• Kidney function
• Kidney stones
• Nephrocalcinosis
• Oxalate
• RNA interference

• Humans
• Hyperoxaluria, Primary/drug therapy
• Hyperoxaluria, Primary/urine
• Hyperoxaluria, Primary/complications
• Hyperoxaluria, Primary/genetics
• Child
• Adolescent
• Male
• Female
• Child, Preschool
• Retrospective Studies
• Infant
• Oxalates/urine
• Oxalates/blood
• Treatment Outcome
• Kidney Calculi/etiology
• Kidney Calculi/urine
• Nephrocalcinosis/etiology
• Renal Dialysis
• Transaminases/genetics

• Universitätsklinikum Hamburg-Eppendorf (UKE) (5411)

• Combined liver-kidney transplant
• Kidney transplant
• Nephrocalcinosis
• Nephrolithiasis
• PH
• Primary hyperoxaluria type 1
• Primary hyperoxalurias
• RNA interference agent

• Humans
• Hyperoxaluria, Primary/therapy
• Hyperoxaluria, Primary/diagnosis
• Hyperoxaluria, Primary/genetics
• Hyperoxaluria, Primary/complications
• Liver Transplantation
• Kidney Transplantation
• Algorithms
• Early Diagnosis
• Renal Dialysis

• Humans
• Kidney Calculi/metabolism
• Kidney Calculi/etiology
• Cardiovascular Diseases/metabolism
• Cardiovascular Diseases/etiology
• Oxalates/metabolism
• Disease Progression
• Renal Insufficiency, Chronic/metabolism

• AGXT
• GRHPR
• HOGA1
• RNA interference
• genetics
• oxalate
• primary hyperoxaluria

• Humans
• Hyperoxaluria, Primary/drug therapy
• Hyperoxaluria, Primary/therapy
• Calcium Oxalate/metabolism
• Oxalates/metabolism
• Quality of Life

• 82070721 National Natural Science Foundation of China
• 82270798 National Natural Science Foundation of China
• 2020YFC2002700 National Key Research and Development Program
• 202102010150 Science and Technology Plan Project of Guangzhou
• 225 Program Hunan Province Foundation of High-level Health Talent

• PH1
• bone health
• children
• kidney transplantation
• liver transplantation
• osteopathy

• Adult
• Humans
• Renal Dialysis
• Hyperoxaluria, Primary/diagnosis
• Hyperoxaluria, Primary/therapy
• Oxalates
• Hyperoxaluria

• multidisciplinary care
• pediatric transplantation
• rare genetic diseases

• Child
• Humans
• Kidney Transplantation/methods
• Quality of Life
• Kidney Diseases/genetics
• Kidney Diseases/surgery
• Urinary Tract
• Kidney

• dialysis
• end-stage renal disease
• genetic testing
• nephrolithiasis
• primary hyperoxaluria type 2 (ph2)

• Children's hospital
• Kidney stones
• Nephrocalcinosis
• Primary hyperoxaluria

• Child
• Humans
• Male
• Infant
• Nephrocalcinosis/genetics
• Hyperoxaluria, Primary/complications
• Hyperoxaluria, Primary/diagnosis
• Hyperoxaluria, Primary/genetics
• Oxalates
• Hyperoxaluria
• Kidney Calculi
• Renal Insufficiency

• CKRT
• EXTRIP
• Ethylene glycol
• Hemodialysis
• Poisoning

• Humans
• Kidney Transplantation/adverse effects
• Calcium Oxalate
• Kidney/pathology
• Hyperoxaluria/etiology
• Hyperoxaluria/complications
• Renal Insufficiency
• Oxalates

• chronic kidney disease
• dialysis
• end stage renal disease
• genetics
• hyperoxaluria
• metabolic
• nephrocalcinosis
• nephrolithiasis
• primary hyperoxaluria type 1

• Humans
• Flank Pain/etiology
• Hyperoxaluria, Primary
• Hyperoxaluria

• children
• end-stage kidney disease
• infant
• infantile oxalosis
• primary hyperoxaluria

• calcium oxalate
• oxalate
• primary hyperoxaluria type 1
• rna interference
• therapy

• Humans
• Hyperoxaluria, Primary/genetics
• Hyperoxaluria, Primary/therapy
• Kidney Calculi
• L-Lactate Dehydrogenase
• Oxalates/metabolism
• RNA, Small Interfering

