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Attieh RM, Bharati J, Sharma P, Nair G, Ayehu G, Jhaveri KD. Kidney transplant in patients with C3 glomerulopathy. Clin Kidney J 2025; 18:sfaf134. [PMID: 40385590 PMCID: PMC12082085 DOI: 10.1093/ckj/sfaf134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Indexed: 05/20/2025] Open
Abstract
Complement protein 3 (C3) glomerulopathy (C3G) is a rare and progressive kidney disease primarily affecting young individuals and frequently advancing to end-stage kidney disease (ESKD). For ESKD, kidney transplantation remains the optimal treatment option; however, C3G has a high recurrence rate post-transplantation, affecting over two-thirds of transplanted patients. Despite advances in our understanding of C3G, significant gaps persist regarding the optimal timing for transplantation and the best strategies for peri-transplant management. Currently, no clear evidence links functional complement levels to the risk of post-transplant recurrence. Genetic counseling is also complex, due to variable gene penetrance and weak genotype-phenotype correlations, which limit predictive accuracy. Transplant-related factors are believed to significantly influence C3G recurrence, yet there are no established methods for preventing recurrence after transplantation. Eculizumab has shown inconsistent efficacy in managing recurrent C3G. However, new proximal complement inhibitors, such as factor B and C3 inhibitors, are under investigation in clinical trials and show promise. Some of these trials include kidney transplant patients with C3G, and their outcomes could potentially shape future treatment protocols.
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Affiliation(s)
| | - Joyita Bharati
- Section of Nephrology, Boston Medical Center and Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Purva Sharma
- Division of Kidney Disease and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Gayatri Nair
- Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Gashu Ayehu
- Division of Kidney Disease and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Kenar D Jhaveri
- Division of Kidney Disease and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
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2
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Rios IP, Elsaidi A, Akin DE, Nowland AM, Budhiraja P, Hommos MS, Heilman RL, Abu Jawdeh BG. A Single-Center Report of Hypertension in Native American Kidney Transplant Recipients. J Immigr Minor Health 2025:10.1007/s10903-025-01691-0. [PMID: 40304949 DOI: 10.1007/s10903-025-01691-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2025] [Indexed: 05/02/2025]
Abstract
Based on the current American Heart Association/American College of Cardiology definition [systolic blood pressure (SBP) ≥ 130 and/or diastolic BP(DBP) ≥ 80], hypertension affects 45% of the adult U.S. population. Post-kidney transplant (KT) hypertension has been associated with immunosuppression and worse graft outcomes. Hypertension data on Native American (NAm) KT recipients (KTR) is scarce. In our center, we serve a significant NAm population, and measure ambulatory blood pressure (AMBP) routinely in KTR at 4- and 12-months post-transplant. In a noninterventional, observational study we queried our transplant database for all NAm KTR who were transplanted at our center between years 2003 and 2023. Patients who had 4- and/or 12-months AMBP were included in our study. 262 NAm KTR met inclusion criteria. Average (sd) BP was 133.0 (15.0)/76.2 (9.7) and 134.1 (15.6)/76.5 (9.9) at 4- and 12-months respectively. Male gender (p = 0.03) and older donor age (p = 0.02) were associated with BP ≥ 130/80 at 4-months. Male gender (p = 0.05) and pre-transplant diabetes (p = 0.01) were associated with BP ≥ 130/80 at 12-months. About two-thirds of NAm KTR had uncontrolled hypertension at 4- and 12-months. The burden of hypertension, as measured by the gold standard AMBP monitoring is significant in NAm KTR, and therefore, attention to hypertension management is prudent in this minority patient population.
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Affiliation(s)
- Ian P Rios
- Division of Nephrology and Hypertension, Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Ahmed Elsaidi
- Department of Medicine, Northwest Medical Center, Tuscon, AZ, USA
| | - Danielle E Akin
- Division of Nephrology and Hypertension, Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Ashlyn M Nowland
- Division of Nephrology and Hypertension, Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Pooja Budhiraja
- Division of Nephrology and Hypertension, Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Musab S Hommos
- Division of Nephrology and Hypertension, Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Raymond L Heilman
- Division of Nephrology and Hypertension, Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Bassam G Abu Jawdeh
- Division of Nephrology and Hypertension, Mayo Clinic Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA.
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Pittappilly M, Sharshir M, Paramesh A. Chronic Allograft Nephropathy-A Narrative Review of Its Pathogenesis, Diagnosis, and Evolving Management Strategies. Biomedicines 2025; 13:929. [PMID: 40299546 PMCID: PMC12024747 DOI: 10.3390/biomedicines13040929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 03/29/2025] [Accepted: 04/03/2025] [Indexed: 04/30/2025] Open
Abstract
Chronic allograft nephropathy is the leading cause of kidney allograft failure. Clinically, it is characterized by a progressive decline in kidney function, often in combination with proteinuria and hypertension. Histologically, interstitial fibrosis and tubular atrophy, along with features of glomerulosclerosis with occasional double contour appearance, arteriolar hyalinosis, and arteriosclerosis, are characteristic findings. The pathophysiology, though complex and incompletely understood, is thought to involve a sequence of immunologic and non-immunologic injuries eventually leading to tissue remodeling and scarring within the graft. The optimal strategy to prevent chronic allograft nephropathy is to minimize both immune- and non-immune-mediated graft injury.
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Affiliation(s)
- Matthew Pittappilly
- Department of Nephrology, Tulane Transplant Institute, East Jefferson Hospital, Tulane University School of Medicine, New Orleans, LA 70112, USA; (M.P.); (M.S.)
| | - Mohammed Sharshir
- Department of Nephrology, Tulane Transplant Institute, East Jefferson Hospital, Tulane University School of Medicine, New Orleans, LA 70112, USA; (M.P.); (M.S.)
| | - Anil Paramesh
- Department of Surgery, Tulane Transplant Institute, East Jefferson Hospital, Tulane University School of Medicine, New Orleans, LA 70112, USA
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Vinson AJ, Matas A. Late Allograft Loss and Contemporary Cardiorenal Metabolic Therapies. J Am Soc Nephrol 2025:00001751-990000000-00615. [PMID: 40193211 DOI: 10.1681/asn.0000000726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025] Open
Abstract
Late kidney allograft loss occurs through one of two mechanisms: ( 1 ) deterioration of kidney function leading to retransplantation or dialysis (death-censored graft loss) and ( 2 ) premature death with a normally functioning transplant (death with graft function)-each accounting for approximately 50% of late kidney graft losses. Late death-censored graft loss typically results from a combination of immune and nonimmune events leading to common nonspecific end points ( e.g ., tubular atrophy, interstitial fibrosis, and glomerulosclerosis). Conversely, leading causes of death with graft function typically include cardiovascular events, malignancy, and infection. With an improved understanding of the multiple mechanism by which late graft dysfunction develops, there is an opportunity to identify patients at greatest risk and institute novel strategies to quell the process. Newer cardiometabolic agents with proven benefit in the general population have not been well-studied in kidney transplant recipients. However, in addition to their potential benefits in reducing cardiovascular, infectious, and malignancy end points (thus minimizing death with graft function risk), many novel agents may have additional anti-inflammatory and/or antifibrotic benefit (minimizing death-censored graft loss risk) in the kidney transplant population. In this review, we summarize existing literature regarding major causes of death-censored graft loss and death with graft function and discuss the potential roles of new cardiorenal metabolic agents including sodium-glucose cotransport 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, glucagon-like peptide 1 receptor agonists, and dual endothelin and angiotensin receptor antagonists in the kidney transplant population, including potential mechanisms to improve death with graft function and death-censored graft loss outcomes.
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Affiliation(s)
- Amanda J Vinson
- Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
- Kidney Research Institute of Nova Scotia
| | - Arthur Matas
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota
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Farkona S, Kotlyar M, Burns K, Knoll G, Brinc D, Jurisica I, Konvalinka A. Urine Measurements of the Renin-Angiotensin System-Regulated Proteins Predict Death and Graft Loss in Kidney Transplant Recipients Enrolled in a Ramipril versus Placebo Randomized Controlled Trial. J Proteome Res 2025; 24:2040-2052. [PMID: 40111290 DOI: 10.1021/acs.jproteome.4c01100] [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] [Indexed: 03/22/2025]
Abstract
The renin-angiotensin system (RAS) is involved in kidney fibrosis. We previously identified six RAS-regulated proteins (RHOB, BST1, LYPA1, GLNA, TSP1, and LAMB2) that were increased in the urine of patients with kidney allograft fibrosis, compared to patients without fibrosis. We hypothesized that these urinary RAS-regulated proteins predicted primary outcomes in kidney transplant recipients enrolled in the largest RAS inhibitor randomized controlled trial. Urine excretion of 10 peptides corresponding to the six RAS-regulated proteins was quantified using parallel reaction monitoring mass spectrometry assays (normalized by urine creatinine) in a subset of patients in the trial. Machine learning models predicting outcomes based on urine peptide excretion rates were developed and evaluated. Urine samples (n = 111) from 56 patients were collected at 0, 6, 12, and 24 months. Twenty-four primary outcomes (doubling of serum creatinine, graft loss, or death) occurred in 17 patients. Logistic regression utilizing eight peptides of TSP1, BST1, LAMB2, LYPA1, and RHOB, from the last urine sample prior to outcomes, predicted a graft loss with an AUC of 0.78 (p = 0.00001). A random forest classifier utilizing BST1 and LYPA1 peptides predicted death with an AUC of 0.80 (p = 0.0016). Urine measurements of RAS-regulated proteins may predict outcomes in kidney transplant recipients, although further prospective studies are required.
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Affiliation(s)
- Sofia Farkona
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2N2, Canada
| | - Max Kotlyar
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health, Toronto, ON M5T 0S8, Canada
| | - Kevin Burns
- Division of Nephrology, Department of Medicine and Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON K1H 8L6, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Greg Knoll
- Division of Nephrology, Department of Medicine and Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON K1H 8L6, Canada
- Department of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada
- Kidney Research Centre, Ottawa Hospital Research Institute and University of Ottawa, Ottawa, ON K1H 8L6, Canada
| | - Davor Brinc
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5S 3K3, Canada
- Division of Clinical Biochemistry, Laboratory Medicine Program, University Health Network, Toronto, Ontario M5S 3K3, Canada
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health, Toronto, ON M5T 0S8, Canada
- Departments of Medical Biophysics and Computer Science and Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1L7, Canada
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava 845 10, Slovakia
| | - Ana Konvalinka
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2N2, Canada
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5S 3K3, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 2N2, Canada
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON M5G 2N2, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 3K3, Canada
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Beaudrey T, Bedo D, Weschler C, Caillard S, Florens N. From Risk Assessment to Management: Cardiovascular Complications in Pre- and Post-Kidney Transplant Recipients: A Narrative Review. Diagnostics (Basel) 2025; 15:802. [PMID: 40218153 PMCID: PMC11988545 DOI: 10.3390/diagnostics15070802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/17/2025] [Accepted: 03/21/2025] [Indexed: 04/14/2025] Open
Abstract
Kidney transplantation remains the best treatment for chronic kidney failure, offering better outcomes and quality of life compared with dialysis. Cardiovascular disease (CVD) is a major cause of morbidity and mortality in kidney transplant recipients and is associated with decreased patient survival and worse graft outcomes. Post-transplant CVD results from a complex interaction between traditional cardiovascular risk factors, such as hypertension and diabetes, and risk factors specific to kidney transplant recipients including chronic kidney disease, immunosuppressive drugs, or vascular access. An accurate assessment of cardiovascular risk is now needed to optimize the management of cardiovascular comorbidities through the detection of risk factors and the screening of hidden pretransplant coronary artery disease. Promising new strategies are emerging, such as GLP-1 receptor agonists and SGLT2 inhibitors, with a high potential to mitigate cardiovascular complications, although further research is needed to determine their role in kidney transplant recipients. Despite this progress, a significant gap remains in understanding the optimal management of post-transplant CVD, especially coronary artery disease, stroke, and peripheral artery disease. Addressing these challenges is essential to improve the short- and long-term outcomes in kidney transplant recipients. This narrative review aims to provide a comprehensive overview of cardiovascular risk assessment and post-transplant CVD management.
