804181 PMCID: PMC11873791 DOI: 10.1093/ndt/gfad221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Indexed: 10/09/2023] Open
Abstract
BACKGROUND To assess whether 24-h urine oxalate (UOx) excretion is a risk factor for incident chronic kidney disease (CKD). METHODS This longitudinal observational USA-based study included 426 896 individuals aged ≥18 years with no CKD at baseline and with at least one UOx, and at least 6 months of baseline and 6 months of follow-up data. Of these, 11 239 (2.6%) had an underlying malabsorptive condition. Incident CKD, defined by relevant International Classification of Diseases codes, was identified from a multi-source data cloud containing individual-level healthcare claims and electronic medical records data. The association between categories of UOx and incident CKD was modeled using logistic regression adjusting for age, sex, race, body mass index, baseline urine calcium, urine citrate, urine volume, tobacco use, hypertension, diabetes, malabsorption and cardiovascular disease. RESULTS Mean follow-up time was 38.9 months (standard deviation 21.7). Compared with individuals with UOx <20 mg/24 h, the odds of developing incident CKD increased for UOx 20-29 mg/24 h [multivariable-adjusted odds ratio (MVOR) 1.14 (95% CI 1.07, 1.21)] through 80+ mg/24 h [MVOR 1.35 (1.21, 1.50)] and was statistically significant for each UOx category. A similar pattern was seen in the subgroup with a malabsorptive condition though the magnitudes of association were larger, with the odds of developing incident CKD increased for UOx 20-29 mg/24 h [MVOR 1.50 (1.03, 2.20)] through 80+ mg/24 h [MVOR 2.34 (1.50, 3.63)] as compared with UOx <20 mg/24 h. CONCLUSIONS The risk of incident CKD increases with increasing 24-h UOx excretion. Future studies should examine whether reducing UOx diminishes the risk of developing CKD.
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Affiliation(s)
| | | | | | | | - Kyle Wood
- University of Alabama, Birmingham, AL, USA
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13
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Nasr SH, Valeri AM, Said SM, Sethi S, Nath KA, Lieske JC, Bu L. Clinicopathologic Characteristics, Etiologies, and Outcome of Secondary Oxalate Nephropathy. Mayo Clin Proc 2024; 99:593-606. [PMID: 38310502 PMCID: PMC11017309 DOI: 10.1016/j.mayocp.2023.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/08/2023] [Accepted: 08/10/2023] [Indexed: 02/05/2024]
Abstract
OBJECTIVE To report the clinicopathologic characteristics, prognostic indicators, prognosis, and transplant outcome of secondary oxalate nephropathy (ON). PATIENTS AND METHODS We performed a retrospective analysis of 113 consecutive patients with secondary ON diagnosed at Mayo Clinic in Rochester, Minnesota, between January 1, 2001, and March 1, 2023. RESULTS The incidence of secondary ON among all native biopsies from Mayo Clinic patients over the study period (n=11,617) was 0.97%. ON was attributed to enteric hyperoxaluria in 60% of the 113 patients (68; most commonly Roux-en-Y gastric bypass), excessive ingestion of foods high in oxalate or oxalate precursors in 23% (26) (most commonly vitamin C), and idiopathic in 17% (19). Most patients presented with acute kidney injury (AKI) (particularly in the ingestion group) or AKI on chronic kidney disease, and 53% (60 of 113) were diabetic. Calcium oxalate crystals were accompanied by acute tubular injury, inflammation, and interstitial fibrosis and tubular atrophy. Concurrent pathologic conditions were present in 53% of the patients (60 of 113), most commonly diabetic nephropathy. After a median follow-up of 36 months, 27% of the patients (30 of 112) had kidney recovery, 19% (21 of 112) had persistent kidney dysfunction, 54% (61 of 112) had development of kidney failure, and 29% (32 of 112) died. The mean kidney survival was worse for patients with a concurrent pathologic lesion (30 months vs 96 months for those without a concurrent pathologic lesion; P<.001). Independent predictors of kidney failure were the degree of interstitial fibrosis and tubular atrophy and nadir estimated glomerular filtration rate but not the degree of crystal deposition. After a median follow-up of 58 months in 23 patients who received kidney transplant, 4 had graft loss (due to ON in 3). The 2-, 5-, and 10-year graft survivals were 90% (18 of 20), 79% (11 of 14), and 50% (6 of 12). CONCLUSION ON is a rare cause of AKI or AKI on chronic kidney disease. Most patients have comorbid pathologic conditions, particularly diabetic nephropathy, which worsen the prognosis. Recurrence in the renal allograft and graft loss may occur if hyperoxaluria is not controlled.
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Affiliation(s)
- Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
| | - Anthony M Valeri
- Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY
| | - Samar M Said
- Department of Pathology, Olmsted Medical Center, Rochester, MN
| | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Karl A Nath
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - John C Lieske
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Lihong Bu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
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14
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Deng JW, Li CY, Huang YP, Liu WF, Zhang Q, Long J, Wu WQ, Huang LH, Zeng GH, Sun XY. Mechanism of Porphyra Yezoensis Polysaccharides in Inhibiting Hyperoxalate-Induced Renal Injury and Crystal Deposition. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:6372-6388. [PMID: 38471112 DOI: 10.1021/acs.jafc.3c09152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/14/2024]
Abstract
Oxidative damage to the kidneys is a primary factor in the occurrence of kidney stones. This study explores the inhibitory effect of Porphyra yezoensis polysaccharides (PYP) on oxalate-induced renal injury by detecting levels of oxidative damage, expression of adhesion molecules, and damage to intracellular organelles and revealed the molecular mechanism by molecular biology methods. Additionally, we validated the role of PYP in vivo using a crystallization model of hyperoxalate-induced rats. PYP effectively scavenged the overproduction of reactive oxygen species (ROS) in HK-2 cells, inhibited the adhesion of calcium oxalate (CaOx) crystals on the cell surface, unblocked the cell cycle, restored the depolarization of the mitochondrial membrane potential, and inhibited cell death. PYP upregulated the expression of antioxidant proteins, including Nrf2, HO-1, SOD, and CAT, while decreasing the expression of Keap-1, thereby activating the Keap1/Nrf2 signaling pathway. PYP inhibited CaOx deposition in renal tubules in the rat crystallization model, significantly reduced high oxalate-induced renal injury, decreased the levels of the cell surface adhesion proteins, improved renal function in rats, and ultimately inhibited the formation of kidney stones. Therefore, PYP, which has crystallization inhibition and antioxidant properties, may be a therapeutic option for the treatment of kidney stones.
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Affiliation(s)
- Ji-Wang Deng
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Chun-Yao Li
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Ya-Peng Huang
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Wei-Feng Liu
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Quan Zhang
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Jun Long
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Wen-Qi Wu
- Department of Urology, Guangdong Key Laboratory of Urology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Ling-Hong Huang
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Guo-Hua Zeng
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
| | - Xin-Yuan Sun
- Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally invasive surgery Robot and Intelligent Equipment, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510230, China
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15
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Stepanova N, Tolstanova G, Aleksandrova I, Korol L, Dovbynchuk T, Driianska V, Savchenko S. Gut Microbiota's Oxalate-Degrading Activity and Its Implications on Cardiovascular Health in Patients with Kidney Failure: A Pilot Prospective Study. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2189. [PMID: 38138292 PMCID: PMC10744410 DOI: 10.3390/medicina59122189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023]
Abstract
Background and Objectives: The present study aims to investigate the association between gut microbiota's oxalate-degrading activity (ODA) and the risk of developing cardiovascular disease (CVD) over a three-year follow-up period in a cohort of patients undergoing kidney replacement therapy (KRT). Additionally, various factors were examined to gain insight into the potential mechanisms underlying the ODA-CVD link. Materials and Methods: A cohort of 32 KRT patients and 18 healthy volunteers was enrolled in this prospective observational pilot study. Total fecal ODA, routine clinical data, plasma oxalic acid (POx), serum indoxyl sulfate, lipid profile, oxidative stress, and proinflammatory markers were measured, and the patients were followed up for three years to assess CVD events. Results: The results revealed that patients with kidney failure exhibited significantly lower total fecal ODA levels compared to the healthy control group (p = 0.017), with a higher proportion showing negative ODA status (≤-1% per 0.01 g) (p = 0.01). Negative total fecal ODA status was associated with a significantly higher risk of CVD events during the three-year follow-up period (HR = 4.1, 95% CI 1.4-16.3, p = 0.003), even after adjusting for potential confounders. Negative total fecal ODA status was significantly associated with elevated POx and indoxyl sulfate levels and linked to dyslipidemia, increased oxidative stress, and inflammation, which are critical contributors to CVD. Conclusions: The findings contribute novel insights into the relationship between gut microbiota's ODA and cardiovascular health in patients undergoing KRT, emphasizing the need for further research to elucidate underlying mechanisms and explore potential therapeutic implications of targeting gut microbiota's ODA in this vulnerable population.
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Affiliation(s)
- Natalia Stepanova
- State Institution “Institute of Nephrology of the National Academy of Medical Sciences of Ukraine”, 04050 Kyiv, Ukraine; (L.K.)
- Educational and Scientific Institute of High Technologies, Taras Shevchenko National University, 01601 Kyiv, Ukraine
| | - Ganna Tolstanova
- Educational and Scientific Institute of High Technologies, Taras Shevchenko National University, 01601 Kyiv, Ukraine
| | - Iryna Aleksandrova
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University, 01601 Kyiv, Ukraine (T.D.)
| | - Lesya Korol
- State Institution “Institute of Nephrology of the National Academy of Medical Sciences of Ukraine”, 04050 Kyiv, Ukraine; (L.K.)
| | - Taisa Dovbynchuk
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University, 01601 Kyiv, Ukraine (T.D.)
| | - Victoria Driianska
- State Institution “Institute of Nephrology of the National Academy of Medical Sciences of Ukraine”, 04050 Kyiv, Ukraine; (L.K.)
| | - Svitlana Savchenko
- State Institution “Institute of Nephrology of the National Academy of Medical Sciences of Ukraine”, 04050 Kyiv, Ukraine; (L.K.)
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16
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Baltazar P, de Melo Junior AF, Fonseca NM, Lança MB, Faria A, Sequeira CO, Teixeira-Santos L, Monteiro EC, Campos Pinheiro L, Calado J, Sousa C, Morello J, Pereira SA. Oxalate (dys)Metabolism: Person-to-Person Variability, Kidney and Cardiometabolic Toxicity. Genes (Basel) 2023; 14:1719. [PMID: 37761859 PMCID: PMC10530622 DOI: 10.3390/genes14091719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 09/29/2023] Open
Abstract
Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet, microbiota, renal and metabolic disease) reasons underlie elevated plasma concentrations and tissue accumulation of oxalate, which is toxic to the body. A classic example is the triad of primary hyperoxaluria, nephrolithiasis, and kidney injury. Lessons learned from this example suggest further investigation of other putative factors associated with oxalate dysmetabolism, namely the identification of precursors (glyoxylate, aromatic amino acids, glyoxal and vitamin C), the regulation of the endogenous pathways that produce oxalate, or the microbiota's contribution to oxalate systemic availability. The association between secondary nephrolithiasis and cardiovascular and metabolic diseases (hypertension, type 2 diabetes, and obesity) inspired the authors to perform this comprehensive review about oxalate dysmetabolism and its relation to cardiometabolic toxicity. This perspective may offer something substantial that helps advance understanding of effective management and draws attention to the novel class of treatments available in clinical practice.