• R21 TR003174 NCATS NIH HHS

• Glycolates
• Glyoxylates
• Humans
• Hyperoxaluria, Primary/drug therapy
• Oxalates/metabolism
• RNA, Small Interfering
• Vitamins

• Universidad de la Laguna

• iRNA
• lumasiran
• nephrolithiasis
• oxalate
• primary hyperoxaluria

• funded

Supportive treatment for primary hyperoxaluria type 1 (PH1) focuses on high fluid intake and crystallization inhibitors. A subset of patients with specific PH1 genotypes (c.508G>A and c.454T>A) will respond to pyridoxine, defined as a >30% reduction in urinary oxalate excretion. Response to pyridoxine is variable and in some patients, urinary oxalate may normalize. The first focused treatment for PH1 using an RNA interference agent to reduce urinary oxalate was approved in 2020, and such therapies may significantly alter treatment approaches and long-term outcomes in PH1. Currently PH1 often presents with kidney function impairment and frequently results in end-stage kidney disease (ESKD). With kidney dysfunction, urinary oxalate clearance decreases and multisystem deposition of oxalate (oxalosis) occurs, commonly in bones, eyes, heart and skin. Once plasma oxalate levels exceed 30 µmol/L, aggressive haemodialysis is indicated to prevent oxalosis, even if the glomerular filtration rate (GFR) remains better than for typical dialysis initiation. Peritoneal dialysis alone does not achieve the needed oxalate clearance. Dialysis is a bridge to future transplantation. Liver transplantation restores hepatic alanine-glyoxylate transaminase enzyme activity, allowing glyoxylate detoxification and preventing further oxalosis. The native liver must be removed as part of this process to avoid ongoing pathologic oxalate production. The timing and type of liver transplantation are dependent on pyridoxine sensitivity, age, weight, residual GFR and evidence of systemic oxalate deposition in extrarenal organs. Liver transplant can be isolated or combined with kidney transplantation in a sequential or simultaneous fashion. Isolated kidney transplantation is generally reserved for pyridoxine-sensitive patients only. Although liver transplantation is curative for PH1 and kidney transplantation treats ESKD, ensuing necessary immunosuppression and potential allograft dysfunction impart significant long-term risks.

• PH1
• RNAi
• dialysis
• infantile PH1
• kidney failure
• lumasiran
• nedosiran
• oxalosis
• primary hyperoxaluria
• transplantation

• dialysis
• hyperoxaluria
• kidney transplantation
• liver transplantation
• pediatrics
• systemic oxalosis

• Alnylam Pharmaceuticals

• clinical research / practice
• kidney transplantation / nephrology
• protocol biopsy
• recurrent disease

Primary hyperoxalurias are a devastating family of diseases leading to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease. Traditional treatment paradigms are limited to conservative management, dialysis and combined transplantation of the kidney and liver, of which the liver is the primary source of oxalate production. However, transplantation is associated with many potential complications, including operative risks, graft rejection, post-transplant organ failure, as well as lifelong immunosuppressive medications and their adverse effects. New therapeutics being developed for primary hyperoxalurias take advantage of biochemical knowledge about oxalate synthesis and metabolism, and seek to specifically target these pathways with the goal of decreasing the accumulation and deposition of oxalate in the body.

Primary hyperoxalurias are a devastating family of diseases that eventually lead to end-stage renal disease. In this Review, Shee and Stoller discuss current treatment paradigms for primary hyperoxalurias, new therapeutics and their mechanisms of action, and future directions for novel research in the field.

Primary hyperoxalurias (PHs) are a devastating family of rare, autosomal-recessive genetic disorders that lead to multisystem oxalate deposition, nephrolithiasis, nephrocalcinosis and end-stage renal disease.

Primary hyperoxaluria (PH) is a rare inherited autosomal recessive disease caused by disturbed glyoxylate metabolism. The disease is characterized by calcium oxalate crystal deposition in various organs, especially in the kidney. Due to the lack of current understanding of PH, nearly all patients are only initially diagnosed with PH when recurrent lithiasis and progressive end-stage renal disease occur. Many cases are not diagnosed in patients until renal allograft insufficiency occurs after renal transplantation. This case report and literature review aim to emphasize the need for careful pre-transplant PH screening of patients with bilateral nephrocalcinosis or nephrolithiasis.