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Affiliation(s)
- Thomas Beaudrey
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
- Inserm UMR_S 1109 Immuno-Rhumatology Laboratory, Translational Medicine Federation of Strasbourg (FMTS), FHU Target, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France
| | - Dimitri Bedo
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
- Inserm UMR_S 1109 Immuno-Rhumatology Laboratory, Translational Medicine Federation of Strasbourg (FMTS), FHU Target, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France
| | - Célia Weschler
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
| | - Sophie Caillard
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
- Inserm UMR_S 1109 Immuno-Rhumatology Laboratory, Translational Medicine Federation of Strasbourg (FMTS), FHU Target, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France
| | - Nans Florens
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
- Inserm UMR_S 1109 Immuno-Rhumatology Laboratory, Translational Medicine Federation of Strasbourg (FMTS), FHU Target, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France
- INI-CRCT (Cardiovascular and Renal Trialists), F-CRIN Network, 67000 Strasbourg, France
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Lee S, Yoon S, Kim S, Jeon H, Lee K, Jang HR, Lee JE, Huh W, Jeon J. Renal Outcomes With Renin-Angiotensin System Blockers After Unilateral Nephrectomy. Kidney Int Rep 2025; 10:184-196. [PMID: 39810785 PMCID: PMC11725802 DOI: 10.1016/j.ekir.2024.09.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 08/31/2024] [Accepted: 09/30/2024] [Indexed: 01/16/2025] Open
Abstract
Introduction Despite the benefits of renin-angiotensin system (RAS) blockers, their immediate use after nephrectomy has been limited because of concerns about impaired renal adaptation. We aimed to evaluate the effect of RAS blockers immediately after unilateral nephrectomy on renal adaptation. Methods This single-center retrospective cohort study included 580 patients who underwent elective unilateral nephrectomy between 2010 and 2020 and had preexisting hypertension with antihypertensive medications. Patients were divided into groups according to the postnephrectomy RAS blocker use. The primary outcome was renal adaptation defined as (postnephrectomy estimated glomerular filtration rate [eGFR] ÷ prenephrectomy eGFR) × 100 at 1 month after surgery. Secondary outcomes included hyperkalemia during the first year and mortality or end-stage kidney disease within 3 years. Results The mean age was 65.2 years, 406 (70%) were male, and 308 (53.1%) received RAS blockers after nephrectomy. The RAS blocker group was younger (63.8 vs. 66.8 years) and had a higher eGFR (79.4 vs. 75.5 ml/min per 1.73 m2) than the control group. There were no differences between the groups in renal adaptation at 1 month (67.1% vs. 66.8%; P = 0.711) or in the incidence of hyperkalemia until 1 year postoperatively. The RAS blocker use was associated with better dialysis-free survival (Adjusted hazard ratio of multivariable Cox-regression model: 0.531; 95% confidence interval: 0.329-0.857; P = 0.010]. Conclusion The immediate use of RAS blockers after unilateral nephrectomy did not deteriorate renal adaptation or increase hyperkalemia. Furthermore, the RAS blockers were associated with improved prognosis in terms of end-stage kidney disease and mortality.
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Affiliation(s)
- Sehun Lee
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Division of Nephrology, Department of Medicine, H+ Yangji Hospital, Seoul, Seoul, Republic of Korea
| | - Sungbin Yoon
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sungmi Kim
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hojin Jeon
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyeongho Lee
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hye Ryoun Jang
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Eun Lee
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Wooseong Huh
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Junseok Jeon
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Akbari A, El Wadia H, Knoll GA, White CA, Sood MM, Massicotte-Azarniouch D, McCudden C, Deschenes MJ, Salman M, Ramsay T, Hundemer GL. Comparison of eGFR Equations to Guide Dosing of Medications for Kidney Transplant Recipients. Transplantation 2024; 108:2270-2277. [PMID: 38831493 DOI: 10.1097/tp.0000000000005098] [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: 06/05/2024]
Abstract
BACKGROUND Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain. METHODS We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m 2 (milliliter per minute per 1.73 m 2 , as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status. RESULTS Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m 2 ). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology Collaboration Cr/CysC equation. CONCLUSIONS Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs.
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Affiliation(s)
- Ayub Akbari
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Hajar El Wadia
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Greg A Knoll
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Christine A White
- Division of Nephrology, Department of Medicine, Queen's University, Kingston, ON, Canada
| | - Manish M Sood
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - David Massicotte-Azarniouch
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Christopher McCudden
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Marie-Josee Deschenes
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Maria Salman
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Tim Ramsay
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Gregory L Hundemer
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Natale P, Mooi PK, Palmer SC, Cross NB, Cooper TE, Webster AC, Masson P, Craig JC, Strippoli GF. Antihypertensive treatment for kidney transplant recipients. Cochrane Database Syst Rev 2024; 7:CD003598. [PMID: 39082471 PMCID: PMC11290053 DOI: 10.1002/14651858.cd003598.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/03/2024]
Abstract
BACKGROUND The comparative effects of specific blood pressure (BP) lowering treatments on patient-important outcomes following kidney transplantation are uncertain. Our 2009 Cochrane review found that calcium channel blockers (CCBs) improved graft function and prevented graft loss, while the evidence for other BP-lowering treatments was limited. This is an update of the 2009 Cochrane review. OBJECTIVES To compare the benefits and harms of different classes and combinations of antihypertensive drugs in kidney transplant recipients. SEARCH METHODS We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 3 July 2024 using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs evaluating any BP-lowering agent in recipients of a functioning kidney transplant for at least two weeks were eligible. DATA COLLECTION AND ANALYSIS Two authors independently assessed the risks of bias and extracted data. Treatment estimates were summarised using the random-effects model and expressed as relative risk (RR) or mean difference (MD) with 95% confidence intervals (CI). Evidence certainty was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) processes. The primary outcomes included all-cause death, graft loss, and kidney function. MAIN RESULTS Ninety-seven studies (8706 participants) were included. One study evaluated treatment in children. The overall risk of bias was unclear to high across all domains. Compared to placebo or standard care alone, CCBs probably reduce all-cause death (23 studies, 3327 participants: RR 0.83, 95% CI 0.72 to 0.95; I2 = 0%; moderate certainty evidence) and graft loss (24 studies, 3577 participants: RR 0.84, 95% CI 0.75 to 0.95; I2 = 0%; moderate certainty evidence). CCBs may make little or no difference to estimated glomerular filtration rate (eGFR) (11 studies, 2250 participants: MD 1.89 mL/min/1.73 m2, 95% CI -0.70 to 4.48; I2 = 48%; low certainty evidence) and acute rejection (13 studies, 906 participants: RR 10.8, 95% CI 0.85 to 1.35; I2 = 0%; moderate certainty evidence). CCBs may reduce systolic BP (SBP) (3 studies, 329 participants: MD -5.83 mm Hg, 95% CI -10.24 to -1.42; I2 = 13%; low certainty evidence) and diastolic BP (DBP) (3 studies, 329 participants: MD -3.98 mm Hg, 95% CI -5.98 to -1.99; I2 = 0%; low certainty evidence). CCBs have uncertain effects on proteinuria. Compared to placebo or standard care alone, angiotensin-converting-enzyme inhibitors (ACEi) may make little or no difference to all-cause death (7 studies, 702 participants: RR 1.13, 95% CI 0.58 to 2.21; I2 = 0%; low certainty evidence), graft loss (6 studies, 718 participants: RR 0.75, 95% CI 0.49 to 1.13; I2 = 0%; low certainty evidence), eGFR (4 studies, 509 participants: MD -2.46 mL/min/1.73 m2, 95% CI -7.66 to 2.73; I2 = 64%; low certainty evidence) and acute rejection (4 studies, 388 participants: RR 1.75, 95% CI 0.76 to 4.04; I2 = 0%; low certainty evidence). ACEi may reduce proteinuria (5 studies, 441 participants: MD -0.33 g/24 hours, 95% CI -0.64 to -0.01; I2 = 67%; low certainty evidence) but had uncertain effects on SBP and DBP. Compared to placebo or standard care alone, angiotensin receptor blockers (ARB) may make little or no difference to all-cause death (6 studies, 1041 participants: RR 0.69, 95% CI 0.36 to 1.31; I2 = 0%; low certainty evidence), eGRF (5 studies, 300 participants: MD -1.91 mL/min/1.73 m2, 95% CI -6.20 to 2.38; I2 = 57%; low certainty evidence), and acute rejection (4 studies, 323 participants: RR 1.00, 95% CI 0.44 to 2.29; I2 = 0%; low certainty evidence). ARBs may reduce graft loss (6 studies, 892 participants: RR 0.35, 95% CI 0.15 to 0.84; I2 = 0%; low certainty evidence), SBP (10 studies, 1239 participants: MD -3.73 mm Hg, 95% CI -7.02 to -0.44; I2 = 63%; moderate certainty evidence) and DBP (9 studies, 1086 participants: MD -2.75 mm Hg, 95% CI -4.32 to -1.18; I2 = 47%; moderate certainty evidence), but has uncertain effects on proteinuria. The effects of CCBs, ACEi or ARB compared to placebo or standard care alone on cardiovascular outcomes (including fatal or nonfatal myocardial infarction, fatal or nonfatal stroke) or other adverse events were uncertain. The comparative effects of ACEi plus ARB dual therapy, alpha-blockers, and mineralocorticoid receptor antagonists compared to placebo or standard care alone were rarely evaluated. Head-to-head comparisons of ACEi, ARB or thiazide versus CCB, ACEi versus ARB, CCB or ACEi versus alpha- or beta-blockers, or ACEi plus CCB dual therapy versus ACEi or CCB monotherapy were scarce. No studies reported outcome data for cancer or life participation. AUTHORS' CONCLUSIONS For kidney transplant recipients, the use of CCB therapy to reduce BP probably reduces death and graft loss compared to placebo or standard care alone, while ARB may reduce graft loss. The effects of ACEi and ARB compared to placebo or standard care on other patient-centred outcomes were uncertain. The effects of dual therapy, alpha-blockers, and mineralocorticoid receptor antagonists compared to placebo or standard care alone and the comparative effects of different treatments were uncertain.
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Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Pamela Kl Mooi
- Department of Nephrology, Christchurch Hospital, Te Whatu Ora Waitaha Canterbury, Christchurch, New Zealand
| | - Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - Nicholas B Cross
- Department of Nephrology, Christchurch Hospital, Te Whatu Ora Waitaha Canterbury, Christchurch, New Zealand
- New Zealand Clinical Research, 3/264 Antigua St, Christchurch, New Zealand
| | - Tess E Cooper
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Angela C Webster
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Westmead Applied Research Centre, The University of Sydney at Westmead, Westmead, Australia
- Department of Transplant and Renal Medicine, Westmead Hospital, Westmead, Australia
| | - Philip Masson
- Department of Renal Medicine, Royal Free London NHS Foundation Trust, London, UK
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Giovanni Fm Strippoli
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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10
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Kung CW, Lin YC, Tseng CS, Chou YH. Impact of Renin-Angiotensin System Blockade on Mortality and Allograft Loss among Renal Transplant Recipients: A Systematic Review and Meta-Analysis. Nephron Clin Pract 2024; 148:744-754. [PMID: 39008959 DOI: 10.1159/000540305] [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: 03/10/2024] [Accepted: 07/08/2024] [Indexed: 07/17/2024] Open
Abstract
INTRODUCTION The blockade of the renin-angiotensin system (RAS) has a beneficial effect on reducing the levels of proteinuria and blood pressure in patients with chronic kidney disease (CKD) and reduces the risk of developing end-stage kidney disease in CKD patients. Nonetheless, a debate persists regarding the impact of RAS inhibitors on outcomes such as mortality and graft survival in renal transplant patients. To assess the effect of RAS inhibitors on graft recipients in the past decade, we conducted a systematic review and meta-analysis. METHODS We searched Embase, PubMed, and the Cochrane Central Register of Clinical Trials from January 1, 2012, to August 1, 2022. We included 14 articles, comprising 5 randomized controlled trials (RCTs) and 9 cohort studies, including 45,377 patients. These studies compared patient or graft survival between an RAS inhibitor treatment arm and a control arm. RESULTS The meta-analysis revealed that RAS blockade was significantly associated with lower mortality in cohort studies (risk ratio [RR] = 0.66, 95% confidence interval [CI]: 0.55-0.79), reduced allograft loss in cohort studies (RR = 0.62, 95% CI: 0.54-0.71), and significant changes in systolic blood pressure in RCTs. Subgroup analysis of the groups of interest (interventions involving RAS blockade, follow-up period of ≥5 years) showed consistently reduced mortality (RR = 0.67, 95% CI: 0.56-0.81) and reduced allograft loss (RR = 0.61, 95% CI: 0.54-0.70). CONCLUSIONS Our results demonstrated that the application of RAS blockade among renal transplant recipients was associated with lower mortality and allograft loss in cohort studies but not in RCTs. More powered clinical trials are needed to evaluate the effects of RAS blockade in renal transplant recipients.