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Affiliation(s)
- Pedro Baltazar
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Antonio Ferreira de Melo Junior
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Nuno Moreira Fonseca
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Miguel Brito Lança
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
| | - Ana Faria
- CHRC, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal;
| | - Catarina O. Sequeira
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
| | - Luísa Teixeira-Santos
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Emilia C. Monteiro
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Luís Campos Pinheiro
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Joaquim Calado
- Centro Hospitalar Universitário de Lisboa Central, E.P.E, 1150-199 Lisboa, Portugal; (P.B.); (N.M.F.); (M.B.L.); (L.C.P.); (J.C.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
- ToxOmics, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal
| | - Cátia Sousa
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
| | - Judit Morello
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
| | - Sofia A. Pereira
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, 1150-082 Lisboa, Portugal; (A.F.d.M.J.); (C.O.S.); (L.T.-S.); (E.C.M.); (C.S.); (J.M.)
- Centro Clínico Académico de Lisboa, 1159-056 Lisboa, Portugal
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17
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Arvans D, Chang C, Alshaikh A, Tesar C, Babnigg G, Wolfgeher D, Kron S, Antonopoulos D, Bashir M, Cham C, Musch M, Chang E, Joachimiak A, Hassan H. Sel1-like proteins and peptides are the major Oxalobacter formigenes-derived factors stimulating oxalate transport by human intestinal epithelial cells. Am J Physiol Cell Physiol 2023; 325:C344-C361. [PMID: 37125773 PMCID: PMC10393326 DOI: 10.1152/ajpcell.00466.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 05/02/2023]
Abstract
Kidney stones (KSs) are very common, excruciating, and associated with tremendous healthcare cost, chronic kidney disease (CKD), and kidney failure (KF). Most KSs are composed of calcium oxalate and small increases in urinary oxalate concentration significantly enhance the stone risk. Oxalate also potentially contributes to CKD progression, kidney disease-associated cardiovascular diseases, and poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, which can be achieved by enhancing enteric oxalate secretion. We previously identified Oxalobacter formigenes (O. formigenes)-derived factors secreted in its culture-conditioned medium (CM), which stimulate oxalate transport by human intestinal Caco2-BBE (C2) cells and reduce urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified Sel1-like proteins as the major O. formigenes-derived secreted factors using mass spectrometry and functional assays. Crystal structures for six proteins were determined to confirm structures and better understand functions. OxBSel1-14-derived small peptides P8 and P9 were identified as the major factors, with P8 + 9 closely recapitulating the CM's effects, acting through the oxalate transporters SLC26A2 and SLC26A6 and PKA activation. Besides C2 cells, P8 + 9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that they work in human tissues. In conclusion, P8 and P9 peptides are identified as the major O. formigenes-derived secreted factors and they have significant therapeutic potential for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KSs, enteric hyperoxaluria, primary hyperoxaluria, CKD, KF, and renal transplant recipients.NEW & NOTEWORTHY We previously identified Oxalobacter formigenes-derived secreted factors stimulating oxalate transport by human intestinal epithelial cells in vitro and reducing urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. We now identified Sel1-like proteins and small peptides as the major secreted factors and they have significant therapeutic potential for hyperoxalemia and hyperoxaluria, impacting the outcomes of patients suffering from kidney stones, primary and secondary hyperoxaluria, chronic kidney disease, kidney failure, and renal transplant recipients.
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Affiliation(s)
- Donna Arvans
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
| | - Changsoo Chang
- Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, Illinois, United States
| | - Altayeb Alshaikh
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
| | - Christine Tesar
- Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, Illinois, United States
| | - Gyorgy Babnigg
- Biosciences Division, Argonne National Laboratory, Lemont, Illinois, United States
| | - Don Wolfgeher
- Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, United States
| | - Stephen Kron
- Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, United States
| | | | - Mohamed Bashir
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
| | - Candace Cham
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
| | - Mark Musch
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
| | - Eugene Chang
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
| | - Andrzej Joachimiak
- Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, Illinois, United States
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, United States
| | - Hatim Hassan
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States
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18
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Bao D, Zhang H, Wang J, Wang Y, Wang S, Zhao MH. Determinants on urinary excretion of oxalate and other key factors related to urolithiasis among patients with chronic kidney disease: a single center study. Urolithiasis 2023; 51:88. [PMID: 37314585 PMCID: PMC10266999 DOI: 10.1007/s00240-023-01458-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 05/24/2023] [Indexed: 06/15/2023]
Abstract
PURPOSE Urolithiasis is a known risk factor for chronic kidney disease (CKD). However, how CKD might affect the risk of incidence of urolithiasis is not widely studied. METHODS Urinary excretion of oxalate as well as other key factors related to urolithiasis was analyzed in a single center study of 572 patients with biopsy-proven kidney disease. RESULTS The mean age of the cohort was 44.9 years and 60% were males. The mean eGFR was 65.9 ml/min/1.73 m2. Median urinary excretion of oxalate was 14.7 (10.4-19.1) mg/24-h and associated with current urolithiasis (OR 12.744, 95% CI: 1.564-103.873 per one logarithm transformed unit of urinary oxalate excretion). Oxalate excretion was not associated with eGFR and urinary protein excretion. Oxalate excretion was higher in patients with ischemia nephropathy as compared with patients with glomerular nephropathy and tubulointerstitial nephropathy (16.4 vs 14.8 vs 12.0 mg, p = 0.018). And ischemia nephropathy (p = 0.027) was associated with urinary oxalate excretion on adjusted linear regression analysis. Urinary excretion of calcium and uric acid was correlated with eGFR and urinary protein excretion (all p < 0.001), with ischemia nephropathy and tubulointerstitial nephropathy associated with uric acid excretion (both p < 0.01) as well. Citrate excretion was correlated with eGFR (p < 0.001) on adjusted linear regression. CONCLUSION Excretion of oxalate and other key factors related to urolithiasis was differentially associated with eGFR, urinary protein, and pathological changes in CKD patients. The influence of these intrinsic traits of the underlining kidney disease should be considered when evaluating urolithiasis risk in patients with CKD.
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Affiliation(s)
- Daorina Bao
- Renal Division, Department of Medicine, Peking University First Hospital, No. 8 Xishiku St., Xicheng District, Beijing, 100034, China
- Institute of Nephrology, Peking University, Beijing, 100034, China
- Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People's Republic of China, Beijing, 100034, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Huimin Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, No. 8 Xishiku St., Xicheng District, Beijing, 100034, China
- Institute of Nephrology, Peking University, Beijing, 100034, China
- Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People's Republic of China, Beijing, 100034, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Jinwei Wang
- Renal Division, Department of Medicine, Peking University First Hospital, No. 8 Xishiku St., Xicheng District, Beijing, 100034, China
- Institute of Nephrology, Peking University, Beijing, 100034, China
- Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People's Republic of China, Beijing, 100034, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Yu Wang
- Renal Division, Department of Medicine, Peking University First Hospital, No. 8 Xishiku St., Xicheng District, Beijing, 100034, China.
- Institute of Nephrology, Peking University, Beijing, 100034, China.
- Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People's Republic of China, Beijing, 100034, China.
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.
| | - Suxia Wang
- Laboratory of Electron Microscopy, Pathological Centre, Peking University First Hospital, Beijing, 100034, China
| | - Ming-Hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, No. 8 Xishiku St., Xicheng District, Beijing, 100034, China
- Institute of Nephrology, Peking University, Beijing, 100034, China
- Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People's Republic of China, Beijing, 100034, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- Peking-Tsinghuric Center for Life Sciences, Beijing, 100871, China
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19
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Stepanova N. Oxalate Homeostasis in Non-Stone-Forming Chronic Kidney Disease: A Review of Key Findings and Perspectives. Biomedicines 2023; 11:1654. [PMID: 37371749 PMCID: PMC10296321 DOI: 10.3390/biomedicines11061654] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/03/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Chronic kidney disease (CKD) is a significant global public health concern associated with high morbidity and mortality rates. The maintenance of oxalate homeostasis plays a critical role in preserving kidney health, particularly in the context of CKD. Although the relationship between oxalate and kidney stone formation has been extensively investigated, our understanding of oxalate homeostasis in non-stone-forming CKD remains limited. This review aims to present an updated analysis of the existing literature, focusing on the intricate mechanisms involved in oxalate homeostasis in patients with CKD. Furthermore, it explores the key factors that influence oxalate accumulation and discusses the potential role of oxalate in CKD progression and prognosis. The review also emphasizes the significance of the gut-kidney axis in CKD oxalate homeostasis and provides an overview of current therapeutic strategies, as well as potential future approaches. By consolidating important findings and perspectives, this review offers a comprehensive understanding of the present knowledge in this field and identifies promising avenues for further research.
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Affiliation(s)
- Natalia Stepanova
- State Institution «Institute of Nephrology of the National Academy of Medical Sciences of Ukraine», 04050 Kyiv, Ukraine
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20
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Scherer L, Schönauer R, Nemitz-Kliemchen M, Hagemann T, Hantmann E, de Fallois J, Petzold F, Blüher M, Halbritter J. Delta weight loss unlike genetic variation associates with hyperoxaluria after malabsorptive bariatric surgery. Sci Rep 2023; 13:9029. [PMID: 37270618 DOI: 10.1038/s41598-023-35941-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 05/26/2023] [Indexed: 06/05/2023] Open
Abstract
The risk of enteric hyperoxaluria is significantly increased after malabsorptive bariatric surgery (MBS). However, its underlying determinants are only poorly characterized. In this case-control study, we aimed at identifying clinical and genetic factors to dissect their individual contributions to the development of post-surgical hyperoxaluria. We determined the prevalence of hyperoxaluria and nephrolithiasis after MBS by 24-h urine samples and clinical questionnaires at our obesity center. Both hyperoxaluric and non-hyperoxaluric patients were screened for sequence variations in known and candidate genes implicated in hyperoxaluria (AGXT, GRHPR, HOGA1, SLC26A1, SLC26A6, SLC26A7) by targeted next generation sequencing (tNGS). The cohort comprised 67 patients, 49 females (73%) and 18 males (27%). While hyperoxaluria was found in 29 patients (43%), only one patient reported postprocedural nephrolithiasis within 41 months of follow-up. Upon tNGS, we did not find a difference regarding the burden of (rare) variants between hyperoxaluric and non-hyperoxaluric patients. However, patients with hyperoxaluria showed significantly greater weight loss accompanied by markers of intestinal malabsorption compared to non-hyperoxaluric controls. While enteric hyperoxaluria is very common after MBS, genetic variation of known hyperoxaluria genes contributes little to its pathogenesis. In contrast, the degree of postsurgical weight loss and levels of malabsorption parameters may allow for predicting the risk of enteric hyperoxaluria and consecutive kidney stone formation.