Renal allograft insufficiency was diagnosed as PH after kidney transplantation. Here, we detail the complete clinical course, including computed tomography images of the original kidney and renal graft, histopathological images of a biopsy of the transplanted kidney, the results of laboratory and molecular genetic tests, and the treatment. In addition, we reviewed the literature from 2000 to 2021 and analyzed 19 reported cases of PH diagnosed after kidney transplantation, and provide a summary of the characteristics, complications, treatment, and prognosis of these cases.

By reviewing and analyzing these cases, we concluded that patients with a history of nephrocalcinosis or nephrolithiasis in both kidneys need preoperative screening for PH and appropriate treatment before kidney transplantation. Delayed graft function caused by PH is easily misdiagnosed as acute rejection, and needle biopsy should be performed at an early stage.

The online version contains supplementary material available at 10.1186/s12882-021-02546-0.

• Acute rejection
• Kidney transplantation
• Needle biopsy
• Primary hyperoxaluria

• Bone
• Children
• Kidney dialysis
• Oxalosis
• Primary hyperoxaluria

• Adolescent
• Female
• Humans
• Compassionate Use Trials
• Hyperoxaluria/blood
• Hyperoxaluria/drug therapy
• Hyperoxaluria/therapy
• Oxalates/blood
• Renal Dialysis
• Treatment Outcome

• Calcium oxalate
• Children
• Clinical trials
• Drug development
• Novel therapies
• Primary hyperoxaluria

• kidney stones
• lanthanum carbonate
• nephrocalcinosis
• oxalate
• primary hyperoxaluria type 1

RNA interference (RNAi) is a natural biological pathway that inhibits gene expression by targeted degradation or translational inhibition of cytoplasmic mRNA by the RNA induced silencing complex. RNAi has long been exploited in laboratory research to study the biological consequences of the reduced expression of a gene of interest. More recently RNAi has been demonstrated as a therapeutic avenue for rare metabolic diseases. This review presents an overview of the cellular RNAi machinery as well as therapeutic RNAi design and delivery. As a clinical example we present primary hyperoxaluria, an ultrarare inherited disease of increased hepatic oxalate production which leads to recurrent calcium oxalate kidney stones. In the most common form of the disease (Type 1), end‐stage kidney disease occurs in childhood or young adulthood, often necessitating combined kidney and liver transplantation. In this context we discuss nedosiran (Dicerna Pharmaceuticals, Inc.) and lumasiran (Alnylam Pharmaceuticals), which are both novel RNAi therapies for primary hyperoxaluria that selectively reduce hepatic expression of lactate dehydrogenase and glycolate oxidase respectively, reducing hepatic oxalate production and urinary oxalate levels. Finally, we consider future optimizations advances in RNAi therapies.

• RNA interference
• calcium oxalate
• end-stage renal disease
• glycolate oxidase
• hyperoxaluria
• kidney stones
• lactate dehydrogenase
• micro-RNA
• primary hyperoxaluria
• small interfering RNAs

• age of onset
• clinical classification
• outcome
• primary hyperoxaluriatype 1
• renal replacement therapy

Background: Primary hyperoxaluria type 1 (PH1) is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage, often requiring renal replacement therapy (RRT). Though systemic oxalate deposition is well-known, the natural history of PH1 during RRT has not been systematically described. In this study, we describe the clinical, laboratory, and echocardiographic features of a cohort of PH1 patients on RRT.

Methods: Patients with PH1 enrolled in the Rare Kidney Stone Consortium PH Registry who progressed to require RRT, had ≥2 plasma oxalate (pOx) measurements 3–36 months after start of RRT, and at least one pair of pOx measurements between 6 and 18 months apart were retrospectively analyzed. Clinical, echocardiographic, and laboratory results were obtained from the Registry.

Results: The 17 PH1 patients in our cohort had a mean total HD hours/week of 17.4 (SD 7.9; range 7.5–36) and a range of age of RRT start of 0.2–75.9 years. The average change in plasma oxalate (pOx) over time on RRT was −0.74 [−2.9, 1.4] μmol/L/month with the mean pOx never declining below 50 μmol/L. Over time on RRT, oxalosis progressively developed in multiple organ systems. Echocardiography performed on 13 subjects showed worsening of left ventricular global longitudinal strain correlated with pOx (p < 0.05).

Conclusions: Even when a cohort of PH1 patients were treated with intensified RRT, their predialysis pOx remained above target and they developed increasing evidence of oxalosis. Echocardiographic data suggest that cardiac dysfunction could be related to elevated pOx and may worsen over time.