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Affiliation(s)
| | - Yi-Chih Lin
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei City, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital Jin-Shan Branch, New Taipei City, Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei City, Taiwan
| | - Chi-Shin Tseng
- Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Yu-Hsiang Chou
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei City, Taiwan
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11
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Sawinski D, Mottl AK. Benefit of Renin Angiotensin Aldosterone Blockade in Kidney Transplant Recipients: Is the Verdict in or Still to Be Answered? Clin J Am Soc Nephrol 2024; 19:691-693. [PMID: 38758607 PMCID: PMC11168816 DOI: 10.2215/cjn.0000000000000479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2024]
Affiliation(s)
- Deirdre Sawinski
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York
- Department of Transplantation Medicine, New York-Presbyterian/Weill Cornell Medical Center, New York, New York
| | - Amy K. Mottl
- University of North Carolina Kidney Center, UNC School of Medicine at Chapel Hill, Chapel Hill, North Carolina
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12
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López Del Moral C, Wu K, Naik M, Osmanodja B, Akifova A, Lachmann N, Stauch D, Hergovits S, Choi M, Bachmann F, Halleck F, Schrezenmeier E, Schmidt D, Budde K. Predictors of graft failure after first detection of de novo donor-specific HLA antibodies in kidney transplant recipients. Nephrol Dial Transplant 2023; 39:84-94. [PMID: 37410616 DOI: 10.1093/ndt/gfad149] [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: 03/06/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND De novo donor-specific antibodies (dnDSAs) may cause antibody-mediated rejection and graft dysfunction. Little is known about the clinical course after first detection of dnDSAs during screening in asymptomatic patients. We aimed to assess the value of estimated glomerular filtration rate (eGFR) and proteinuria to predict graft failure in patients with dnDSAs and their potential utility as surrogate endpoints. METHODS All 400 kidney transplant recipients with dnDSAs at our centre (1 March 2000-31 May 2021) were included in this retrospective study. The dates of graft loss, rejection, doubling of creatinine, ≥30% eGFR decline, proteinuria ≥500 mg/g and ≥1000 mg/g were registered from the first dnDSA appearance. RESULTS During 8.3 years of follow-up, graft failure occurred in 33.3% of patients. Baseline eGFR and proteinuria correlated with 5-year graft loss (area under the receiver operating characteristics curve 0.75 and 0.80, P < .001). Creatinine doubled after a median of 2.8 years [interquartile range (IQR) 1.5-5.0] from dnDSA and the time from doubling creatinine to graft failure was 1.0 year (IQR 0.4-2.9). Analysing eGFR reduction ≥30% as a surrogate endpoint (148/400), the time from dnDSA to this event was 2.0 years (IQR 0.6-4.2), with a positive predictive value (PPV) of 45.9% to predict graft loss, which occurred after 2.0 years (IQR 0.8-3.2). The median time from proteinuria ≥500 mg/g and ≥1000 mg/g to graft failure was identical, 1.8 years, with a PPV of 43.8% and 49.0%, respectively. Composite endpoints did not improve PPV. Multivariable analysis showed that rejection was the most important independent risk factor for all renal endpoints and graft loss. CONCLUSIONS Renal function, proteinuria and rejection are strongly associated with graft failure in patients with dnDSA and may serve as surrogate endpoints.
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Affiliation(s)
- Covadonga López Del Moral
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Nephrology, Marqués de Valdecilla University Hospital-IDIVAL, Santander, Spain
| | - Kaiyin Wu
- Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Marcel Naik
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Bilgin Osmanodja
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Aylin Akifova
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nils Lachmann
- Institute for Transfusion Medicine, HLA-Laboratory, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Diana Stauch
- Institute for Transfusion Medicine, HLA-Laboratory, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sabine Hergovits
- Institute for Transfusion Medicine, HLA-Laboratory, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Mira Choi
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Friederike Bachmann
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Eva Schrezenmeier
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health Charité - Universitätsmedizin Berlin, BIH Academy, Berlin, Germany
| | - Danilo Schmidt
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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13
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Hu Y, Liang L, Liu S, Kung JY, Banh HL. Angiotensin-converting enzyme inhibitor induced cough compared with placebo, and other antihypertensives: A systematic review, and network meta-analysis. J Clin Hypertens (Greenwich) 2023; 25:661-688. [PMID: 37417783 PMCID: PMC10423763 DOI: 10.1111/jch.14695] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/08/2023]
Abstract
Studies have shown that angiotensin converting enzyme inhibitors (ACEIs) are superior in primary and secondary prevention for cardiac mortality and morbidity to angiotensin receptor blocker (ARBs). One of the common side effects from ACEI is dry cough. The aims of this systematic review, and network meta-analysis are to rank the risk of cough induced by different ACEIs and between ACEI and placebo, ARB or calcium channel blockers (CCB). We performed a systematic review, and network meta-analysis of randomized controlled trials to rank the risk of cough induced by each ACEI and between ACEI and placebo, ARB or CCB. A total of 135 RCTs with 45,420 patients treated with eleven ACEIs were included in the analyses. The pooled estimated relative risk (RR) between ACEI and placebo was 2.21 (95% CI: 2.05-2.39). ACEI had more incidences of cough than ARB (RR 3.2; 95% CI: 2.91, 3.51), and pooled estimated of RR between ACEI and CCB was 5.30 (95% CI: 4.32-6.50) Moexipril ranked as number one for inducing cough (SUCRA 80.4%) and spirapril ranked the least (SUCRA 12.3%). The order for the rest of the ACEIs are as follows: ramipril (SUCRA 76.4%), fosinopril (SUCRA 72.5%), lisinopril (SUCRA 64.7%), benazepril (SUCRA 58.6%), quinapril (SUCRA 56.5%), perindopril (SUCRA 54.1%), enalapril (SUCRA 49.7%), trandolapril (SUCRA 44.6%) and, captopril (SUCRA 13.7%). All ACEI has the similar risk of developing a cough. ACEI should be avoided in patients who have risk of developing cough, and an ARB or CCB is an alternative based on the patient's comorbidity.
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Affiliation(s)
- Yiyun Hu
- Department of PharmacySecond Xiangya Hospital of Central South UniversityChangshaChina
| | - Ling Liang
- Department of CardiologyThe Third Clinical Medical College, Fujian Medical UniversityFuzhouChina
- Department of CardiologyThe First Affiliated Hospital of Xiamen UniversityXiamenChina
| | - Shuang Liu
- Medical Affairs Management DepartmentSecond Xiangya Hospital of Central South UniversityChangshaChina
| | - Janice Y. Kung
- University of Alberta, John W. Scott Health Sciences LibraryEdmontonCanada
| | - Hoan Linh Banh
- Faculty of Medicine and DentistryDepartment of Family MedicineUniversity of AlbertaEdmontonCanada
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14
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Alshahrani S. Renin-angiotensin-aldosterone pathway modulators in chronic kidney disease: A comparative review. Front Pharmacol 2023; 14:1101068. [PMID: 36860293 PMCID: PMC9970101 DOI: 10.3389/fphar.2023.1101068] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 01/10/2023] [Indexed: 02/16/2023] Open
Abstract
Chronic kidney disease presents a health challenge that has a complex underlying pathophysiology, both acquired and inherited. The pharmacotherapeutic treatment options available today lower the progression of the disease and improve the quality of life but cannot completely cure it. This poses a challenge to the healthcare provider to choose, from the available options, the best way to manage the disease as per the presentation of the patient. As of now, the recommended first line of treatment to control the blood pressure in chronic kidney disease is the administration of renin-angiotensin-aldosterone system modulators. These are represented mainly by the direct renin inhibitor, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. These modulators are varied in their structure and mechanisms of action, hence showing varying treatment outcomes. The choice of administration of these modulators is determined by the presentation and the co-morbidities of the patient, the availability and affordability of the treatment option, and the expertise of the healthcare provider. A direct head-to-head comparison between these significant renin-angiotensin-aldosterone system modulators is lacking, which can benefit healthcare providers and researchers. In this review, a comparison has been drawn between the direct renin inhibitor (aliskiren), angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. This can be of significance for healthcare providers and researchers to find the particular loci of interest, either in structure or mechanism, and to intervene as per the case presentation to obtain the best possible treatment option.
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Affiliation(s)
- Saeed Alshahrani
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jizan, Saudi Arabia
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15
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Lim MA, Bloom RD. How to maximize graft survival. Curr Opin Organ Transplant 2023; 28:55-63. [PMID: 36579685 DOI: 10.1097/mot.0000000000001039] [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: 12/30/2022]
Abstract
PURPOSE OF REVIEW Kidney transplant failure results in significant patient morbidity and mortality, increased financial burden and exacerbates the organ shortage faced by kidney transplant candidates. The different strategies to maximize graft survival in kidney transplant recipients is presented in this review. RECENT FINDINGS Maximizing kidney graft survival requires optimizing immunosuppression, preventing and managing recurrent disease and using general chronic kidney disease strategies to slow allograft injury. Herein, we review: 1) strategies to tailor immunosuppression to the individual patient to avoid over and underimmunosuppression, and avoid immunosuppression-related drug toxicities, 2) latest findings in the following recurrent diseases: focal segmental glomerulosclerosis, membranous nephropathy, complement-mediated kidney disease and monoclonal gammopathy of renal significance, and, 3) approaches to slow allograft injury including BP control, and the use of antiproteinuric agents and SGLT-2 inhibitors. SUMMARY The last two decades has seen significant improvement in allograft outcomes resulting from advances in immunosuppression. With the federal government's renewed focus on kidney disease and transplantation, and recent advances in biomarkers, genetic testing, big data analytics and machine learning, we hope to see further outcome improvements in the next decade.
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Affiliation(s)
- Mary Ann Lim
- Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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16
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Sharif A. Interventions Against Posttransplantation Diabetes: A Scientific Rationale for Treatment Hierarchy Based on Literature Review. Transplantation 2022; 106:2301-2313. [PMID: 35696695 DOI: 10.1097/tp.0000000000004198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Posttransplant diabetes (PTD) is a common medical complication after solid organ transplantation. Because of adverse outcomes associated with its development and detrimental impact on long-term survival, strategies to prevent or manage PTD are critically important but remain underresearched. Treatment hierarchies of antidiabetic therapies in the general population are currently being revolutionized based on cardiovascular outcome trials, providing evidence-based rationale for optimization of medical management. However, opportunities for improving medical management of PTD are challenged by 2 important considerations: (1) translating clinical evidence data from the general population to underresearched solid organ transplant cohorts and (2) targeting treatment based on primary underlying PTD pathophysiology. In this article, the aim is to provide an overview of PTD treatment options from a new angle. Rationalized by a consideration of underlying PTD pathophysiological defects, which are heterogeneous among diverse transplant patient cohorts, a critical appraisal of the published literature and summary of current research in progress will be reviewed. The aim is to update transplant professionals regarding medical management of PTD from a new perspective tailored therapeutic intervention based on individualized characteristics. As the gap in clinical evidence between management of PTD versus type 2 diabetes widens, it is imperative for the transplant community to bridge this gap with targeted clinical trials to ensure we optimize outcomes for solid organ transplant recipients who are at risk or develop PTD. This necessary clinical research should help efforts to improve long-term outcomes for solid transplant patients from both a patient and graft survival perspective.