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Affiliation(s)
- Lotte Scherer
- Division of Nephrology, University of Leipzig Medical Center, Leipzig, Germany
| | - Ria Schönauer
- Division of Nephrology, University of Leipzig Medical Center, Leipzig, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité University, Berlin, Germany
| | - Melanie Nemitz-Kliemchen
- Department of Nephrology and Internal Intensive Care Medicine, Charité University, Berlin, Germany
| | - Tobias Hagemann
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Ph.-Rosenthal-Str. 27, 04103, Leipzig, Germany
| | - Elena Hantmann
- Department of Nephrology and Internal Intensive Care Medicine, Charité University, Berlin, Germany
| | - Jonathan de Fallois
- Division of Nephrology, University of Leipzig Medical Center, Leipzig, Germany
| | - Friederike Petzold
- Division of Nephrology, University of Leipzig Medical Center, Leipzig, Germany
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Ph.-Rosenthal-Str. 27, 04103, Leipzig, Germany
| | - Jan Halbritter
- Division of Nephrology, University of Leipzig Medical Center, Leipzig, Germany.
- Department of Nephrology and Internal Intensive Care Medicine, Charité University, Berlin, Germany.
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21
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Arnous MG, Vaughan L, Mehta RA, Schulte PJ, Lieske JC, Milliner DS. Characterization of Stone Events in Patients With Type 3 Primary Hyperoxaluria. J Urol 2023; 209:1141-1150. [PMID: 36888927 PMCID: PMC11034812 DOI: 10.1097/ju.0000000000003400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/28/2023] [Indexed: 03/10/2023]
Abstract
PURPOSE Hallmarks of primary hyperoxaluria type 3 are nephrolithiasis and hyperoxaluria. However, little is known about factors influencing stone formation in this disease. We characterized stone events and examined associations with urine parameters and kidney function in a primary hyperoxaluria type 3 population. MATERIALS AND METHODS We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry. RESULTS Kidney stones occurred in 65/70 primary hyperoxaluria type 3 patients (93%). Among the 49 patients with imaging available, the median (IQR) number of stones was 4 (2, 5), with largest stone 7 mm (4, 10) at first imaging. Clinical stone events occurred in 62/70 (89%) with median number of events per patient 3 (2, 6; range 1-49). Age at first stone event was 3 years (0.99, 8.7). Lifetime stone event rate was 0.19 events/year (0.12, 0.38) during follow-up of 10.7 (4.2, 26.3) years. Among 326 total clinical stone events, 139 (42.6%) required surgical intervention. High stone event rates persisted for most patients through the sixth decade of life. Analysis was available for 55 stones: pure calcium oxalate accounted for 69%, with mixed calcium oxalate and phosphate in 22%. Higher calcium oxalate supersaturation was associated with increased lifetime stone event rate after adjusting for age at first event (IRR [95%CI] 1.23 [1.16, 1.32]; P < .001). By the fourth decade, estimated glomerular filtration rate was lower in primary hyperoxaluria type 3 patients than the general population. CONCLUSIONS Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.
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Affiliation(s)
- Muhammad G. Arnous
- Divison of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Lisa Vaughan
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Ramila A. Mehta
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Phillip J. Schulte
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - John C. Lieske
- Divison of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Dawn S. Milliner
- Divison of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Division of Pediatric Nephrology, Mayo Clinic, Rochester, MN USA
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22
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Simmons KE, Nair HR, Phadke M, Motamedinia P, Singh D, Montgomery TA, Dahl NK. Risk Factors for Common Kidney Stones Are Correlated with Kidney Function Independent of Stone Composition. Am J Nephrol 2023; 54:329-336. [PMID: 37253348 DOI: 10.1159/000531046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/01/2023] [Indexed: 06/01/2023]
Abstract
INTRODUCTION Kidney stone type varies with age, sex, season, and medical conditions. Lower estimate glomerular filtration rate (eGFR) leads to changes in urine chemistry, and risk factors for kidney stones are thought to vary by stone type. We explore the association between eGFR, urine risk factors, and common stone compositions. METHODS This was a retrospective cohort study of 811 kidney stone patients seen at Yale Medicine between 1994 and 2021 with serum chemistries and 24-h urine chemistries matched within 1 year of baseline stone analysis. Patients' eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation. Demographics and medical history were compared by χ2 tests. 24-h urine chemistries and stone analyses were analyzed by one-way ANOVA. Linear regressions were performed to control for demographics, comorbidities, and stone composition. RESULTS With lower eGFR, the proportion of calcium stones declined while uric acid (UA) stones increased. On univariable analysis, lower eGFR was associated with lower urine pH, calcium, citrate, UA, magnesium, phosphorus, and ammonium. On multivariable analysis, controlling for age, sex, ethnicity, body mass index, comorbidities, and stone type, these factors remained significant. Stone formers with lower eGFR had elevated supersaturation for UA, but reduced supersaturations for calcium-containing stones. Though urine oxalate was significant on univariable analysis, it was not on multivariable analysis. CONCLUSION Changes in urine parameters are strongly correlated with eGFR regardless of stone type. Renal function may play a key role in modulating kidney stone risk factors. Strategies to mitigate stone risk may need to vary with kidney function, especially when patient urine or stone composition data are unavailable.
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Affiliation(s)
- Kathryn E Simmons
- Yale Section of Nephrology, Yale School of Medicine, New Haven, Connecticut, USA,
| | - Hari R Nair
- Yale Section of Nephrology, Yale School of Medicine, New Haven, Connecticut, USA
- Yale Department of Urology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Manali Phadke
- Yale School of Public Health, New Haven, Connecticut, USA
| | - Piruz Motamedinia
- Yale Department of Urology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Dinesh Singh
- Yale Department of Urology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Tinika A Montgomery
- Yale Section of Nephrology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Neera K Dahl
- Yale Section of Nephrology, Yale School of Medicine, New Haven, Connecticut, USA
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23
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Mapuskar KA, Vasquez-Martinez G, Mayoral-Andrade G, Tomanek-Chalkley A, Zepeda-Orozco D, Allen BG. Mitochondrial Oxidative Metabolism: An Emerging Therapeutic Target to Improve CKD Outcomes. Biomedicines 2023; 11:1573. [PMID: 37371668 DOI: 10.3390/biomedicines11061573] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/15/2023] [Accepted: 05/19/2023] [Indexed: 06/29/2023] Open
Abstract
Chronic kidney disease (CKD) predisposes one toward end-stage renal disease (ESRD) and its associated morbidity and mortality. Significant metabolic perturbations in conjunction with alterations in redox status during CKD may induce increased production of reactive oxygen species (ROS), including superoxide (O2●-) and hydrogen peroxide (H2O2). Increased O2●- and H2O2 may contribute to the overall progression of renal injury as well as catalyze the onset of comorbidities. In this review, we discuss the role of mitochondrial oxidative metabolism in the pathology of CKD and the recent developments in treating CKD progression specifically targeted to the mitochondria. Recently published results from a Phase 2b clinical trial by our group as well as recently released data from a ROMAN: Phase 3 trial (NCT03689712) suggest avasopasem manganese (AVA) may protect kidneys from cisplatin-induced CKD. Several antioxidants are under investigation to protect normal tissues from cancer-therapy-associated injury. Although many of these antioxidants demonstrate efficacy in pre-clinical models, clinically relevant novel compounds that reduce the severity of AKI and delay the progression to CKD are needed to reduce the burden of kidney disease. In this review, we focus on the various metabolic pathways in the kidney, discuss the role of mitochondrial metabolism in kidney disease, and the general involvement of mitochondrial oxidative metabolism in CKD progression. Furthermore, we present up-to-date literature on utilizing targets of mitochondrial metabolism to delay the pathology of CKD in pre-clinical and clinical models. Finally, we discuss the current clinical trials that target the mitochondria that could potentially be instrumental in advancing the clinical exploration and prevention of CKD.
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Affiliation(s)
- Kranti A Mapuskar
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Gabriela Vasquez-Martinez
- Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Gabriel Mayoral-Andrade
- Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Ann Tomanek-Chalkley
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Diana Zepeda-Orozco
- Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University, College of Medicine, Columbus, OH 43210, USA
| | - Bryan G Allen
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
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24
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Kalim S, Zhao S, Tang M, Rhee EP, Allegretti AS, Nigwekar S, Karumanchi SA, Lash JP, Berg AH. Protein Carbamylation and the Risk of ESKD in Patients with CKD. J Am Soc Nephrol 2023; 34:876-885. [PMID: 36757153 PMCID: PMC10125635 DOI: 10.1681/asn.0000000000000078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 12/18/2022] [Indexed: 02/05/2023] Open
Abstract
SIGNIFICANCE STATEMENT Protein carbamylation, a nonenzymatic post-translational protein modification partially driven by elevated blood urea levels, associates with mortality and adverse outcomes in patients with ESKD on dialysis. However, little is known about carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. In this prospective observational cohort study of 3111 individuals with CKD stages 2-4, higher levels of carbamylated albumin (a marker of protein carbamylation burden) were associated with a greater risk of developing ESKD and other significant adverse clinical outcomes. These findings indicate that protein carbamylation is an independent risk factor for CKD progression. They suggest that further study of therapeutic interventions to prevent or reduce carbamylation is warranted. BACKGROUND Protein carbamylation, a post-translational protein modification partially driven by elevated blood urea levels, associates with adverse outcomes in ESKD. However, little is known about protein carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. METHODS To test associations between protein carbamylation and the primary outcome of progression to ESKD, we measured baseline serum carbamylated albumin (C-Alb) in 3111 patients with CKD stages 2-4 enrolled in the prospective observational Chronic Renal Insufficiency Cohort study. RESULTS The mean age of study participants was 59 years (SD 10.8); 1358 (43.7%) were female, and 1334 (42.9%) were White. The mean eGFR at the time of C-Alb assessment was 41.8 (16.4) ml/minute per 1.73 m 2 , and the median C-Alb value was 7.8 mmol/mol (interquartile range, 5.8-10.7). During an average of 7.9 (4.1) years of follow-up, 981 (31.5%) individuals developed ESKD. In multivariable adjusted Cox models, higher C-Alb (continuous or quartiles) independently associated with an increased risk of ESKD. For example, compared with quartile 1 (C-Alb ≤5.80 mmol/mol), those in quartile 4 (C-Alb >10.71 mmol/mol) had a greater risk for ESKD (adjusted hazard ratio, 2.29; 95% confidence interval, 1.75 to 2.99), and the ESKD incidence rate per 1000 patient-years increased from 15.7 to 88.5 from quartile 1 to quartile 4. The results remained significant across numerous subgroup analyses, when treating death as a competing event, and using different assessments of eGFR. CONCLUSIONS Having a higher level of protein carbamylation as measured by circulating C-Alb is an independent risk factor for ESKD in individuals with CKD stages 2-4. PODCAST This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_04_24_JSN_URE_EP22_042423.mp3.