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Affiliation(s)
- Adnan Sharif
- Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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17
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Rebelo RNDS, Rodrigues CIS. Arterial hypertension in kidney transplantation: huge importance, but few answers. J Bras Nefrol 2022; 45:84-94. [PMID: 36269977 PMCID: PMC10139712 DOI: 10.1590/2175-8239-jbn-2022-0109en] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/29/2022] [Indexed: 11/07/2022] Open
Abstract
Abstract Arterial hypertension (AH) after renal transplantation (RTX) is correlated with worse cardiovascular and renal outcomes, with loss of renal function, decreased graft survival and higher mortality. RTX recipients have discrepant blood pressure (BP) values when measured in the office or by systematic methodologies, such as Ambulatory Blood Pressure Monitoring (ABPM), with significant prevalence of no nocturnal dipping or nocturnal hypertension, white coat hypertension and masked hypertension. The aim of the present study was to review the issue of hypertension in RTX, addressing its multifactorial pathophysiology and demonstrating the importance of ABPM as a tool for monitoring BP in these patients. Treatment is based on lifestyle changes and antihypertensive drugs, with calcium channel blockers considered first-line treatment. The best blood pressure target and treatment with more favorable outcomes in RTX are yet to be determined, through well-conducted scientific studies, that is, in terms of AH in RTX, we currently have more questions to answer than answers to give.
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18
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Rebelo RNDS, Rodrigues CIS. Hipertensão arterial no transplante renal: grande importância, mas poucas respostas. J Bras Nefrol 2022. [DOI: 10.1590/2175-8239-jbn-2022-0109pt] [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
Resumo Hipertensão arterial (HA) no póstransplante renal (TXR) se correlaciona com piores desfechos cardiovasculares e renais, com perda de função renal, diminuição da sobrevida do enxerto e maior mortalidade. Receptores de TXR apresentam valores discrepantes de pressão arterial (PA) quando ela é obtida em consultório ou por metodologias sistematizadas, como a Monitorização Ambulatorial da PA (MAPA), com prevalências significantes de ausência de descenso noturno ou hipertensão noturna, hipertensão do avental branco e hipertensão mascarada. O objetivo do presente estudo foi rever a temática da hipertensão no TXR, abordando sua fisiopatologia multifatorial e demonstrando a importância da MAPA como ferramenta de acompanhamento da PA nesses pacientes. O tratamento é baseado em mudanças no estilo de vida e em fármacos anti-hipertensivos, sendo os bloqueadores de canais de cálcio considerados de primeira linha. A melhor meta pressórica e o tratamento com desfechos mais favoráveis no TXR ainda estão por ser determinados, por meio de estudos bem conduzidos cientificamente, ou seja, em termos de HA no TXR temos atualmente mais questões a responder do que respostas a dar.
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19
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Hundemer GL, White CA, Norman PA, Knoll GA, Tangri N, Sood MM, Hiremath S, Burns KD, McCudden C, Akbari A. Performance of the 2021 Race-Free CKD-EPI Creatinine- and Cystatin C-Based Estimated GFR Equations Among Kidney Transplant Recipients. Am J Kidney Dis 2022; 80:462-472.e1. [PMID: 35588905 DOI: 10.1053/j.ajkd.2022.03.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 03/11/2022] [Indexed: 01/29/2023]
Abstract
RATIONALE & OBJECTIVE Race-free estimated glomerular filtration rate (eGFR) equations incorporating creatinine with and without cystatin C were recently developed and recommended for routine use. However, the performance of these equations among kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN Cross-sectional study to validate the 2021 race-free Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) eGFR equation based on creatinine alone (eGFRcr) or based on creatinine and cystatin C (eGFRcr-cys) among KTRs. SETTING & PARTICIPANTS KTRs in stable condition (N = 415) from Canada and New Zealand with same-day measurements of creatinine, cystatin C, and glomerular filtration rate (GFR) using radiolabeled diethylenetriaminepentaacetic acid. TESTS COMPARED The 2009 CKD-EPI eGFRcr, 2021 CKD-EPI eGFRcr, 2012 CKD-EPI eGFRcr-cys, 2021 CKD-EPI eGFRcr-cys, 2012 CKD-EPI eGFRcys, and Modification of Diet in Renal Disease (MDRD) Study eGFR equations were compared with measured GFR. OUTCOMES Bias, precision, accuracy, and correct classification by CKD stage. Bias was defined as the difference between estimated and measured GFR. Precision was represented by the interquartile range. Accuracy was defined as the percentages of participants with eGFRs within 10%/20%/30% (P10/P20/P30) of measured GFR, root mean square error, and mean absolute error. RESULTS 87% of patients studied were White, 3% Black, and 10% other races. Mean measured GFR was 53 ± 19 (SD) mL/min/1.73 m2. The 2009 and 2021 CKD-EPI eGFRcr equations demonstrated similar median bias (-2.3 vs -0.2 mL/min/1.73 m2, respectively), precision (14.5 vs 14.9 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/65%/84% vs 33%/63%/84%). The 2012 and 2021 CKD-EPI eGFRcr-cys equations also demonstrated similar median bias (-3.6 vs 0.3 mL/min/1.73 m2, respectively), precision (13.3 vs 14.3 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/63%/80% vs 32%/67%/83%). No clear difference in performance was detected between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations among KTRs. The proportion of correct classification by CKD stage was similar across all eGFR equations. LIMITATIONS Moderate sample size, few patients had a GFR <30 mL/min/1.73 m2, and the large majority of patients were White. CONCLUSIONS Among KTRs, the 2021 race-free CKD-EPI eGFR equations perform similarly to the previous CKD-EPI equations that included race correction terms. No significant difference in performance was observed between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations in the kidney transplant population.
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Affiliation(s)
- Gregory L Hundemer
- Department of Medicine, Division of Nephrology, and Ottawa Hospital Research Institute, University of Ottawa, Ottawa
| | | | - Patrick A Norman
- Department of Public Health Sciences, Kingston, Ontario; Queen's University, Kingston General Health Research Institute, Kingston, Ontario
| | - Greg A Knoll
- Department of Medicine, Division of Nephrology, and Ottawa Hospital Research Institute, University of Ottawa, Ottawa
| | - Navdeep Tangri
- Division of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Manish M Sood
- Department of Medicine, Division of Nephrology, and Ottawa Hospital Research Institute, University of Ottawa, Ottawa
| | - Swapnil Hiremath
- Department of Medicine, Division of Nephrology, and Ottawa Hospital Research Institute, University of Ottawa, Ottawa
| | - Kevin D Burns
- Department of Medicine, Division of Nephrology, and Ottawa Hospital Research Institute, University of Ottawa, Ottawa
| | | | - Ayub Akbari
- Department of Medicine, Division of Nephrology, and Ottawa Hospital Research Institute, University of Ottawa, Ottawa
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20
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Swanson KJ. Kidney disease in non-kidney solid organ transplantation. World J Transplant 2022; 12:231-249. [PMID: 36159075 PMCID: PMC9453292 DOI: 10.5500/wjt.v12.i8.231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/07/2022] [Accepted: 07/11/2022] [Indexed: 02/05/2023] Open
Abstract
Kidney disease after non-kidney solid organ transplantation (NKSOT) is a common post-transplant complication associated with deleterious outcomes. Kidney disease, both acute kidney injury and chronic kidney disease (CKD) alike, emanates from multifactorial, summative pre-, peri- and post-transplant events. Several factors leading to kidney disease are shared amongst solid organ transplantation in addition to distinct mechanisms unique to individual transplant types. The aim of this review is to summarize the current literature describing kidney disease in NKSOT. We conducted a narrative review of pertinent studies on the subject, limiting our search to full text studies in the English language. Kidney disease after NKSOT is prevalent, particularly in intestinal and lung transplantation. Management strategies in the peri-operative and post-transplant periods including proteinuria management, calcineurin-inhibitor minimization/ sparing approaches, and nephrology referral can counteract CKD progression and/or aid in subsequent kidney after solid organ transplantation. Kidney disease after NKSOT is an important consideration in organ allocation practices, ethics of transplantation. Kidney disease after SOT is an incipient condition demanding further inquiry. While some truths have been revealed about this chronic disease, as we have aimed to describe in this review, continued multidisciplinary efforts are needed more than ever to combat this threat to patient and allograft survival.
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Affiliation(s)
- Kurtis J Swanson
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN 55414, United States
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21
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Hilbrands L, Budde K, Bellini MI, Diekmann F, Furian L, Grinyó J, Heemann U, Hesselink DA, Loupy A, Oberbauer R, Pengel L, Reinders M, Schneeberger S, Naesens M. Allograft Function as Endpoint for Clinical Trials in Kidney Transplantation. Transpl Int 2022; 35:10139. [PMID: 35669976 PMCID: PMC9163811 DOI: 10.3389/ti.2022.10139] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/11/2022] [Indexed: 12/14/2022]
Abstract
Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials, given the pathophysiological similarities between both conditions. Kidney dysfunction is reflected in the glomerular filtration rate (GFR), and although a predefined (e.g., 50%) reduction in GFR was recommended as an endpoint by the European Medicines Agency (EMA) in 2016, many other endpoints are also included in clinical trials. End-stage renal disease is strongly associated with a change in estimated (e)GFR, and eGFR trajectories or slopes are increasingly used as endpoints in clinical intervention trials in chronic kidney disease (CKD). Similar approaches could be considered for clinical trials in kidney transplantation, although several factors should be taken into account. The present Consensus Report was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the EMA in 2020. This paper provides a contemporary discussion of primary endpoints used in clinical trials involving CKD, including proteinuria and albuminuria, and evaluates the validity of these concepts as endpoints for clinical trials in kidney transplantation.
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Affiliation(s)
- Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Vall d’Hebrón University Hospital, Barcelona, Spain
| | - Lucrezia Furian
- Kidney and Pancreas Transplantation Unit, University of Padua, Padua, Italy
| | - Josep Grinyó
- Department of Clinical Sciences, University of Barcelona, Barcelona, Spain
| | - Uwe Heemann
- Department of Nephrology, Technical University of Munich, Munich, Germany
| | - Dennis A. Hesselink
- Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Liset Pengel
- Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Marlies Reinders
- Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- *Correspondence: Maarten Naesens,
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22
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Naesens M, Budde K, Hilbrands L, Oberbauer R, Bellini MI, Glotz D, Grinyó J, Heemann U, Jochmans I, Pengel L, Reinders M, Schneeberger S, Loupy A. Surrogate Endpoints for Late Kidney Transplantation Failure. Transpl Int 2022; 35:10136. [PMID: 35669974 PMCID: PMC9163814 DOI: 10.3389/ti.2022.10136] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/18/2022] [Indexed: 12/13/2022]
Abstract
In kidney transplant recipients, late graft failure is often multifactorial. In addition, primary endpoints in kidney transplantation studies seek to demonstrate the short-term efficacy and safety of clinical interventions. Although such endpoints might demonstrate short-term improvement in specific aspects of graft function or incidence of rejection, such findings do not automatically translate into meaningful long-term graft survival benefits. Combining many factors into a well-validated model is therefore more likely to predict long-term outcome and better reflect the complexity of late graft failure than using single endpoints. If conditional marketing authorization could be considered for therapies that aim to improve long-term outcomes following kidney transplantation, then the surrogate endpoint for graft failure in clinical trial settings needs clearer definition. This Consensus Report considers the potential benefits and drawbacks of several candidate surrogate endpoints (including estimated glomerular filtration rate, proteinuria, histological lesions, and donor-specific anti-human leukocyte antigen antibodies) and composite scoring systems. The content was created from information prepared by a working group within the European Society for Organ Transplantation (ESOT). The group submitted a Broad Scientific Advice request to the European Medicines Agency (EMA), June 2020: the request focused on clinical trial design and endpoints in kidney transplantation. Following discussion and refinement, the EMA made final recommendations to ESOT in December 2020 regarding the potential to use surrogate endpoints in clinical studies that aim to improving late graft failure.