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Affiliation(s)
- Sahir Kalim
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Sophia Zhao
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Analytica Now, Brookline, Massachusetts
| | - Mengyao Tang
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Eugene P. Rhee
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew S. Allegretti
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Sagar Nigwekar
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | | | - James P. Lash
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Anders H. Berg
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
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25
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Noonin C, Itsaranawet T, Thongboonkerd V. Calcium oxalate crystal-induced secretome derived from proximal tubular cells, not that from distal tubular cells, induces renal fibroblast activation. Eur J Med Res 2023; 28:150. [PMID: 37031165 PMCID: PMC10082508 DOI: 10.1186/s40001-023-01109-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/24/2023] [Indexed: 04/10/2023] Open
Abstract
BACKGROUND Kidney stone disease (KSD) is commonly accompanied with renal fibrosis, characterized by accumulation and reorganization of extracellular matrix (ECM). During fibrogenesis, resident renal fibroblasts are activated to become myofibroblasts that actively produce ECM. However, such fibroblast-myofibroblast differentiation in KSD remained unclear. Our present study thus examined effects of secreted products (secretome) derived from proximal (HK-2) vs. distal (MDCK) renal tubular cells exposed to calcium oxalate monohydrate (COM) crystals on activation of renal fibroblasts (BHK-21). METHODS HK-2 and MDCK cells were treated with 100 µg/ml COM crystals under serum-free condition for 16 h. In parallel, the cells maintained in serum-free medium without COM treatment served as the control. Secretome derived from culture supernatant of each sample was mixed (1:1) with fresh serum-free medium and then used for BHK-21 culture for another 24 h. RESULTS Analyses revealed that COM-treated-HK-2 secretome significantly induced proliferation, caused morphological changes, increased spindle index, and upregulated fibroblast-activation markers (F-actin, α-SMA and fibronectin) in BHK-21 cells. However, COM-treated-MDCK secretome had no significant effects on these BHK-21 parameters. Moreover, level of transforming growth factor-β1 (TGF-β1), a profibrotic factor, significantly increased in the COM-treated-HK-2 secretome but not in the COM-treated-MDCK secretome. CONCLUSIONS These data indicate, for the first time, that proximal and distal tubular epithelial cells exposed to COM crystals send different messages to resident renal fibroblasts. Only the secretome derived from proximal tubular cells, not that from the distal cells, induces renal fibroblast activation after their exposure to COM crystals. Such differential effects are partly due to TGF-β1 secretion, which is induced by COM crystals only in proximal tubular cells.
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Affiliation(s)
- Chadanat Noonin
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, 6th Floor - SiMR Building, 2 Wanglang Road, Bangkoknoi, 10700, Bangkok, Thailand
| | - Tanakorn Itsaranawet
- Biological Sciences Program, Mahidol University International College, Nakhon Pathom, 73170, Thailand
| | - Visith Thongboonkerd
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, 6th Floor - SiMR Building, 2 Wanglang Road, Bangkoknoi, 10700, Bangkok, Thailand.
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Abstract
Oxalate homeostasis is maintained through a delicate balance between endogenous sources, exogenous supply and excretion from the body. Novel studies have shed light on the essential roles of metabolic pathways, the microbiome, epithelial oxalate transporters, and adequate oxalate excretion to maintain oxalate homeostasis. In patients with primary or secondary hyperoxaluria, nephrolithiasis, acute or chronic oxalate nephropathy, or chronic kidney disease irrespective of aetiology, one or more of these elements are disrupted. The consequent impairment in oxalate homeostasis can trigger localized and systemic inflammation, progressive kidney disease and cardiovascular complications, including sudden cardiac death. Although kidney replacement therapy is the standard method for controlling elevated plasma oxalate concentrations in patients with kidney failure requiring dialysis, more research is needed to define effective elimination strategies at earlier stages of kidney disease. Beyond well-known interventions (such as dietary modifications), novel therapeutics (such as small interfering RNA gene silencers, recombinant oxalate-degrading enzymes and oxalate-degrading bacterial strains) hold promise to improve the outlook of patients with oxalate-related diseases. In addition, experimental evidence suggests that anti-inflammatory medications might represent another approach to mitigating or resolving oxalate-induced conditions.
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Affiliation(s)
- Theresa Ermer
- Department of Surgery, Division of Thoracic Surgery, Yale School of Medicine, New Haven, CT, USA
| | - Lama Nazzal
- Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA
| | - Maria Clarissa Tio
- Division of Nephrology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Sushrut Waikar
- Department of Medicine, Section of Nephrology, Boston University, Boston, MA, USA
| | - Peter S Aronson
- Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT, USA
| | - Felix Knauf
- Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT, USA.
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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27
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Aziz F, Jorgenson M, Garg N. Secondary oxalate nephropathy and kidney transplantation. Curr Opin Organ Transplant 2023; 28:15-21. [PMID: 36342385 DOI: 10.1097/mot.0000000000001035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
PURPOSE OF REVIEW Secondary hyperoxaluria is associated with poor kidney allograft outcomes after the kidney transplant. Calcium oxalate (CaOx) deposition is common in early allograft biopsies leading to acute tubular necrosis and poor kidney allograft function. Though treatment options for secondary hyperoxaluria are limited, it is crucial to identify patients at increased risk of oxalate nephropathy after the transplant. RECENT FINDINGS Recent data suggest that significant changes in renal replacement therapies and dietary modifications in high-risk patients can prevent kidney allograft damage from the calcium oxalate deposition leading to improve allograft outcomes. SUMMARY The accurate and timely diagnosis of secondary oxalate nephropathy in kidney transplant recipients is paramount to preserving graft function in the long-term. This review will discuss the incidence, risk factors, prevention, and management of oxalate nephropathy in the kidney allograft.
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Affiliation(s)
- Fahad Aziz
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health
| | - Margaret Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Neetika Garg
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health
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Shegani A, Kealey S, Luzi F, Basagni F, Machado JDM, Ekici SD, Ferocino A, Gee AD, Bongarzone S. Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds. Chem Rev 2023; 123:105-229. [PMID: 36399832 PMCID: PMC9837829 DOI: 10.1021/acs.chemrev.2c00398] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Indexed: 11/19/2022]
Abstract
The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.
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Affiliation(s)
- Antonio Shegani
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Steven Kealey
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Federico Luzi
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Filippo Basagni
- Department
of Pharmacy and Biotechnology, Alma Mater
Studiorum−University of Bologna, via Belmeloro 6, 40126 Bologna, Italy
| | - Joana do Mar Machado
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Sevban Doğan Ekici
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Alessandra Ferocino
- Institute
of Organic Synthesis and Photoreactivity, Italian National Research Council, via Piero Gobetti 101, 40129 Bologna, Italy
| | - Antony D. Gee
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Salvatore Bongarzone
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
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Mirmiran P, Bahadoran Z, Azizi F. Dietary oxalate-calcium balance and the incidence of hypertension and chronic kidney disease: a prospective study among an Asian population. Nutr Metab (Lond) 2022; 19:74. [PMID: 36329523 PMCID: PMC9632065 DOI: 10.1186/s12986-022-00709-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 10/22/2022] [Indexed: 11/05/2022] Open
Abstract
Background The potential effects of dietary oxalate (Ox) intake on cardio-renal function have remained unestablished. We evaluated the effect of usual Ox intake and its interaction with dietary calcium (Ca) on incident hypertension (HTN) and chronic kidney disease (CKD).
Methods Adult men and women, free of HTN and CKD at baseline (2006–2008), were recruited. Dietary intakes were assessed using a validated food frequency questionnaire, and the outcomes were documented up to 2014–2017. Multivariate Cox proportional hazard regression models were used to estimate the development of HTN and CKD in relation to Ox intakes. Repeated-measures generalized estimating equation (GEE) linear regression models were used to assess possible effect of Ox-intake on the estimated glomerular filtration rate (eGFR) and blood pressure levels over eight years.
Results Dietary Ox intakes were positively associated with incident CKD (HR = 2.59, 95% CI = 1.46–4.64) and HTN (HR = 1.79, 95% CI = 1.05–3.04). Compared to high-Ca consumers, subjects who had lower Ca intakes (< 990 vs. 1580 mg/d) had a higher incidence of CKD and HTN (HR = 2.43, 95% CI = 1.06–5.55, and HR = 1.72, 95% CI = 0.76–3.78). Participants with higher intakes of Ox (> 220 vs. < 150 mg/d) had lower eGFR values (75.3, 95% CI = 75.0–76.5 vs. 77.3, 95% CI = 76.6–78.1 mL/min/1.73m2, Ptime×group = 0.004) and higher SBP levels (112, 95% CI = 111–113 vs. 109, 95% CI = 108–110 mmHg, Ptime×group = 0.007) overtime.
Conclusion Higher dietary Ox intake may increase the risk of HTN and CKD. The relation between dietary Ox and risk of HTN and CKD seems to be varied by Ca intake, and subjects with lower Ca intakes may be more burdened by excessive amounts of dietary Ox.
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Hou B, Liu M, Chen Y, Ni W, Suo X, Xu Y, He Q, Meng X, Hao Z. Cpd-42 protects against calcium oxalate nephrocalcinosis-induced renal injury and inflammation by targeting RIPK3-mediated necroptosis. Front Pharmacol 2022; 13:1041117. [PMID: 36408256 PMCID: PMC9669592 DOI: 10.3389/fphar.2022.1041117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
Calcium oxalate (CaOx) crystals, as the predominant component of human kidney stones, can trigger excessive cell death and inflammation of renal tubular epithelial cells, involved in the pathogenesis of nephrocalcinosis. Necroptosis mediated by receptor-interacting protein kinase 3 (RIPK3) serves a critical role in the cytotoxicity of CaOx crystals. Here, we assessed the therapeutic potential of a novel RIPK3 inhibitor, compound 42 (Cpd-42), for CaOx nephrocalcinosis by comparison with dabrafenib, a classic RIPK3 inhibitor. Our results demonstrated that Cpd-42 pretreatment attenuated CaOx crystals-induced renal tubular epithelial cell (TEC) injury by inhibiting necroptosis and inflammation in vitro and in vivo. Furthermore, in an established mouse model of CaOx nephrocalcinosis, Cpd-42 also reduced renal injury while improving the impaired kidney function and intrarenal crystal deposition. Consistent with this finding, Cpd-42 was confirmed to exhibit superior inhibition of necroptosis and protection against renal TEC injury compared to the classic RIPK3 inhibitor dabrafenib in vitro and in vivo. Mechanistically, RIPK3 knockout (KO) tubular epithelial cells pretreated with Cpd-42 did not show further enhancement of the protective effect on crystals-induced cell injury and inflammation. We confirmed that Cpd-42 exerted protective effects by specifically targeting and inhibiting RIPK3-mediated necroptosis to block the formation of the RIPK1-RIPK3 necrosome. Taken together, targeted inhibition of RIPK3-mediated necroptosis with Cpd-42 may provide a potential therapeutic approach for CaOx nephrocalcinosis.
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Affiliation(s)
- Bingbing Hou
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Institute of Urology, Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Mingming Liu
- The Key Laboratory of Anti-inflammatory of Immune Medicines, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Ministry of Education, Anhui Medical University, Hefei, China
| | - Yang Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Institute of Urology, Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Weijian Ni
- The Key Laboratory of Anti-inflammatory of Immune Medicines, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiaoguo Suo
- The Key Laboratory of Anti-inflammatory of Immune Medicines, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Ministry of Education, Anhui Medical University, Hefei, China
| | - Yuexian Xu
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Institute of Urology, Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Qiushi He
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Institute of Urology, Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Xiaoming Meng
- The Key Laboratory of Anti-inflammatory of Immune Medicines, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Ministry of Education, Anhui Medical University, Hefei, China
- *Correspondence: Zongyao Hao, ; Xiaoming Meng,
| | - Zongyao Hao
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Institute of Urology, Anhui Medical University, Hefei, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
- *Correspondence: Zongyao Hao, ; Xiaoming Meng,
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Bao D, Wang Y, Yu X, Zhao M. Acute oxalate nephropathy: A potential cause of acute kidney injury in diabetes mellitus—A case series from a single center. Front Med (Lausanne) 2022; 9:929880. [PMID: 36133577 PMCID: PMC9484473 DOI: 10.3389/fmed.2022.929880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundAcute oxalate nephropathy (AON) is an uncommon condition that causes acute kidney injury (AKI), characterized by the massive deposition of calcium oxalate crystals in the renal parenchyma. In previous studies, urinary oxalate excretion has been found to be increased in patients with diabetes mellitus (DM). Here, we report a case series of diabetic patients with AKI with biopsy-proven AON, aiming to alert physicians to the potential of AON as a trigger of AKI in diabetic patients in clinical practice.Materials and methodsCases with pathological diagnosis of AON who presented with AKI clinically and had DM between January 2016 and December 2020 were retrospectively enrolled. Their clinical and pathological manifestations, treatment, and prognosis were collected.ResultsSix male patients with biopsy-proven AON out of a total of 5,883 native kidney biopsies were identified, aged 58.3 ± 9.1 years at the time of kidney biopsy. Only one patient who had received Roux-en-Y gastric bypass surgery took oxalate-rich food before the onset of the disease. None of them had clinical features of enteric malabsorption. Three patients were currently on renin-angiotensin system inhibitor treatment for hypertension, and 5 of them received non-steroidal anti-inflammatory drugs. Three patients presented with oliguria and 4 patients needed dialysis at the beginning with none requiring dialysis at discharge. Four patients received a course of corticosteroid treatment empirically. Among them, two patients had estimated glomerular filtration rate (eGFR) recovered to over 60 ml/min/1.73 m2, while the other two patients remained with kidney dysfunction at the last follow-up. In two patients without corticosteroid treatment, one patient fully recovered with eGFR over 90 ml/min/1.73 m2 and the other patient remained with kidney dysfunction at the last follow-up.ConclusionAON might be a rare but potentially trigger of AKI in patients with DM. A kidney biopsy could help physicians to make the correct diagnosis. The proper treatment to alleviate oxalate-induced injury needs to be further studied.
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Affiliation(s)
- Daorina Bao
- Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People’s Republic of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China
| | - Yu Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People’s Republic of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China
- *Correspondence: Yu Wang,
| | - Xiaojuan Yu
- Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People’s Republic of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China
| | - Minghui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People’s Republic of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China
- Laboratory of Electron Microscopy, Pathological Centre, Peking University First Hospital, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
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Moore JP, Mauler DJ, Narang GL, Stern KL, Humphreys MR, Keddis MT. Etiology, urine metabolic risk factors, and urine oxalate patterns in patients with significant hyperoxaluria and recurrent nephrolithiasis. Int Urol Nephrol 2022; 54:2819-2825. [PMID: 35917078 DOI: 10.1007/s11255-022-03311-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/17/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE American Urology Association guidelines recommend genetic testing for patients with recurrent stones and urine oxalate > 75 mg/day. The goal of this study was to examine the treatment of patients in this category in a large multidisciplinary adult stone clinic. METHODS Patients were evaluated from a single institution between 2006 and 2019. Those with at least one level of urinary oxalate excretion (uOx) above 75 mg/day were identified. A chart review identified enteric risk factors and genetic testing results. Patients without an identifiable enteric cause were considered idiopathic. RESULTS A total of 4229 separate 24-h urine collections in 1302 patients were reviewed. At least one measurement of uOx above 75 mg/day was found in 103 (7.9%) patients. Enteric hyperoxaluria (EH) was seen in 28 (27%) and idiopathic hyperoxaluria (IH) in 76 (74%). 20 (71%) patients in the EH group had undergone gastric bypass. The median uOx was significantly higher level in the EH group (121.0 vs. 93.0 mg/day). For the entire cohort, there was a drop in uOx (- 33.8 mg/day) with medical and dietary therapy after a follow-up of 46.6 months. The final oxalate was higher in EH (88.9 vs. 60.1 mg/day). Only one patient had referral for genetic testing and was found to have primary hyperoxaluria type 2. CONCLUSIONS The most common cause of significant hyperoxaluria in patients with recurrent nephrolithiasis remains idiopathic. Patients with IH have more significant improvement in uOx compared to EH; however, both groups had hyperoxaluria at last follow-up. Rate of genetic testing is low despite guideline recommendations.
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Affiliation(s)
- Jonathan P Moore
- Department of Urologic Surgery, UC Davis Medical Center, Sacramento, CA, USA
| | - David J Mauler
- Department of Urology, Mayo Clinic Arizona, Phoenix, AZ, USA
| | - Gopal L Narang
- Department of Urology, University of North Carolina, Chapel Hill, NC, USA
| | - Karen L Stern
- Department of Urology, Mayo Clinic Arizona, Phoenix, AZ, USA.
| | | | - Mira T Keddis
- Department of Nephrology, Mayo Clinic Arizona, Phoenix, AZ, USA
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Phelps KR, Gemoets DE, May PM. Chemical evidence for the tradeoff-in-the-nephron hypothesis to explain secondary hyperparathyroidism. PLoS One 2022; 17:e0272380. [PMID: 35913960 PMCID: PMC9342777 DOI: 10.1371/journal.pone.0272380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 07/18/2022] [Indexed: 11/28/2022] Open
Abstract
Background Secondary hyperparathyroidism (SHPT) complicates advanced chronic kidney disease (CKD) and causes skeletal and other morbidity. In animal models of CKD, SHPT was prevented and reversed by reduction of dietary phosphate in proportion to GFR, but the phenomena underlying these observations are not understood. The tradeoff-in-the-nephron hypothesis states that as GFR falls, the phosphate concentration in the distal convoluted tubule ([P]DCT]) rises, reduces the ionized calcium concentration in that segment ([Ca++]DCT), and thereby induces increased secretion of parathyroid hormone (PTH) to maintain normal calcium reabsorption. In patients with CKD, we previously documented correlations between [PTH] and phosphate excreted per volume of filtrate (EP/Ccr), a surrogate for [P]DCT. In the present investigation, we estimated [P]DCT from physiologic considerations and measurements of phosphaturia, and sought evidence for a specific chemical phenomenon by which increased [P]DCT could lower [Ca++]DCT and raise [PTH]. Methods and findings We studied 28 patients (“CKD”) with eGFR of 14–49 mL/min/1.73m2 (mean 29.9 ± 9.5) and 27 controls (“CTRL”) with eGFR > 60 mL/min/1.73m2 (mean 86.2 ± 10.2). In each subject, total [Ca]DCT and [P]DCT were deduced from relevant laboratory data. The Joint Expert Speciation System (JESS) was used to calculate [Ca++]DCT and concentrations of related chemical species under the assumption that a solid phase of amorphous calcium phosphate (Ca3(PO4)2 (am., s.)) could precipitate. Regressions of [PTH] on eGFR, [P]DCT, and [Ca++]DCT were then examined. At filtrate pH of 6.8 and 7.0, [P]DCT was found to be the sole determinant of [Ca++]DCT, and precipitation of Ca3(PO4)2 (am., s.) appeared to mediate this result. At pH 6.6, total [Ca]DCT was the principal determinant of [Ca++]DCT, [P]DCT was a minor determinant, and precipitation of Ca3(PO4)2 (am., s.) was predicted in no CKD and five CTRL. In CKD, at all three pH values, [PTH] varied directly with [P]DCT and inversely with [Ca++]DCT, and a reduced [Ca++]DCT was identified at which [PTH] rose unequivocally. Relationships of [PTH] to [Ca++]DCT and to eGFR resembled each other closely. Conclusions As [P]DCT increases, chemical speciation calculations predict reduction of [Ca++]DCT through precipitation of Ca3(PO4)2 (am., s.). [PTH] appears to rise unequivocally if [Ca++]DCT falls sufficiently. These results support the tradeoff-in-the-nephron hypothesis, and they explain why proportional phosphate restriction prevented and reversed SHPT in experimental CKD. Whether equally stringent treatment can be as efficacious in humans warrants investigation.
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Affiliation(s)
- Kenneth R. Phelps
- Research Service, Stratton Veterans’ Affairs Medical Center, Albany, NY, Uniyed States of America
- Department of Medicine, Albany Medical College, Albany, NY, Uniyed States of America
- * E-mail:
| | - Darren E. Gemoets
- Research Service, Stratton Veterans’ Affairs Medical Center, Albany, NY, Uniyed States of America
| | - Peter M. May
- Department of Chemistry, Murdoch University, Murdoch, WA, Australia
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Gao L, Shi Y, Zhang E, You J, Han J, Su X, Han S. Biocapture-Directed Chemical Labeling for Discerning Stressed States of Organelles. Anal Chem 2022; 94:9903-9910. [PMID: 35754322 DOI: 10.1021/acs.analchem.2c01892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Lysosomal rupture engaged in diverse diseases remains poorly discerned from lysosomal membrane permeabilization (LMP). We herein reported biocapture-directed chemical labeling (BCCL) for the discern of lysosomal rupture by tracking the release of optically labeled cathepsins from damaged lysosomes into the cytosol. BCCL entails covalent anchoring of an azide-tagged suicide substrate (Epo-LeuTyrAz) to the enzyme active site and bioorthogonal ligation of the introduced azide with DBCORC, a ratiometric sensor featuring an acidity-reporting red emissive X-rhodamine-lactam (ROX), blue emissive coumarin (CM) inert to pH, and DBCO reactive to azide. Aided with fluorescein isocyanate-labeled sialic acid (FITC-Sia), a probe remained in pH-elevated lysosomes but dissipated from LMP+ lysosomes, BCCL enables optical discern of four states of lysosomes: ruptured lysosomes (blue in cytosol), LMP+ lysosomes (blue in lysosomes), pH-elevated lysosomes (blue and green in lysosomes), and physiological lysosomes (blue, green and red in lysosomes). This approach could find applicability to study lysosome rupture over LMP in diseases and to evaluate lysosome rupture-inducing drugs.