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Affiliation(s)
- Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | | | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Hôpital Saint Louis, Paris, France
| | | | - Uwe Heemann
- Department of Nephrology, Technical University of Munich, Munich, Germany
| | - Ina Jochmans
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Liset Pengel
- Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Marlies Reinders
- Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
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23
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Sridhar VS, Ambinathan JPN, Gillard P, Mathieu C, Cherney DZI, Lytvyn Y, Singh SK. Cardiometabolic and Kidney Protection in Kidney Transplant Recipients With Diabetes: Mechanisms, Clinical Applications, and Summary of Clinical Trials. Transplantation 2022; 106:734-748. [PMID: 34381005 DOI: 10.1097/tp.0000000000003919] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Kidney transplantation is the therapy of choice for patients with end-stage renal disease. Preexisting diabetes is highly prevalent in kidney transplant recipients (KTR), and the development of posttransplant diabetes is common because of a number of transplant-specific risk factors such as the use of diabetogenic immunosuppressive medications and posttransplant weight gain. The presence of pretransplant and posttransplant diabetes in KTR significantly and variably affect the risk of graft failure, cardiovascular disease (CVD), and death. Among the many available therapies for diabetes, there are little data to determine the glucose-lowering agent(s) of choice in KTR. Furthermore, despite the high burden of graft loss and CVD among KTR with diabetes, evidence for strategies offering cardiovascular and kidney protection is lacking. Recent accumulating evidence convincingly shows glucose-independent cardiorenal protective effects in non-KTR with glucose-lowering agents, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. Therefore, our aim was to review cardiorenal protective strategies, including the evidence, mechanisms, and rationale for the use of these glucose-lowering agents in KTR with diabetes.
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Affiliation(s)
- Vikas S Sridhar
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- The Kidney Transplant Program and the Ajmera Tranplant Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Jaya Prakash N Ambinathan
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- The Kidney Transplant Program and the Ajmera Tranplant Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Pieter Gillard
- Department of Endocrinology, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium
| | - Chantal Mathieu
- Department of Endocrinology, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium
| | - David Z I Cherney
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Sunita K Singh
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- The Kidney Transplant Program and the Ajmera Tranplant Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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24
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Cheddani L, Massy Z, Liabeuf S. Does kidney transplantation influence a form of discrimination for antihypertensive drugs prescriptions? Clin Kidney J 2021; 14:2618-2619. [PMID: 34950474 PMCID: PMC8690149 DOI: 10.1093/ckj/sfab154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/23/2021] [Indexed: 11/25/2022] Open
Affiliation(s)
- Lynda Cheddani
- Assistance Publique-Hôpitaux de Paris, Unité HTA, prévention et thérapeutique cardiovasculaires, Hôpital Hôtel Dieu, Paris, France
| | - Ziad Massy
- Assistance Publique-Hôpitaux de Paris, Service de Néphrologie, Hôpital Ambroise Paré, Boulogne-Billancourt, Université Paris Saclay-Versailles-St-Quentin-en-Yvelines (UVSQ), France
| | - Sophie Liabeuf
- Centre Hospitalo-Universitaire Amiens-Picardie, Service de Pharmacologie Clinique, Département de recherche Clinique, Amiens, France
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25
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Abstract
Rationale & Objective Adaptive design methods are intended to improve the efficiency of clinical trials and are relevant to evaluating interventions in dialysis populations. We sought to determine the use of adaptive designs in dialysis clinical trials and quantify trends in their use over time. Study Design We completed a novel full-text systematic review that used a machine learning classifier (RobotSearch) for filtering randomized controlled trials and adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Setting & Study Populations We searched MEDLINE (PubMed) and ClinicalTrials.gov using sensitive dialysis search terms. Selection Criteria for Studies We included all randomized clinical trials with patients receiving dialysis or clinical trials with dialysis as a primary or secondary outcome. There was no restriction of disease type or intervention type. Data Extraction & Analytical Approach We performed a detailed data extraction of trial characteristics and a completed a narrative synthesis of the data. Results 57 studies, available as 68 articles and 7 ClinicalTrials.gov summaries, were included after full-text review (initial search, 209,033 PubMed abstracts and 6,002 ClinicalTrials.gov summaries). 31 studies were conducted in a dialysis population and 26 studies included dialysis as a primary or secondary outcome. Although the absolute number of adaptive design methods is increasing over time, the relative use of adaptive design methods in dialysis trials is decreasing over time (6.12% in 2009 to 0.43% in 2019, with a mean of 1.82%). Group sequential designs were the most common type of adaptive design method used. Adaptive design methods affected the conduct of 50.9% of trials, most commonly resulting in stopping early for futility (41.2%) and early stopping for safety (23.5%). Acute kidney injury was studied in 32 trials (56.1%), kidney failure requiring dialysis was studied in 24 trials (42.1%), and chronic kidney disease was studied in 1 trial (1.75%). 27 studies (47.4%) were supported by public funding. 44 studies (77.2%) did not report their adaptive design method in the title or abstract and would not be detected by a standard systematic review. Limitations We limited our search to 2 databases (PubMed and ClinicalTrials.gov) due to the scale of studies sourced (209,033 and 6,002 results, respectively). Conclusions Adaptive design methods are used in dialysis trials but there has been a decline in their relative use over time.
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26
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Ibrahim HN, Murad DN, Knoll GA. Thinking Outside the Box: Novel Kidney Protective Strategies in Kidney Transplantation. Clin J Am Soc Nephrol 2021; 16:1890-1897. [PMID: 33757985 PMCID: PMC8729499 DOI: 10.2215/cjn.15070920] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Despite the reduction in the incidence of acute rejection, a major risk factor for graft loss, there has been only modest improvement in long-term graft survival. Most cases of kidney graft loss have an identifiable cause that is not idiopathic fibrosis/atrophy or calcineurin inhibitor nephrotoxicity. Distinct immunologic and nonimmunologic factors conspire to lead to a common pathway of allograft fibrosis. It remains plausible that mitigating nonimmunologic damage using strategies proven effective in native kidney disease may yield benefit in kidney transplantation. In this review, we will focus on nonimmunologic aspects of kidney transplant care that may prove to be valuable adjuncts to a well-managed immunosuppression regimen. Topics to be addressed include the roles of hypertension and agents used to treat it, lipid lowering, sodium and water intake, elevated uric acid, metabolic acidosis, and the use of sodium-glucose cotransporter 2 inhibitors on long-term kidney transplant health.
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Affiliation(s)
- Hassan N. Ibrahim
- Division of Renal Diseases and Hypertension, Department of Medicine, Houston Methodist Hospital, Houston, Texas
| | - Dina N. Murad
- Division of Renal Diseases and Hypertension, Department of Medicine, Houston Methodist Hospital, Houston, Texas
| | - Greg A. Knoll
- Division of Nephrology, Department of Medicine, Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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27
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Nguyen MN, Skov K, Pedersen BB, Buus NH. Unattended automated office blood pressure in living donor kidney transplant recipients. Blood Press 2021; 30:386-394. [PMID: 34664539 DOI: 10.1080/08037051.2021.1991778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE Hypertension is common in kidney transplant recipients (KTRs). For the evaluation of blood pressure (BP), 24-h ambulatory BP measurements (ABPM) are considered superior to usual office measurements but are also resource demanding and troublesome to many patients. We therefore evaluated the use of unattended automated office BP (AOBP) during the first year following living donor kidney transplantation and compared AOBP with ABPM as obtained 12 months after transplantation. MATERIALS AND METHODS Data were retrieved from a cohort of 57 KTRs (mean age 45 ± 14 years, 75% males) who all received kidneys from living donors and had a good graft function (estimated glomerular filtration rate (eGFR) 52 ± 16 ml/min/1.73 m2 at 12 months). Unattended AOBP was measured at each visit to the outpatient clinic using the BpTru® device, while ABPM was obtained by Spacelabs® equipment before and 12 months after transplantation. RESULTS AOBP remained stable from month 2 (130.2 ± 10.8/82.2 ± 7.8 mmHg) to month 12 (129.0 ± 12.8/83.1 ± 9.6 mmHg) post-transplantation. At 12 months follow-up, ambulatory daytime systolic BP was slightly higher than AOBP (132.7 ± 10.7 vs. 129.4 ± 12.2 mmHg, p = 0.04), while diastolic BP was similar (82.7 ± 7.7 vs. 82.0 ± 10.2 mmHg). Using Bland-Altman plots, 95% limits of agreements were -17.9 to 24.5 mmHg for systolic and -16.5 to 15.1 mmHg for diastolic BP. When considering a target BP of ≤130/<80 mmHg, 62% had sustained hypertension, 9% white coat hypertension and 11% masked hypertension. Using multiple linear regression analysis, only urine albumin-creatinine ratio tended to predict a higher systolic AOBP (p = 0.07). CONCLUSION In a cohort of stable living donor KTRs, mean values of unattended AOBP using BpTru® are comparable to daytime ABPM with a misclassification rate of approximately 20%.
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Affiliation(s)
- Minh Ngoc Nguyen
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Karin Skov
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | - Niels Henrik Buus
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
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28
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Naik AS, Wang SQ, Chowdhury M, Aqeel J, O'Connor CL, Wiggins JE, Bitzer M, Wiggins RC. Critical timing of ACEi initiation prevents compensatory glomerular hypertrophy in the remaining single kidney. Sci Rep 2021; 11:19605. [PMID: 34599260 PMCID: PMC8486841 DOI: 10.1038/s41598-021-99124-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/20/2021] [Indexed: 01/05/2023] Open
Abstract
Increasing evidence suggests that single in kidney states (e.g., kidney transplantation and living donation) progressive glomerulosclerosis limits kidney lifespan. Modeling shows that post-nephrectomy compensatory glomerular volume (GV) increase drives podocyte depletion and hypertrophic stress resulting in proteinuria and glomerulosclerosis, implying that GV increase could serve as a therapeutic target to prevent progression. In this report we examine how Angiotensin Converting Enzyme inhibition (ACEi), started before uninephrectomy can reduce compensatory GV increase in wild-type Fischer344 rats. An unbiased computer-assisted method was used for morphometric analysis. Urine Insulin-like growth factor-1 (IGF-1), the major diver of body and kidney growth, was used as a readout. In long-term (40-week) studies of uni-nephrectomized versus sham-nephrectomized rats a 2.2-fold increase in GV was associated with reduced podocyte density, increased proteinuria and glomerulosclerosis. Compensatory GV increase was largely prevented by ACEi started a week before but not after uni-nephrectomy with no measurable impact on long-term eGFR. Similarly, in short-term (14-day) studies, ACEi started a week before uni-nephrectomy reduced both GV increase and urine IGF-1 excretion. Thus, timing of ACEi in relation to uni-nephrectomy had significant impact on post-nephrectomy "compensatory" glomerular growth and outcomes that could potentially be used to improve kidney transplantation and live kidney donation outcomes.
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Affiliation(s)
- Abhijit S Naik
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
- , F6676 UHS, 1500 E Medical Center Dr, Ann Arbor, MI, 48109-5676, USA.
| | - Su Q Wang
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mahboob Chowdhury
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jawad Aqeel
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | - Jocelyn E Wiggins
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Markus Bitzer
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Roger C Wiggins
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
- , 1570B MSRB2, 1150 W Medical Center Dr, Ann Arbor, MI, 48109-5676, USA.