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Affiliation(s)
- Lei Gao
- Department of Chemical Biology, College of Chemistry and Chemical Engineering, State Key Laboratory for Physical Chemistry of Solid Surfaces, The Key Laboratory for Chemical Biology of Fujian Province, and The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Xiamen University, Xiamen 361005, China
| | - Yilong Shi
- College of Life Science and State Key Laboratory for Cell Stress, Xiamen University, Xiamen 361005, China
| | - Enkang Zhang
- Department of Chemical Biology, College of Chemistry and Chemical Engineering, State Key Laboratory for Physical Chemistry of Solid Surfaces, The Key Laboratory for Chemical Biology of Fujian Province, and The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Xiamen University, Xiamen 361005, China
| | - Jinxuan You
- Department of Chemical Biology, College of Chemistry and Chemical Engineering, State Key Laboratory for Physical Chemistry of Solid Surfaces, The Key Laboratory for Chemical Biology of Fujian Province, and The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Xiamen University, Xiamen 361005, China
| | - Jiahuai Han
- College of Life Science and State Key Laboratory for Cell Stress, Xiamen University, Xiamen 361005, China
| | - Xinhui Su
- PET Center, Department of Nuclear Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Shoufa Han
- Department of Chemical Biology, College of Chemistry and Chemical Engineering, State Key Laboratory for Physical Chemistry of Solid Surfaces, The Key Laboratory for Chemical Biology of Fujian Province, and The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Xiamen University, Xiamen 361005, China
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Cil O, Chu QT, Lee S, Haggie PM, Verkman AS. Small molecule inhibitor of intestinal anion exchanger SLC26A3 for therapy of hyperoxaluria and nephrolithiasis. JCI Insight 2022; 7:153359. [PMID: 35608921 PMCID: PMC9310519 DOI: 10.1172/jci.insight.153359] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 05/20/2022] [Indexed: 11/17/2022] Open
Abstract
Nephrolithiasis is a common and recurrent disease affecting 9% of the US population. Hyperoxaluria is major risk factor for calcium oxalate kidney stones, which constitute two-thirds of all kidney stones. SLC26A3 (DRA, downregulated in adenoma) is an anion exchanger of chloride, bicarbonate, and oxalate thought to facilitate intestinal oxalate absorption, as evidenced by approximately 70% reduced urine oxalate excretion in knockout mice. We previously identified a small-molecule SLC26A3 inhibitor (DRAinh-A270) that selectively inhibited SLC26A3-mediated chloride/bicarbonate exchange (IC50 ~ 35 nM) and, as found here, oxalate/chloride exchange (IC50 ~ 60 nM). In colonic closed loops in mice, luminal DRAinh-A270 inhibited oxalate absorption by 70%. Following oral sodium oxalate loading in mice, DRAinh-A270 largely prevented the 2.5-fold increase in urine oxalate/creatinine ratio. In a mouse model of oxalate nephropathy produced by a high-oxalate low-calcium diet, vehicle-treated mice developed marked hyperoxaluria with elevated serum creatinine, renal calcium oxalate crystal deposition, and renal injury, which were largely prevented by DRAinh-A270 (10 mg/kg twice daily). DRAinh-A270 administered over 7 days to healthy mice did not show significant toxicity. Our findings support a major role of SLC26A3 in intestinal oxalate absorption and suggest the therapeutic utility of SLC26A3 inhibition for treatment of hyperoxaluria and prevention of calcium oxalate nephrolithiasis.
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Affiliation(s)
- Onur Cil
- Department of Medicine and Physiology, University of California, San Francisco, San Francisco, United States of America
| | - Qi Tifany Chu
- Department of Pediatrics, University of California, San Francisco, San Francisco, United States of America
| | - Sujin Lee
- Department of Medicine and Physiology, University of California, San Francisco, San Francisco, United States of America
| | - Peter M Haggie
- Department of Medicine and Physiology, University of California, San Francisco, San Francisco, United States of America
| | - Alan S Verkman
- Department of Medicine and Physiology, University of California, San Francisco, San Francisco, United States of America
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Demoulin N, Aydin S, Gillion V, Morelle J, Jadoul M. Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review. Am J Kidney Dis 2022; 79:717-727. [PMID: 34508834 DOI: 10.1053/j.ajkd.2021.07.018] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 07/27/2021] [Indexed: 01/11/2023]
Abstract
Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.
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Affiliation(s)
- Nathalie Demoulin
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
| | - Selda Aydin
- Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Valentine Gillion
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Johann Morelle
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Michel Jadoul
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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Choy SH, Nyanatay SA, Sothilingam S, Malek R, J. R. S, Toh CC, Sundram M, Md Yusoff NA, Nagappan P, Kamaruzaman S, Yeoh WS, Ong TA, Lim J. Cardiovascular risk factors, ethnicity and infection stone are independent factors associated with reduced renal function in renal stone formers. PLoS One 2022; 17:e0265510. [PMID: 35421118 PMCID: PMC9009641 DOI: 10.1371/journal.pone.0265510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 03/02/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Recent evidence suggested the link between nephrolithiasis and renal function impairment. We aimed to determine the renal function profile and potential factors associated with reduced renal function amongst renal stone formers in multi-ethnic Asians. METHODS We conducted a cross-sectional study involving patients undergoing percutaneous nephrolithotomy between May 2015 and December 2019. Reduced renal function was defined as having estimated glomerular filtration rate < 60 ml/min per 1.73 m2. Renal stone samples were collected and quantified using infrared spectroscopy. Potential factors associated with reduced renal function including age, ethnicity, educational level, history of diabetes, hypertension, gout, hydronephrosis, serum uric acid level, and type of renal stone were evaluated using univariable and multivariable analyses. RESULTS A total of 1162 patients from a multi-ethnic population (Malays 67%, Chinese 19%, Indians 13% and indigenous people 1%) with median age of 57 years (Interquartile range 48-64) were enrolled in the study. Almost a third of patients were found with reduced renal function. Multivariable analysis showed that the odds of having reduced renal function increased with age, ethnicity, lower educational level, history of diabetes, hypertension, gout, bilateral hydronephrosis, elevated serum uric acid level and infection stone. CONCLUSIONS Reduced renal function varies between ethnicities and all age groups of renal stone formers. In addition to age and ethnicity, cardiovascular risk factors including diabetes and hypertension may also need to be taken into account in managing stone patients with reduced renal function.
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Affiliation(s)
- Seow Huey Choy
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Selina Ann Nyanatay
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Rohan Malek
- Department of Urology, Hospital Selayang, Selangor, Malaysia
| | | | - Charng Chee Toh
- Department of Urology, Hospital Selayang, Selangor, Malaysia
| | - Murali Sundram
- Department of Urology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | | | | | - Shakirin Kamaruzaman
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Wei Sien Yeoh
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Teng Aik Ong
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jasmine Lim
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Krogstad V, Elgstøen KBP, Johnsen LF, Hartmann A, Mørkrid L, Åsberg A. High Plasma Oxalate Levels Early After Kidney Transplantation Are Associated With Impaired Long-Term Outcomes. Transpl Int 2022; 35:10240. [PMID: 35368646 PMCID: PMC8971183 DOI: 10.3389/ti.2022.10240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 02/04/2022] [Indexed: 11/13/2022]
Abstract
Background: Elevated levels of oxalate are common in renal failure patients and non-hyperoxaluria disease, and may cause damage after transplantation. We examined outcomes after 15 years for 167 kidney transplant recipients who had plasma oxalate measured early after transplantation. Analyses included plasma oxalate, recipient age, donor age, live donor, HLA-DR mismatch, mGFR, and smoking. Results: Median age was 52 years (range 18-81), 63% were male and 38% had live donors. Median plasma oxalate concentration 10 weeks after transplantation was 9.0 μmol/L (range 2.7-53.0), one third above the upper reference limit (11.0 μmol/L). Multivariable analysis revealed upper quartile plasma oxalate (>13.0 μmol/L, p = 0.008), recipient age (p < 0.001), deceased donor (p = 0.003), and current smoking (p < 0.001) as significant factors associated with patient survival. Upper quartile plasma oxalate (p = 0.021), recipient age (p = 0.001), deceased donor kidney (p = 0.001), HLA-DR mismatch (p = 0.015), and current smoking (p = 0.014) were also associated with graft loss. Factors associated with death censored graft losses were donor age (p = 0.012), deceased donor (p = 0.032), and HLA-DR mis-matched kidneys (p = 0.005) but plasma oxalate was not (p = 0.188). Conclusions: Plasma oxalate in the upper quartile early after transplantation was significantly associated with impaired long-term patient survival and graft losses, but not when censored for death.
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Affiliation(s)
- Veronica Krogstad
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | | | - Linda Flaa Johnsen
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Anders Hartmann
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Lars Mørkrid
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Blindern, Oslo, Norway.,The Norwegian Renal Registry, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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Estève E, Buob D, Jamme F, Jouanneau C, Kascakova S, Haymann JP, Letavernier E, Galmiche L, Ronco P, Daudon M, Bazin D, Réfrégiers M. Detection and localization of calcium oxalate in kidney using synchrotron deep ultraviolet fluorescence microscopy. JOURNAL OF SYNCHROTRON RADIATION 2022; 29:214-223. [PMID: 34985438 PMCID: PMC8733991 DOI: 10.1107/s1600577521011371] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 10/28/2021] [Indexed: 05/14/2023]
Abstract
Renal oxalosis is a rare cause of renal failure whose diagnosis can be challenging. Synchrotron deep ultraviolet (UV) fluorescence was assayed to improve oxalosis detection on kidney biopsies spatial resolution and sensitivity compared with the Fourier transform infrared microspectroscopy gold standard. The fluorescence spectrum of synthetic mono-, di- and tri-hydrated calcium oxalate was investigated using a microspectrometer coupled to the synchrotron UV beamline DISCO, Synchrotron SOLEIL, France. The obtained spectra were used to detect oxalocalcic crystals in a case control study of 42 human kidney biopsies including 19 renal oxalosis due to primary (PHO, n = 11) and secondary hyperoxaluria (SHO, n = 8), seven samples from PHO patients who received combined kidney and liver transplants, and 16 controls. For all oxalocalcic hydrates samples, a fluorescence signal is detected at 420 nm. These spectra were used to identify standard oxalocalcic crystals in patients with PHO or SHO. They also revealed micrometric crystallites as well as non-aggregated oxalate accumulation in tubular cells. A nine-points histological score was established for the diagnosis of renal oxalosis with 100% specificity (76-100) and a 73% sensitivity (43-90). Oxalate tubular accumulation and higher histological score were correlated to lower estimated glomerular filtration rate and higher urinary oxalate over creatinine ratio.
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Affiliation(s)
- Emmanuel Estève
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, F-75020 Paris, France
| | - David Buob
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, F-75020 Paris, France
| | - Frédéric Jamme
- Synchrotron SOLEIL, DISCO Beamline, L'Orme des Merisiers, Saint-Aubin, 91192 Gif sur Yvette, France
| | - Chantal Jouanneau
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, F-75020 Paris, France
| | - Slavka Kascakova
- Synchrotron SOLEIL, DISCO Beamline, L'Orme des Merisiers, Saint-Aubin, 91192 Gif sur Yvette, France
| | - Jean Philippe Haymann
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, F-75020 Paris, France
| | - Emmanuel Letavernier
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, F-75020 Paris, France
| | - Louise Galmiche
- Pathology Department, Necker-Enfants Malades Hospital, Public Assistance-Hospitals of Paris, Université Paris, 75015 Paris, France
| | - Pierre Ronco
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, F-75020 Paris, France
| | - Michel Daudon
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, F-75020 Paris, France
| | - Dominique Bazin
- Laboratoire de Physique des Solides, CNRS UMR8502, Université Paris Saclay, Orsay, France
| | - Matthieu Réfrégiers
- Synchrotron SOLEIL, DISCO Beamline, L'Orme des Merisiers, Saint-Aubin, 91192 Gif sur Yvette, France
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Wu MT, Wu CF, Liu CC, Tsai YC, Chen CC, Wang YH, Hsieh TJ. Melamine and oxalate coexposure induces early kidney tubular injury through mitochondrial aberrations and oxidative stress. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 225:112756. [PMID: 34507040 DOI: 10.1016/j.ecoenv.2021.112756] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 08/09/2021] [Accepted: 09/03/2021] [Indexed: 06/13/2023]
Abstract
Exposure to melamine, which is ubiquitous in daily life, is linked to adverse kidney outcomes. The melamine tolerable daily intake in humans is based on the no-observed-effect-level (NOEL) established in a single-toxicant murine model. However, humans are often simultaneously exposed to multiple environmental nephrotoxicants. The NOEL of melamine during coexposure with other toxicants needs to be evaluated. Oxalate is a potentially nephrotoxic terminal metabolite, and hyperoxaluria is reportedly associated with chronic kidney disease. We explored whether these two potential nephrotoxicants can interact and enhance kidney injury. We established a Sprague-Dawley rat model of coexposure to the melamine NOEL (63 mg/kg/day) and 2% hydroxy-L-proline (HLP, an oxalate precursor) in drinking water to simulate human environmental melamine exposure. Melamine/oxalate coexposure increased proximal tubular cell mitochondrial reactive oxygen species levels, lipid peroxidation and oxidative DNA damage. The degrees of mitochondrial damage, tubular cell apoptosis, tubular atrophy, and interstitial fibrosis were elevated in coexposed rat kidneys. The evidence indicated that exposure to the melamine NOEL can cause renal tubular injury via oxidative stress and that this effect may be enhanced via interaction of melamine with other environmental factors, such as oxalate. Thus, melamine risk assessment and toxicity prevention should be conducted carefully in different susceptible populations.
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Affiliation(s)
- Ming-Tsang Wu
- Ph.D. Program of Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Chia-Fang Wu
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Chia-Chu Liu
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Pingtung Hospital, Ministry of Health and Welfare, Pingtung City, Taiwan.
| | - Yi-Chun Tsai
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Divisions of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Chu-Chih Chen
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
| | - Yin-Han Wang
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
| | - Tusty-Jiuan Hsieh
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
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Reddy S, Bolen E, Abdelmalek M, Lieske JC, Ryan M, Keddis MT. Clinical Outcomes and Histological Patterns in Oxalate Nephropathy due to Enteric and Nonenteric Risk Factors. Am J Nephrol 2021; 52:961-968. [PMID: 34844241 DOI: 10.1159/000520286] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/05/2021] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Current knowledge of risk factors and renal histologic patterns of oxalate nephropathy (ON) not due to primary hyperoxaluria (PH) has been limited to small case series and case reports. Thus, we analyzed and compared clinical risk factors, histologic characteristics, and renal outcomes of patients with biopsy-confirmed ON among a cohort of patients with enteric and nonenteric risk factors. METHODS A clinical data repository of native kidney pathology reports from 2009 to 2020 at all Mayo Clinic sites was used to identify 421 ON cases. RESULTS After excluding cases in transplanted kidneys or due to PH, 64 cases remained. Enteric risk factors were present in 30 and nonenteric in 34. Roux-en-Y gastric bypass (17) and pancreatic insufficiency (6) were most common in the enteric hyperoxaluria group. In the nonenteric group, vitamin C (7) and dietary oxalate (7) were common, while no apparent risk was noted in 16. Acute kidney injury (AKI) stage III at the time of diagnosis was present in 60%, and 40.6% required dialysis. Patients in the nonenteric group had more interstitial inflammation (p = 0.01), and a greater number of tubules contained intratubular calcium oxalate (CaOx) crystals (p = 0.001) than the nonenteric group. Patients in the enteric group were more likely to have baseline chronic kidney disease (CKD) (p = 0.02) and moderate-to-severe tubulointerstitial fibrosis and atrophy (IFTA) (OR 3.49, p = 0.02). After a median follow-up of 10 months, 39% were dialysis dependent, 11% received a kidney transplant, and 32% died. On univariate analysis, >10 tubules with CaOx crystals, baseline CKD, and AKI requiring dialysis correlated with the risk of dialysis, transplant, or death. On multivariate analysis, only AKI requiring dialysis correlated with adverse renal outcomes. CONCLUSION This is the largest cohort study of ON not due to PH. Histologic features differ in patients with enteric versus nonenteric risks. Patients in the enteric group are more likely to have baseline CKD and significant IFTA, while patients in the nonenteric group were more likely to have a greater number of tubules with CaOx crystals and corresponding interstitial inflammation. AKI requiring dialysis at the time of diagnosis was the single most significant predictor of adverse renal outcome.
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Affiliation(s)
- Swetha Reddy
- Division of Nephrology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA,
| | - Erin Bolen
- Mayo Clinic Alix School of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - Mina Abdelmalek
- Division of Nephrology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - John C Lieske
- Division of Nephrology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Maggie Ryan
- Department of Pathology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Mira T Keddis
- Division of Nephrology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA
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Mehra Y, Viswanathan P. High-quality whole-genome sequence analysis of Lactobacillus paragasseri UBLG-36 reveals oxalate-degrading potential of the strain. PLoS One 2021. [DOI: https://doi.org/10.1371/journal.pone.0260116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Lactobacillus paragasseri was identified as a novel sister taxon of L. gasseri in 2018. Since the reclassification of L. paragasseri, there has been hardly any report describing the probiotic properties of this species. In this study, an L. paragasseri strain UBLG-36 was sequenced and analyzed to determine the molecular basis that may confer the bacteria with probiotic potential. UBLG-36 was previously documented as an L. gasseri strain. Average nucleotide identity and phylogenomic analysis allowed accurate taxonomic identification of UBLG-36 as an L. paragasseri strain. Analysis of the draft genome (~1.94 Mb) showed that UBLG-36 contains 5 contigs with an average G+C content of 34.85%. Genes essential for the biosynthesis of bacteriocins, adhesion to host epithelium, stress resistance, host immunomodulation, defense, and carbohydrate metabolism were identified in the genome. Interestingly, L. paragasseri UBLG-36 also harbored genes that code for enzymes involved in oxalate catabolism, such as formyl coenzyme A transferase (frc) and oxalyl coenzyme A decarboxylase (oxc). In vitro oxalate degradation assay showed that UBLG-36 is highly effective in degrading oxalate (averaging more than 45% degradation), a feature that has not been reported before. As a recently identified bacterium, there are limited genomic reports on L. paragasseri, and our draft genome sequence analysis is the first to describe and emphasize the probiotic potential and oxalate degrading ability of this species. With results supporting the probiotic functionalities and oxalate catabolism of UBLG-36, we propose that this strain is likely to have immense biotechnological applications upon appropriate characterization.
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Lee O, Park K, Sun K, O'Shea JP, Gordon S. Cashew-Induced Oxalate Nephropathy: A Rare Cause of Acute Renal Failure. Mil Med 2021; 188:usab453. [PMID: 34741455 DOI: 10.1093/milmed/usab453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/19/2021] [Accepted: 10/21/2021] [Indexed: 11/13/2022] Open
Abstract
We present a rare case of cashew-induced oxalate nephropathy in a 69 year old veteran male with history of type 2 diabetes mellitus, nephrolithiasis, and undiagnosed chronic kidney disease (CKD). Oxalate nephropathy is a rare cause of acute renal failure with poor prognosis. The various causes of oxalate nephropathy are categorized as primary or secondary hyperoxaluria. Primary hyperoxaluria is caused by genetic mutation in genes involved in the metabolism of glyoxylate. Secondary hyperoxaluria is caused by mal-absorptive state, excessive intake of oxalate-rich diet, inflammatory diseases, and medications such as orlistat and antibiotics. Diet-induced oxalate nephropathy is often identified after unexplained acute kidney injury in patients with underlying CKD. Definitive diagnosis requires renal biopsy as laboratory tests are non-specific. A simple dietary history in CKD patients during routine primary care visit may lead to early diagnosis and lead to prevention of acute renal failure and progression of renal disease.
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Affiliation(s)
- Oliver Lee
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA
| | - Katherine Park
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA
| | - Kelly Sun
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA
| | - John-Paul O'Shea
- Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA
| | - Sarah Gordon
- Department of Nephrology, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
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Wu CF, Liu CC, Tsai YC, Chen CC, Wu MT, Hsieh TJ. Diminishment of Nrf2 Antioxidative Defense Aggravates Nephrotoxicity of Melamine and Oxalate Coexposure. Antioxidants (Basel) 2021; 10:antiox10091464. [PMID: 34573096 PMCID: PMC8471505 DOI: 10.3390/antiox10091464] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 01/31/2023] Open
Abstract
Chronic kidney disease (CKD) usually causes devastating healthy impacts on patients. However, the causes affecting the decline of kidney function are not fully revealed, especially the involvement of environmental pollutants. We have revealed that exposure to melamine, a ubiquitous chemical in daily life, is linked to adverse kidney outcomes. Hyperoxaluria that results from exposure to excessive oxalate, a potentially nephrotoxic terminal metabolite, is reportedly associated with CKD. Thus, we explored whether interaction of these two potential nephrotoxicants could enhance kidney injury. We established a renal proximal tubular HK-2 cell model and a Sprague-Dawley rat model of coexposure to melamine with sodium oxalate or hydroxy-L-proline to investigate the interacting adverse effects on kidneys. Melamine and oxalate coexposure enhanced the levels of reactive oxygen species, lipid peroxidation and oxidative DNA damage in the HK-2 cells and kidney tissues. The degrees of tubular cell apoptosis, tubular atrophy, and interstitial fibrosis were elevated under the coexposed condition, which may result from the diminishment of Nrf2 antioxidative capacity. To conclude, melamine and oxalate coexposure aggravates renal tubular injury via impairment of antioxidants. Accumulative harmful effects of exposure to multiple environmental nephrotoxicants should be carefully investigated in the etiology of CKD progression.
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Affiliation(s)
- Chia-Fang Wu
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.W.); (C.-C.L.); (Y.-C.T.); (C.-C.C.); (M.-T.W.)
- International Master Program of Translational Medicine, National United University, Miaoli 360301, Taiwan
| | - Chia-Chu Liu
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.W.); (C.-C.L.); (Y.-C.T.); (C.-C.C.); (M.-T.W.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Department of Urology, Pingtung Hospital, Ministry of Health and Welfare, Pingtung City 900027, Taiwan
| | - Yi-Chun Tsai
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.W.); (C.-C.L.); (Y.-C.T.); (C.-C.C.); (M.-T.W.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Divisions of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Chu-Chih Chen
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.W.); (C.-C.L.); (Y.-C.T.); (C.-C.C.); (M.-T.W.)
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli 350401, Taiwan
| | - Ming-Tsang Wu
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.W.); (C.-C.L.); (Y.-C.T.); (C.-C.C.); (M.-T.W.)
- Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Tusty-Jiuan Hsieh
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.W.); (C.-C.L.); (Y.-C.T.); (C.-C.C.); (M.-T.W.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan
- Correspondence: ; Tel.: +886-7-3121101 (ext. 2759#423)
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Pfau A, Ermer T, Coca SG, Tio MC, Genser B, Reichel M, Finkelstein FO, März W, Wanner C, Waikar SS, Eckardt KU, Aronson PS, Drechsler C, Knauf F. High Oxalate Concentrations Correlate with Increased Risk for Sudden Cardiac Death in Dialysis Patients. J Am Soc Nephrol 2021; 32:2375-2385. [PMID: 34281958 PMCID: PMC8729829 DOI: 10.1681/asn.2020121793] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 05/10/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The clinical significance of accumulating toxic terminal metabolites such as oxalate in patients with kidney failure is not well understood. METHODS To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of patients with kidney failure requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis (4D) Study; this study included 1255 European patients on hemodialysis with diabetes followed-up for a median of 4 years. The results obtained via Cox proportional hazards models were confirmed by competing risk regression and restricted cubic spline modeling in the 4D Study cohort and validated in a separate cohort of 104 US patients on dialysis after a median follow-up of 2.5 years. RESULTS A total of 1108 patients had baseline oxalate measurements, with a median oxalate concentration of 42.4 µM. During follow-up, 548 patients died, including 139 (25.4%) from sudden cardiac death. A total of 413 patients reached the primary composite cardiovascular end point (cardiac death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Patients in the highest oxalate quartile (≥59.7 µM) had a 40% increased risk for cardiovascular events (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [95% CI], 1.08 to 1.81) and a 62% increased risk of sudden cardiac death (aHR, 1.62; 95% CI, 1.03 to 2.56), compared with those in the lowest quartile (≤29.6 µM). The associations remained when accounting for competing risks and with oxalate as a continuous variable. CONCLUSIONS Elevated serum oxalate is a novel risk factor for cardiovascular events and sudden cardiac death in patients on dialysis. Further studies are warranted to test whether oxalate-lowering strategies improve cardiovascular mortality in patients on dialysis.
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Affiliation(s)
- Anja Pfau
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Theresa Ermer
- Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany,Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut,London School of Hygiene & Tropical Medicine, University of London, London, United Kingdom
| | - Steven G. Coca
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Maria Clarissa Tio
- Division of Renal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Bernd Genser
- BGStats Consulting, Vienna, Austria,Mannheim Institute of Public Health, Social and Preventive Medicine, University of Heidelberg, Heidelberg, Germany
| | - Martin Reichel
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Fredric O. Finkelstein
- Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
| | - Winfried März
- Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University of Heidelberg, Mannheim, Germany,Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria,Synlab Academy, Mannheim, Germany
| | - Christoph Wanner
- Division of Nephrology, Department of Internal Medicine 1 and Comprehensive Heart Failure Centre, University Hospital of Würzburg, Würzburg, Germany
| | - Sushrut S. Waikar
- Section of Nephrology, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Peter S. Aronson
- Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
| | - Christiane Drechsler
- Division of Nephrology, Department of Internal Medicine 1 and Comprehensive Heart Failure Centre, University Hospital of Würzburg, Würzburg, Germany,KfH Kidney Center for Dialysis and Kidney Transplantation, Würzburg, Germany
| | - Felix Knauf
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany,Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
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47
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Gianmoena K, Gasparoni N, Jashari A, Gabrys P, Grgas K, Ghallab A, Nordström K, Gasparoni G, Reinders J, Edlund K, Godoy P, Schriewer A, Hayen H, Hudert CA, Damm G, Seehofer D, Weiss TS, Boor P, Anders HJ, Motrapu M, Jansen P, Schiergens TS, Falk-Paulsen M, Rosenstiel P, Lisowski C, Salido E, Marchan R, Walter J, Hengstler JG, Cadenas C. Epigenomic and transcriptional profiling identifies impaired glyoxylate detoxification in NAFLD as a risk factor for hyperoxaluria. Cell Rep 2021; 36:109526. [PMID: 34433051 DOI: 10.1016/j.celrep.2021.109526] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 05/12/2021] [Accepted: 07/22/2021] [Indexed: 02/07/2023] Open
Abstract
Epigenetic modifications (e.g. DNA methylation) in NAFLD and their contribution to disease progression and extrahepatic complications are poorly explored. Here, we use an integrated epigenome and transcriptome analysis of mouse NAFLD hepatocytes and identify alterations in glyoxylate metabolism, a pathway relevant in kidney damage via oxalate release-a harmful waste product and kidney stone-promoting factor. Downregulation and hypermethylation of alanine-glyoxylate aminotransferase (Agxt), which detoxifies glyoxylate, preventing excessive oxalate accumulation, is accompanied by increased oxalate formation after metabolism of the precursor hydroxyproline. Viral-mediated Agxt transfer or inhibiting hydroxyproline catabolism rescues excessive oxalate release. In human steatotic hepatocytes, AGXT is also downregulated and hypermethylated, and in NAFLD adolescents, steatosis severity correlates with urinary oxalate excretion. Thus, this work identifies a reduced capacity of the steatotic liver to detoxify glyoxylate, triggering elevated oxalate, and provides a mechanistic explanation for the increased risk of kidney stones and chronic kidney disease in NAFLD patients.
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Affiliation(s)
- Kathrin Gianmoena
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Nina Gasparoni
- Department of Genetics, Saarland University, 66123 Saarbrücken, Germany
| | - Adelina Jashari
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Philipp Gabrys
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Katharina Grgas
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Ahmed Ghallab
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany; Department of Forensic and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt
| | - Karl Nordström
- Department of Genetics, Saarland University, 66123 Saarbrücken, Germany
| | - Gilles Gasparoni
- Department of Genetics, Saarland University, 66123 Saarbrücken, Germany
| | - Jörg Reinders
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Karolina Edlund
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Patricio Godoy
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Alexander Schriewer
- Department of Analytical Chemistry, Institute of Inorganic and Analytical Chemistry, University of Münster, 48149 Münster, Germany
| | - Heiko Hayen
- Department of Analytical Chemistry, Institute of Inorganic and Analytical Chemistry, University of Münster, 48149 Münster, Germany
| | - Christian A Hudert
- Department of Pediatric Gastroenterology, Hepatology and Metabolic Diseases, Charité-University Medicine Berlin, 13353 Berlin, Germany
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany; Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany; Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Thomas S Weiss
- University Children Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
| | - Peter Boor
- Institute of Pathology and Department of Nephrology, University Clinic of RWTH Aachen, 52074 Aachen, Germany
| | - Hans-Joachim Anders
- Department of Medicine IV, Renal Division, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
| | - Manga Motrapu
- Department of Medicine IV, Renal Division, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
| | - Peter Jansen
- Maastricht Centre for Systems Biology, University of Maastricht, 6229 Maastricht, the Netherlands
| | - Tobias S Schiergens
- Biobank of the Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Maren Falk-Paulsen
- Institute of Clinical Molecular Biology (IKMB), Kiel University and University Hospital Schleswig Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology (IKMB), Kiel University and University Hospital Schleswig Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Clivia Lisowski
- Institute of Experimental Immunology, University Hospital Bonn, Rheinische-Friedrich-Wilhelms University Bonn, 53127 Bonn, Germany
| | - Eduardo Salido
- Hospital Universitario de Canarias, Universidad La Laguna, CIBERER, 38320 Tenerife, Spain
| | - Rosemarie Marchan
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Jörn Walter
- Department of Genetics, Saarland University, 66123 Saarbrücken, Germany
| | - Jan G Hengstler
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
| | - Cristina Cadenas
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany.
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48
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Crivelli JJ, Wood KD, Assimos DG. Is It Time to Retire the Low-Oxalate Diet? No! J Endourol 2021; 35:1435-1437. [PMID: 34409855 DOI: 10.1089/end.2021.0576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Joseph J Crivelli
- Department of Urology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | - Kyle D Wood
- Department of Urology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | - Dean G Assimos
- Department of Urology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
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49
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Uebanso T, Suyama M, Shimohata T, Mawatari K, Takahashi A. Effect of Vitamin B2-Deficient Diet on Hydroxyproline- or Obesity-Induced Hyperoxaluria in Mice. Mol Nutr Food Res 2021; 65:e2100226. [PMID: 34110671 DOI: 10.1002/mnfr.202100226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/16/2021] [Indexed: 12/17/2022]
Abstract
SCOPE Hyperoxaluria is a major cause of kidney stone disease. Around half of the oxalate in mammals is supplied from the diet and the other half is endogenously synthesized from glyoxylate. Reduction of hepatic glycolate oxidase (GO) activity is one approach to reduce endogenous production of oxalate. However, there are currently few effective dietary approaches to reduce hepatic GO activity. METHODS AND RESULTS In the present study, it is investigated whether restriction of dietary vitamin B2 (VB2) can reduce hepatic GO activity and oxalate excretion in mice with hyperoxaluria induce by hydroxyproline (Hyp) or obesity. It is found that VB2 restriction significantly reduces hepatic GO activity in both the Hyp- and obesity-induced model of hyperoxaluria in mice. However, VB2 restriction reduces urinary oxalate excretion only in the Hyp-treated mice and not the obese mice. This difference could be due to the contribution of endogenous oxalate production that manifests as increased hepatic GO activity in Hyp-treated mice but not obese mice. CONCLUSION Together these results suggest that VB2 restriction could be a new dietary approach to improve hyperoxaluria when endogenous production of oxalate is increased.
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Affiliation(s)
- Takashi Uebanso
- Department of Preventive Environment and Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Mai Suyama
- Department of Preventive Environment and Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Takaaki Shimohata
- Department of Preventive Environment and Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Kazuaki Mawatari
- Department of Preventive Environment and Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Akira Takahashi
- Department of Preventive Environment and Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
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50
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Prochaska ML, Moe OW, Asplin JR, Coe FL, Worcester EM. Evidence for abnormal linkage between urine oxalate and citrate excretion in human kidney stone formers. Physiol Rep 2021; 9:e14943. [PMID: 34231328 PMCID: PMC9814525 DOI: 10.14814/phy2.14943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Animal models have demonstrated an interactive relationship between the epithelial anion exchanger SLC26A6 and transporter NaDC-1 that regulates citrate and oxalate homeostasis. This relationship is a potential mechanism to protect against kidney stones as higher urine oxalate is accompanied by higher urine citrate but it has not been explored in humans. METHODS We examined 24-h urine data on 13,155 kidney stone forming patients (SF) from separate datasets at the University of Chicago and Litholink, a national laboratory, and 143 non-kidney stone forming participants (NSF) to examine this relationship in humans. We used multivariate linear regression models to examine the association between oxalate and citrate in all study participants and separately in SF and NSF. RESULTS Higher urinary oxalate was associated with higher urinary citrate in both SF and NSF. In NSF, the multivariate adjusted urine citrate excretion was 3.0 (1.5-4.6) (mmol)/creatinine (mmol) per oxalate (mmol)/creatinine (mmol). In SF, the multivariate adjusted urine citrate excretion was 0.3 (0.2-0.4) (mmol)/creatinine (mmol) per oxalate (mmol)/creatinine (mmol). CONCLUSIONS Higher urinary oxalate excretion was associated with higher urinary citrate excretion and this effect was larger in non-kidney stone forming participants compared with those who form kidney stones.
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Affiliation(s)
| | - Orson W. Moe
- Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - John R. Asplin
- Litholink CorporationLaboratory Corporation of America® HoldingsItascaILUSA
| | - Fredric L. Coe
- Department of MedicineUniversity of Chicago MedicineChicagoILUSA
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