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29
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Bussalino E, Panaro L, Marsano L, Bellino D, Ravera M, Paoletti E. Prevalence and clinical correlates of hyperkalemia in stable kidney transplant recipients. Intern Emerg Med 2021; 16:1787-1792. [PMID: 33544373 DOI: 10.1007/s11739-021-02649-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/19/2021] [Indexed: 12/28/2022]
Abstract
Although hyperkalemia (HK) is often associated with adverse clinical outcomes in renal patients, few studies are available in the setting of kidney transplantation. Therefore, we evaluated prevalence and clinical correlates of HK in stable kidney transplant recipients (KTRs) on standard of care immunosuppressive therapy. We studied 160 stable KTRs (post-transplant vintage 46.6 ± 16.6 months), most of whom (96.2%) on calcineurin inhibitor (CNI)-based immunosuppressive therapy. HK was defined as plasma potassium levels above 5 mEq/L, confirmed in two consecutive samples. Office blood pressure was measured, and renal graft function was expressed by estimated glomerular filtration rate (eGFR), calculated according to the CKD-EPI formula. HK prevalence was 8.8%, and plasma K above 5.5 mEq/L was found in 2.5% of all KTRs. In the univariate logistic regression analysis HK was significantly associated with serum urea concentration (OR 1.03, 95% CI 1.01-1.05 for each 1 mg/dL increase), tCO2 (OR 0.77, 95% CI 0.66-0.90 for each 1 mmol/L increase), the presence of arterial hypertension (OR 4.01, 95% CI 1.3-12.64), the use of RAAS inhibitors (OR 5.26, 95% CI 1.6-17.7), and eGFR less than 30 ml/min/1.73 m2 (OR 7.51, 95% CI 2.37-23.77). By multivariable backward stepwise regression analysis, the presence of metabolic acidosis (OR 0.83, 95% CI 0.69-0.99, P = 0.04), arterial hypertension (OR 4.65 95% CI 1.01-17.46 P = 0.03), and to be administered RAAS inhibitors (OR 6.11, 95% CI 1.03-25.96 P = 0.03) remained significantly associated with HK. We conclude that in stable KTRs the prevalence of HK is about 9%, slightly lower than previously reported. Moreover, it is not associated with eGFR, but with metabolic acidosis, arterial hypertension, and the use of RAAS inhibitors.
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Affiliation(s)
- Elisabetta Bussalino
- Nephrology, Dialysis, and Transplantation, University of Genoa, and Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy
| | - Laura Panaro
- Nephrology, Dialysis, and Transplantation, University of Genoa, and Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy
| | - Luigina Marsano
- Nephrology, Dialysis, and Transplantation, University of Genoa, and Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy
| | - Diego Bellino
- Nephrology, Dialysis, and Transplantation, University of Genoa, and Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy
| | - Maura Ravera
- Nephrology, Dialysis, and Transplantation, University of Genoa, and Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy
| | - Ernesto Paoletti
- Nephrology, Dialysis, and Transplantation, University of Genoa, and Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy.
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Codina S, Manonelles A, Tormo M, Sola A, Cruzado JM. Chronic Kidney Allograft Disease: New Concepts and Opportunities. Front Med (Lausanne) 2021; 8:660334. [PMID: 34336878 PMCID: PMC8316649 DOI: 10.3389/fmed.2021.660334] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 06/10/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic kidney disease (CKD) is increasing in most countries and kidney transplantation is the best option for those patients requiring renal replacement therapy. Therefore, there is a significant number of patients living with a functioning kidney allograft. However, progressive kidney allograft functional deterioration remains unchanged despite of major advances in the field. After the first post-transplant year, it has been estimated that this chronic allograft damage may cause a 5% graft loss per year. Most studies focused on mechanisms of kidney graft damage, especially on ischemia-reperfusion injury, alloimmunity, nephrotoxicity, infection and disease recurrence. Thus, therapeutic interventions focus on those modifiable factors associated with chronic kidney allograft disease (CKaD). There are strategies to reduce ischemia-reperfusion injury, to improve the immunologic risk stratification and monitoring, to reduce calcineurin-inhibitor exposure and to identify recurrence of primary renal disease early. On the other hand, control of risk factors for chronic disease progression are particularly relevant as kidney transplantation is inherently associated with renal mass reduction. However, despite progress in pathophysiology and interventions, clinical advances in terms of long-term kidney allograft survival have been subtle. New approaches are needed and probably a holistic view can help. Chronic kidney allograft deterioration is probably the consequence of damage from various etiologies but can be attenuated by kidney repair mechanisms. Thus, besides immunological and other mechanisms of damage, the intrinsic repair kidney graft capacity should be considered to generate new hypothesis and potential therapeutic targets. In this review, the critical risk factors that define CKaD will be discussed but also how the renal mechanisms of regeneration could contribute to a change chronic kidney allograft disease paradigm.
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Affiliation(s)
- Sergi Codina
- Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
| | - Anna Manonelles
- Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain
| | - Maria Tormo
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
| | - Anna Sola
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
| | - Josep M. Cruzado
- Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, University of Barcelona, Barcelona, Spain
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31
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Laghlam D, Jozwiak M, Nguyen LS. Renin-Angiotensin-Aldosterone System and Immunomodulation: A State-of-the-Art Review. Cells 2021; 10:cells10071767. [PMID: 34359936 PMCID: PMC8303450 DOI: 10.3390/cells10071767] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/30/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.
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Giani JF, Veiras LC, Shen JZY, Bernstein EA, Cao D, Okwan-Duodu D, Khan Z, Gonzalez-Villalobos RA, Bernstein KE. Novel roles of the renal angiotensin-converting enzyme. Mol Cell Endocrinol 2021; 529:111257. [PMID: 33781839 PMCID: PMC8127398 DOI: 10.1016/j.mce.2021.111257] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 02/03/2021] [Accepted: 03/20/2021] [Indexed: 12/14/2022]
Abstract
The observation that all components of the renin angiotensin system (RAS) are expressed in the kidney and the fact that intratubular angiotensin (Ang) II levels greatly exceed the plasma concentration suggest that the synthesis of renal Ang II occurs independently of the circulating RAS. One of the main components of this so-called intrarenal RAS is angiotensin-converting enzyme (ACE). Although the role of ACE in renal disease is demonstrated by the therapeutic effectiveness of ACE inhibitors in treating several conditions, the exact contribution of intrarenal versus systemic ACE in renal disease remains unknown. Using genetically modified mouse models, our group demonstrated that renal ACE plays a key role in the development of several forms of hypertension. Specifically, although ACE is expressed in different cell types within the kidney, its expression in renal proximal tubular cells is essential for the development of high blood pressure. Besides hypertension, ACE is involved in several other renal diseases such as diabetic kidney disease, or acute kidney injury even when blood pressure is normal. In addition, studies suggest that ACE might mediate at least part of its effect through mechanisms that are independent of the Ang I conversion into Ang II and involve other substrates such as N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), Ang-(1-7), and bradykinin, among others. In this review, we summarize the recent advances in understanding the contribution of intrarenal ACE to different pathological conditions and provide insight into the many roles of ACE besides the well-known synthesis of Ang II.
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Affiliation(s)
- Jorge F Giani
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Luciana C Veiras
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Justin Z Y Shen
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ellen A Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - DuoYao Cao
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Derick Okwan-Duodu
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Zakir Khan
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Kenneth E Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Update on Treatment of Hypertension After Renal Transplantation. Curr Hypertens Rep 2021; 23:25. [PMID: 33961145 DOI: 10.1007/s11906-021-01151-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE OF REVIEW To incorporate novel findings on pathophysiology and treatment of posttransplant hypertension. RECENT FINDINGS (1) The sodium retaining effects of CNIs are mediated by stimulation of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule and in this regard chlorthalidone was proven to be an effective antihypertensive drug in renal transplantation. (2) Local and not systemic activation of the renin-angiotensin-aldosterone system plays a crucial role in the pathogenesis of posttransplant hypertension. (3) Recent randomized controlled trials failed to prove the presumed superiority of renin-angiotensin blockers in kidney transplantation. (4) Steroid-free and mammalian target of rapamycin-based immunosuppressive drug combinations did not show favorable effects on blood pressure control. (5) In a recent report the risk of non-melanoma skin cancer was higher with thiazide diuretics. But the increased cancer risk in transplant recipients is mainly attributed to comorbidities, such as diabetes and hypertension and of course to the transplantation condition itself or the obligatory application of immunosuppression, and has little to do with the antihypertensive medication Actual recommendations about BP targets in adult renal transplant recipients are coming from a post hoc analysis of a large randomized trial with another primary endpoint. Unless convincing studies on treatment of hypertension after renal transplantation are available, the ESC/ESH Guidelines 2018 should apply for these patients.
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Ari E, Fici F, Robles NR. Hypertension in Kidney Transplant Recipients: Where Are We Today? Curr Hypertens Rep 2021; 23:21. [PMID: 33847830 DOI: 10.1007/s11906-021-01139-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE OF REVIEW Cardiovascular disease is the leading cause of death and allograft loss among kidney transplant recipients, and hypertension is an independent risk factor for cardiovascular morbidity of this patient population. The etiology of hypertension is multifactorial, including pre-transplant volume overload, post-transplant recipient and donor-associated variables, and transplant-specific causes (immunosuppressive medications, allograft dysfunction and surgical complications such as transplant artery stenosis). RECENT FINDINGS No randomized controlled trials have assessed the optimal blood pressure targets and explored the best antihypertensive regimen for kidney transplant recipients. According to the large observational studies, it is reasonable to achieve a blood pressure goal of equal to or less than 130/80 mmHg in the long-term follow-up for minimizing the cardiovascular morbidity. The selection of antihypertensive agents should be based on the patient's co-morbidities; however, the initial choice could be calcium channel blockers especially in the first few months of transplantation. In patients with cardiovascular indications of renin-angiotensin-aldosterone system inhibition, given the well-described benefits in diabetic and proteinuric patients, it is reasonable to consider the use of renin-angiotensin-aldosterone system inhibitors. There is a need for future prospective trials in the transplant population to define optimal blood pressure goals and therapies.
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Affiliation(s)
- Elif Ari
- Department of Nephrology, Bahcesehir University, 34734, Istanbul, Turkey.
| | - Francesco Fici
- Cardiovascular Risk Chair, University of Salamanca School of Medicine, Salamanca, Spain
| | - Nicolas Roberto Robles
- Department of Nephrology, Hospital Universitario de Badajoz, and Cardiovascular Risk Chair, University of Salamanca School of Medicine, Salamanca, Spain
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Cheung AK, Chang TI, Cushman WC, Furth SL, Hou FF, Ix JH, Knoll GA, Muntner P, Pecoits-Filho R, Sarnak MJ, Tobe SW, Tomson CR, Mann JF. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int 2021; 99:S1-S87. [PMID: 33637192 DOI: 10.1016/j.kint.2020.11.003] [Citation(s) in RCA: 516] [Impact Index Per Article: 129.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 12/19/2022]
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Should ACE inhibitors or calcium channel blockers be used for post-transplant hypertension? Pediatr Nephrol 2021; 36:539-549. [PMID: 32060819 DOI: 10.1007/s00467-020-04485-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 01/14/2020] [Accepted: 01/17/2020] [Indexed: 10/25/2022]
Abstract
Arterial hypertension in renal transplant recipients warrants antihypertensive treatment. The preferable choice of antihypertensives that should be used in patients after kidney transplantation remains a matter of debate; however, calcium channel blockers (CCB) and angiotensin-converting enzyme inhibitors (ACEI) are currently the most commonly used antihypertensives. This educational review summarizes the current evidence about the effects of these two classes of medications in transplant recipients. Several studies have demonstrated that both classes of drugs can reduce blood pressure (BP) to similar extents. Meta-analyses of adult randomized controlled trials have shown that graft survival is improved in patients treated with ACEIs and CCBs, and that CCBs increase, yet ACEIs decrease, graft function. Proteinuria is usually decreased by ACEIs but remains unchanged with CCBs. In children, no randomized controlled study has ever been performed to compare BP or graft survival between CCBs and ACEIs. Post-transplant proteinuria could be reduced in children along with BP by ACEIs. The results of the most current meta-analyses recommend that due to their positive effects on graft function and survival, along with their lack of negative effects on serum potassium, CCBs could be the preferred first-line antihypertensive agent in renal transplant recipients. However, antihypertensive therapy should be individually tailored based on other factors, such as time after transplantation, presence of proteinuria/albuminuria, or hyperkalemia. Furthermore, due to the difficulty in controlling hypertension, combination therapy containing both CCBs and ACEIs could be a reasonable first-step therapy in treating children with severe post-transplantation hypertension.
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Abstract
Interstitial fibrosis with tubule atrophy (IF/TA) is the response to virtually any sustained kidney injury and correlates inversely with kidney function and allograft survival. IF/TA is driven by various pathways that include hypoxia, renin-angiotensin-aldosterone system, transforming growth factor (TGF)-β signaling, cellular rejection, inflammation and others. In this review we will focus on key pathways in the progress of renal fibrosis, diagnosis and therapy of allograft fibrosis. This review discusses the role and origin of myofibroblasts as matrix producing cells and therapeutic targets in renal fibrosis with a particular focus on renal allografts. We summarize current trends to use multi-omic approaches to identify new biomarkers for IF/TA detection and to predict allograft survival. Furthermore, we review current imaging strategies that might help to identify and follow-up IF/TA complementary or as alternative to invasive biopsies. We further discuss current clinical trials and therapeutic strategies to treat kidney fibrosis.Supplemental Visual Abstract; http://links.lww.com/TP/C141.
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Zhang Q, Rudolph B, Choi M, Bachmann F, Schmidt D, Duerr M, Naik MG, Duettmann W, Schrezenmeier E, Mayrdorfer M, Halleck F, Wu K, Budde K. The relationship between proteinuria and allograft survival in patients with transplant glomerulopathy: a retrospective single-center cohort study. Transpl Int 2020; 34:259-271. [PMID: 33205460 DOI: 10.1111/tri.13787] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/27/2020] [Accepted: 11/11/2020] [Indexed: 12/21/2022]
Abstract
Proteinuria and transplant glomerulopathy (TG) are common in kidney transplantation. To date, there is limited knowledge regarding proteinuria in different types of TG and its relationship to allograft survival. A retrospective cohort analysis of TG patients from indication biopsies was performed to investigate the relationship of proteinuria, histology, and graft survival. One hundred and seven (57.5%) out of 186 TG patients lost their grafts with a median survival of 14 [95% confidence interval (CI) 10-22] months after diagnosis. Proteinuria ≥1 g/24 h at the time of biopsy was detected in 87 patients (46.8%) and the median of proteinuria was 0.89 (range 0.05-6.90) g/24 h. TG patients with proteinuria ≥1 g/24 h had worse 5-year graft survival (29.9% vs. 53.5%, P = 0.001) compared with proteinuria <1 g/24 h. Proteinuria was associated with graft loss in univariable Cox regression [hazard ratio (HR) 1.25, 95% CI, 1.11-1.41, P < 0.001], and in multivariable analysis (adjusted HR 1.26, 95% CI 1.11-1.42, P < 0.001) independent of other risk factors including creatinine at biopsy, positive C4d, history of rejection, and Banff lesion score mesangial matrix expansion. In this cohort of TG patients, proteinuria at indication biopsy is common and associated with a higher proportion of graft loss.
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Affiliation(s)
- Qiang Zhang
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Birgit Rudolph
- Department of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Mira Choi
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Friederike Bachmann
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Danilo Schmidt
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Duerr
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Marcel G Naik
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Wiebke Duettmann
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Eva Schrezenmeier
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Manuel Mayrdorfer
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Kaiyin Wu
- Department of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
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Koraishy FM, Yamout H, Naik AS, Zhang Z, Schnitzler MA, Ouseph R, Lam NN, Dharnidharka VR, Axelrod D, Hess GP, Segev DL, Kasiske BL, Lentine KL. Impacts of center and clinical factors in antihypertensive medication use after kidney transplantation. Clin Transplant 2020; 34:e13803. [DOI: 10.1111/ctr.13803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 12/16/2019] [Accepted: 01/20/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Farrukh M. Koraishy
- Division of Nephrology Department of Medicine Stony Brook University Stony Brook NY USA
| | - Hala Yamout
- Division of Nephrology Department of Medicine Saint Louis University St. Louis MO USA
| | - Abhijit S. Naik
- Division of Nephrology Department of Medicine University of Michigan Ann Arbor MI USA
| | - Zidong Zhang
- Center for Abdominal Transplantation Saint Louis University School of Medicine St. Louis MO USA
| | - Mark A. Schnitzler
- Center for Abdominal Transplantation Saint Louis University School of Medicine St. Louis MO USA
| | - Rosemary Ouseph
- Center for Abdominal Transplantation Saint Louis University School of Medicine St. Louis MO USA
| | - Ngan N. Lam
- Division of Nephrology Department of Medicine University of Calgary Calgary AB Canada
| | - Vikas R. Dharnidharka
- Division of Nephrology Department of Pediatrics Washington University St. Louis MO USA
| | - David Axelrod
- University of Iowa Transplant Institute University of Iowa School of Medicine Iowa City IA USA
| | | | - Dorry L. Segev
- Center for Transplantation Johns Hopkins School of Medicine Baltimore MD USA
| | - Bertram L. Kasiske
- Department of Medicine Hennepin County Medical Center Minneapolis MN USA
| | - Krista L. Lentine
- Division of Nephrology Department of Medicine Saint Louis University St. Louis MO USA
- Center for Abdominal Transplantation Saint Louis University School of Medicine St. Louis MO USA
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Rangaswami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine KL, Lerma EV, Mezue K, Molitch M, Mullens W, Ronco C, Tang WHW, McCullough PA. Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association. Circulation 2020; 139:e840-e878. [PMID: 30852913 DOI: 10.1161/cir.0000000000000664] [Citation(s) in RCA: 731] [Impact Index Per Article: 146.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need for a cardiorenal education track that will guide future cardiorenal trials and integrate the clinical and research needs of this important field in the future.
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Tsuchimoto A, Masutani K, Ueki K, Nakagawa K, Matsukuma Y, Tanaka S, Unagami K, Kakuta Y, Okumi M, Noguchi H, Kaku K, Okabe Y, Nakano T, Kitazono T, Nakamura M, Ishida H, Tanabe K. Effect of renin–angiotensin system blockade on graft survival and cardiovascular disease in kidney transplant recipients: retrospective multicenter study in Japan. Clin Exp Nephrol 2019; 24:369-378. [DOI: 10.1007/s10157-019-01827-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 11/25/2019] [Indexed: 01/13/2023]
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Diena D, Messina M, De Biase C, Fop F, Scardino E, Rossetti MM, Barreca A, Verri A, Biancone L. Relationship between early proteinuria and long term outcome of kidney transplanted patients from different decades of donor age. BMC Nephrol 2019; 20:443. [PMID: 31791270 PMCID: PMC6889703 DOI: 10.1186/s12882-019-1635-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 11/21/2019] [Indexed: 01/13/2023] Open
Abstract
Background Proteinuria after kidney transplantation portends a worse graft survival. However the magnitude of proteinuria related to patient and graft survival and its correlation with donor and recipient characteristics are poorly explored. Methods This study investigated the impact of post transplant proteinuria in the first year in 1127 kidney transplants analyzing the impact of different donor ages. Proteinuria cut off was set at 0.5 g/day. Results Transplants with proteinuria > 0.5 g/day correlated with poor graft and patient outcome in all donor age groups. In addition, 6-month-1-year proteinuria increase was significantly associated with graft outcome, especially with donors > 60 years old (p < 0.05; Odd Ratio 1.8). 1-year graft function (eGFR < or ≥ 44 ml/min) had similar impact to proteinuria (≥ 0.5 g/day) on graft failure (Hazard Ratio 2.77 vs Hazard Ratio 2.46). Low-grade proteinuria (0.2–0.5 g/day) demonstrated a trend for worse graft survival with increasing donor age. Also in kidney-paired analysis proteinuria ≥0.5 effect was more significant with donors > 50 years old (Odd Ratio 2.3). Conclusions Post-transplant proteinuria was increasingly harmful with older donor age. Proteinuria ≥0.5 g/day correlates with worse outcomes in all transplanted patients. Prognostic value of proteinuria and eGFR for graft and patient survival was comparable and these two variables remain significant risk factors even in a multivariate model that take into consideration the most important clinical variables (donor age, rejection, delayed graft function and cytomegalovirus viremia among others).
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Affiliation(s)
- Davide Diena
- Renal Transplant Center "A. Vercellone", Nephrology, Dialysis and Renal Transplant Division, "Città della Salute e della Scienza Hospital", Department of Medical Sciences, University of Turin, Corso Dogliotti14, 10126, Torino, Italy
| | - Maria Messina
- Renal Transplant Center "A. Vercellone", Nephrology, Dialysis and Renal Transplant Division, "Città della Salute e della Scienza Hospital", Department of Medical Sciences, University of Turin, Corso Dogliotti14, 10126, Torino, Italy
| | - Consuelo De Biase
- Renal Transplant Center "A. Vercellone", Nephrology, Dialysis and Renal Transplant Division, "Città della Salute e della Scienza Hospital", Department of Medical Sciences, University of Turin, Corso Dogliotti14, 10126, Torino, Italy
| | - Fabrizio Fop
- Renal Transplant Center "A. Vercellone", Nephrology, Dialysis and Renal Transplant Division, "Città della Salute e della Scienza Hospital", Department of Medical Sciences, University of Turin, Corso Dogliotti14, 10126, Torino, Italy
| | - Edoardo Scardino
- Renal Transplant Center "A. Vercellone", Nephrology, Dialysis and Renal Transplant Division, "Città della Salute e della Scienza Hospital", Department of Medical Sciences, University of Turin, Corso Dogliotti14, 10126, Torino, Italy
| | - Maura M Rossetti
- Renal Transplant Center "A. Vercellone", Nephrology, Dialysis and Renal Transplant Division, "Città della Salute e della Scienza Hospital", Department of Medical Sciences, University of Turin, Corso Dogliotti14, 10126, Torino, Italy
| | - Antonella Barreca
- Division of Pathology, "Città della Salute e della Scienza Hospital", Department of Medical Sciences, University of Turin, Turin, Italy
| | - Aldo Verri
- Department of Vascular Surgery, "Città della Salute e della Scienza Hospital", University of Turin, Turin, Italy
| | - Luigi Biancone
- Renal Transplant Center "A. Vercellone", Nephrology, Dialysis and Renal Transplant Division, "Città della Salute e della Scienza Hospital", Department of Medical Sciences, University of Turin, Corso Dogliotti14, 10126, Torino, Italy.
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Abstract
Chronic kidney disease (CKD) is an increasingly prevalent condition globally and is strongly associated with incident cardiovascular disease (CVD). Hypertension is both a cause and effect of CKD and affects the vast majority of CKD patients. Control of hypertension is important in those with CKD as it leads to slowing of disease progression as well as reduced CVD risk. Existing guidelines do not offer a consensus on optimal blood pressure (BP) targets. Therefore, an understanding of the evidence used to create these guidelines is vital when considering how best to manage individual patients. Non-pharmacological interventions are useful in reducing BP in CKD but are rarely sufficient to control BP adequately. Patients with CKD and hypertension will often require a combination of antihypertensive medications to achieve target BP. Certain pharmacological therapies provide additional BP-independent renoprotective and/or cardioprotective action and this must be considered when instituting therapy. Managing hypertension in the context of haemodialysis and following kidney transplantation presents further challenges. Novel therapies may enhance treatment in the near future. Importantly, a personalised and evidence-based management plan remains key to achieving BP targets, reducing CVD risk and slowing progression of CKD.
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Affiliation(s)
- Dan Pugh
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.,Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Peter J Gallacher
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK
| | - Neeraj Dhaun
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK. .,Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
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Caring for the patient with a failing allograft: challenges and opportunities. Curr Opin Organ Transplant 2019; 24:416-423. [DOI: 10.1097/mot.0000000000000655] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Intrarenal Renin-Angiotensin-System Dysregulation after Kidney Transplantation. Sci Rep 2019; 9:9762. [PMID: 31278281 PMCID: PMC6611786 DOI: 10.1038/s41598-019-46114-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 06/17/2019] [Indexed: 02/07/2023] Open
Abstract
Angiotensin-converting enzyme inhibitors (ACEis) are beneficial in patients with chronic kidney disease (CKD). Yet, their clinical effects after kidney transplantation (KTx) remain ambiguous and local renin-angiotensin system (RAS) regulation including the ‘classical’ and ‘alternative’ RAS has not been studied so far. Here, we investigated both systemic and kidney allograft-specific intrarenal RAS using tandem mass-spectrometry in KTx recipients with or without established ACEi therapy (n = 48). Transplant patients were grouped into early (<2 years), intermediate (2–12 years) or late periods after KTx (>12 years). Patients on ACEi displayed lower angiotensin (Ang) II plasma levels (P < 0.01) and higher levels of Ang I (P < 0.05) and Ang-(1–7) (P < 0.05) compared to those without ACEi independent of graft vintage. Substantial intrarenal Ang II synthesis was observed regardless of ACEi therapy. Further, we detected maximal allograft Ang II synthesis in the late transplant vintage group (P < 0.005) likely as a consequence of increased allograft chymase activity (P < 0.005). Finally, we could identify neprilysin (NEP) as the central enzyme of ‘alternative RAS’ metabolism in kidney allografts. In summary, a progressive increase of chymase-dependent Ang II synthesis reveals a transplant-specific distortion of RAS regulation after KTx with considerable pathogenic and therapeutic implications.
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Cockfield SM, Wilson S, Campbell PM, Cantarovich M, Gangji A, Houde I, Jevnikar AM, Keough‐Ryan TM, Monroy‐Cuadros F, Nickerson PW, Pâquet MR, Ramesh Prasad GV, Senécal L, Shoker A, Wolff J, Howell J, Schwartz JJ, Rush DN. Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts. Am J Transplant 2019; 19:1730-1744. [PMID: 30582281 PMCID: PMC6590452 DOI: 10.1111/ajt.15225] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 12/10/2018] [Accepted: 12/12/2018] [Indexed: 01/25/2023]
Abstract
Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.
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Affiliation(s)
| | - Sam Wilson
- Astellas Pharma Global DevelopmentNorthbrookIllinois
| | | | | | - Azim Gangji
- St. Joseph's Healthcare HamiltonHamiltonOntarioCanada
| | | | | | | | | | | | | | | | | | | | | | - John Howell
- Astellas Pharma Global Development, Inc.MarkhamOntarioCanada
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Pisano A, Bolignano D, Mallamaci F, D’Arrigo G, Halimi JM, Persu A, Wuerzner G, Sarafidis P, Watschinger B, Burnier M, Zoccali C. Comparative effectiveness of different antihypertensive agents in kidney transplantation: a systematic review and meta-analysis. Nephrol Dial Transplant 2019; 35:878-887. [DOI: 10.1093/ndt/gfz092] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 04/11/2019] [Indexed: 12/19/2022] Open
Abstract
Abstract
Background
We conducted a systematic review and meta-analysis to compare benefits and harms of different antihypertensive drug classes in kidney transplant recipients, as post-transplant hypertension (HTN) associates with increased cardiovascular (CV) morbidity and mortality.
Methods
The Ovid-MEDLINE, PubMed and CENTRAL databases were searched for randomized controlled trials (RCTs) comparing all main antihypertensive agents versus placebo/no treatment, routine treatment.
Results
The search identified 71 RCTs. Calcium channel blockers (CCBs) (26 trials) reduced the risk for graft loss {risk ratio [RR] 0.58 [95% confidence interval (CI) 0.38–0.89]}, increased glomerular filtration rate (GFR) [mean difference (MD) 3.08 mL/min (95% CI 0.38–5.78)] and reduced blood pressure (BP). Angiotensin-converting enzyme inhibitors (ACEIs) (13 trials) reduced the risk for graft loss [RR 0.62 (95% CI 0.40–0.96)] but decreased renal function and increased the risk for hyperkalaemia. Angiotensin receptor blockers (ARBs) (10 trials) did not modify the risk of death, graft loss and non-fatal CV events and increased the risk for hyperkalaemia. When pooling ACEI and ARB data, the risk for graft failure was lower in renin–angiotensin system (RAS) blockade as compared with control treatments. In direct comparison with ACEIs or ARBs (11 trials), CCBs increased GFR [MD 11.07 mL/min (95% CI 6.04–16.09)] and reduced potassium levels but were not more effective in reducing BP. There are few available data on mortality, graft loss and rejection. Very few studies performed comparisons with other active drugs.
Conclusions
CCBs could be the preferred first-step antihypertensive agents in kidney transplant patients, as they improve graft function and reduce graft loss. No definite patient or graft survival benefits were associated with RAS inhibitor use over conventional treatment.
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Affiliation(s)
- Anna Pisano
- CNR-Institute of Clinical Physiology, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy
| | - Davide Bolignano
- CNR-Institute of Clinical Physiology, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy
| | - Francesca Mallamaci
- CNR-Institute of Clinical Physiology, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy
| | - Graziella D’Arrigo
- CNR-Institute of Clinical Physiology, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy
| | - Jean-Michel Halimi
- Service de Néphrologie et Immunologie clinique, CHRU de Tours—Hôpital Bretonneau, Tours, France
| | - Alexandre Persu
- Division of Cardiology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
- Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Gregoire Wuerzner
- Service of Nephrology and Hypertension, University Hospital, Lausanne, Switzerland
| | | | - Bruno Watschinger
- Department of Internal Medicine III, Division of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Michel Burnier
- Service of Nephrology and Hypertension, University Hospital, Lausanne, Switzerland
| | - Carmine Zoccali
- CNR-Institute of Clinical Physiology, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy
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Carminatti M, Tedesco-Silva H, Silva Fernandes NM, Sanders-Pinheiro H. Chronic kidney disease progression in kidney transplant recipients: A focus on traditional risk factors. Nephrology (Carlton) 2019; 24:141-147. [PMID: 30159972 DOI: 10.1111/nep.13483] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2018] [Indexed: 12/31/2022]
Abstract
Kidney transplant recipients are a subset of patients with chronic kidney disease (CKD) that remain at high risk for progression to dialysis and mortality. Recent advances in immunosuppression have only partially improved long-term graft and patient survival. Discovery of new immunosuppressive regimens is a slow and resource-intensive process. Hence, recognition and management of modifiable allogeneic and non-allogeneic risk factors for progression to CKD among kidney transplant recipients is of major interest for improving long-term outcomes. Graft survival is mainly determined by the quality of the allograft and by the patient's alloimmune response, which is influenced by human leukocyte antigen matching and the presence of donor-specific antibodies. Alloimmune responses manifest as acute and chronic forms of cell- and antibody-mediated rejection, which can be worsened by patient non-adherence or under-immunosuppression. However, donor and patient ages, glomerular disease recurrence, time on dialysis, pre-existing cardiovascular burden, medication side-effects and traditional risk factors, such as hypertension, proteinuria, anaemia, dyslipidaemia, diabetes and bone mineral disorder, which can ultimately lead to severe endothelial derangement, also contribute to graft loss and mortality. These traditional risk factors, common to pre-dialysis patients, often are considered of secondary importance when compared to alloimmunity and immunosuppression concerns. In this review article, we focus on the epidemiological, pathophysiological and therapeutic features of non-allogeneic traditional risk factors for CKD. We also discuss the benefit of adopting a multidisciplinary approach to pursue the same therapeutic targets recommended for pre-dialysis patients.
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Affiliation(s)
- Moisés Carminatti
- Nephrology Division, Interdisciplinary Nucleus of Studies and Research in Nephrology (NIEPEN), Renal Transplantation Unit, Juiz de Fora, Brazil
| | - Hélio Tedesco-Silva
- Nephrology Division, Hospital do Rim, Federal University of São Paulo UNIFESP, São Paulo, Brazil
| | - Natália Maria Silva Fernandes
- Nephrology Division, Interdisciplinary Nucleus of Studies and Research in Nephrology (NIEPEN), Renal Transplantation Unit, Juiz de Fora, Brazil
| | - Helady Sanders-Pinheiro
- Nephrology Division, Interdisciplinary Nucleus of Studies and Research in Nephrology (NIEPEN), Renal Transplantation Unit, Juiz de Fora, Brazil
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Impact of Using Alternative Graft Function Endpoints: A Secondary Analysis of a Kidney Transplant Trial. Transplant Direct 2019; 5:e439. [PMID: 30993193 PMCID: PMC6445653 DOI: 10.1097/txd.0000000000000880] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/05/2019] [Indexed: 11/26/2022] Open
Abstract
Supplemental digital content is available in the text. Background Nephrology trials assessing the impact of interventions on “standard” outcomes, such as doubling of creatinine, end-stage renal disease (ESRD), and/or death, are difficult to conduct given the time required for endpoints to accrue. The objective of this study was to determine if using lesser declines in kidney function would alter the interpretation of a previous randomized controlled trial. Methods This study was a secondary analysis of a kidney transplant trial comparing the use of a 40% or greater, 30% or greater, or 20% or greater decline in estimated glomerular filtration rate (eGFR) as a substitute for doubling of serum creatinine. Declines in eGFR were determined relative to baseline. This trial enrolled 212 kidney transplant patients with proteinuria and assessed the clinical impact of ramipril versus placebo on a primary outcome of doubling of serum creatinine, ESRD, or death. In this analysis, the declines in eGFR replaced doubling of creatinine in the composite endpoint. Results Mean trial follow-up was 41 months. A time-to-event composite of death, ESRD, or a 40% or greater, 30% or greater, or 20% or greater eGFR decline occurred in 45 (26 placebo vs 19 ramipril), 68 (35 vs 33), and 99 (50 vs 49) patients, respectively. Substituting these eGFR declines for doubling of serum creatinine resulted in an increase of 12, 35, and 66 endpoints compared with the original trial. In all 3 eGFR declines, ramipril treatment was not associated with any statistically significant differences despite the increase in events. Conclusions Substituting doubling of serum creatinine for lesser eGFR percentage decline thresholds did not alter trial interpretation but did increase the number of events.
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Abstract
Kidney donors face a small but definite risk of end-stage renal disease 15 to 30 years postdonation. The development of proteinuria, hypertension with gradual decrease in kidney function in the donor after surgical resection of 1 kidney, has been attributed to hyperfiltration. Genetic variations, physiological adaptations, and comorbidities exacerbate the hyperfiltration-induced loss of kidney function in the years after donation. A focus on glomerular hemodynamics and capillary pressure has led to the development of drugs that target the renin-angiotensin-aldosterone system (RAAS), but these agents yield mixed results in transplant recipients and donors. Recent work on glomerular biomechanical forces highlights the differential effects of tensile stress and fluid flow shear stress (FFSS) from hyperfiltration. Capillary wall stretch due to glomerular capillary pressure increases tensile stress on podocyte foot processes that cover the capillary. In parallel, increased flow of the ultrafiltrate due to single-nephron glomerular filtration rate elevates FFSS on the podocyte cell body. Although tensile stress invokes the RAAS, FFSS predominantly activates the cyclooxygenase 2-prostaglandin E2-EP2 receptor axis. Distinguishing these 2 mechanisms is critical, as current therapeutic approaches focus on the RAAS system. A better understanding of the biomechanical forces can lead to novel therapeutic agents to target FFSS through the cyclooxygenase 2-prostaglandin E2-EP2 receptor axis in hyperfiltration-mediated injury. We present an overview of several aspects of the risk to transplant donors and discuss the relevance of FFSS in podocyte injury, loss of glomerular barrier function leading to albuminuria and gradual loss of renal function, and potential therapeutic strategies to mitigate hyperfiltration-mediated injury to the remaining kidney.
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