• dialysis
• echocardiography
• oxalosis
• primary hyperoxaluria
• renal replacement therapy 2

• dialysis (ESKD)
• hyperoxaluria type 1
• infant
• kidney transplanation
• liver transplatation

• RNA interference drugs
• kidney transplantation
• liver transplantation
• primary hyperoxaluria type 1

• Oxalobacter formigenes
• OC5
• dialysis
• hyperoxaluria
• kidney function

Primary hyperoxaluria (PH) is an inherited disease lacking of hepatic oxalic acid metabolic enzymes which could lead to irreverisible renal damage. Currently, liver–kidney transplantation is a curative but highly invasive therapy used to treat patients with PH. However, limited studies have focused on combined liver–kidney transplantation (CLKT) and sequential liver and kidney transplantation (SLKT) in patients with PH.

The present study included 201 patients with PH who received both liver and kidney transplants and who were listed on the Scientific Registry of Transplant Recipients from 1987 to 2018. According to the liver–kidney transplant procedure, patients were separated into a CLKT group and a SLKT group. Patient demographics and transplant outcomes were assessed in each group.

Compared with the SLKT group, The CLKT group got a worse pretransplant dialysis condition in both the proportion of patients under pretransplant dialysis (p = 0.048) and the duration of the pretransplant dialysis (p < 0.001). The SLKT group got higher human leukocyte antigen mismatch score of kidney donor (p < 0.001) and liver donor (p = 0.003). The CLKT group utilized higher proportion (98.9%) of organs from a single deceased donor, while the SLKT group utilized 75.0% of organs from deceased liver donors and only 35.0% of organs from deceased kidney donors (p < 0.001). Kidney function measured by serum creatinine concentration before liver transplantation (LT) or CLKT was similar (p = 0.305) between groups. Patient survival was not significantly different between the two groups (p = 0.717) and liver (p = 0.685) and kidney (p = 0.464) graft outcomes were comparable between the two groups.

SLKT seems to be an alternative option with strict condition for CLKT, further exploration about the SLKT is still required.

• Combined liver and kidney transplantation
• Inherited disease
• Liver–kidney transplantation
• Primary hyperoxaluria
• Sequential liver and kidney transplantation

• Cystinuria
• Cystinurie
• Hyperoxaliuria
• Hyperoxaliurie
• Inherited disease
• Kidney stones
• Lithiase urinaire
• Maladie héréditaire
• Renal tubulopathy
• Tubulopathie rénale

• Primary hyperoxaluria
• kidney transplantation
• liver transplantation
• living donor

• Nephrocalcinosis
• PH
• nephrolithiasis
• primary hyperoxaluria
• therapy
• treatment

• Hyperoxaluria
• Kidney transplant
• Liver transplant
• Liver–kidney transplant
• Oxalate
• Pediatric

• Calcium oxalate
• Nephrocalcinosis
• Primary hyperoxaluria
• Renal stone
• Urolithiasis

The perioperative management of patients presenting for simultaneous liver and kidney transplantation (SLKT) is a complex process. We analysed SLKTs performed in our institution to identify preoperative, intraoperative and post-operative challenges encountered in the management.

We retrospectively studied the case records of 12 patients who underwent SLKT between 2009 and 2014 and analysed details of pre-operative evaluation and optimisation, intraoperative anaesthetic management and the implications of use of perioperative continuous renal replacement therapy (CRRT) and the post-operative course of these patients.

Of the total 12 cases, 4 were under 16 years of age. The indications for SLKT were primary hyperoxaluria (5), congenital hepatic fibrosis with polycystic kidney disease (2), ethanol-related end-stage liver disease (ESLD) with hepatorenal syndrome type 1 (1). Four patients had ESLD with end-stage renal disease due to other causes. Six recipients received live donor grafts and 6 patients received cadaveric grafts. Seven patients received intraoperative CRRT. Mean duration of surgery was 12.5 h. Cardiac output monitors used were trans-oesophageal echocardiogram (2), pulmonary artery catheter (1) and pulse contour cardiac output monitor (3). There was 1 sepsis-related mortality on 7^th post-operative day.

A thorough pre-operative evaluation and optimisation, knowledge and anticipation of potential problems, and meticulous intraoperative fluid management guided by appropriate monitoring and use of CRRT when needed can help in achieving successful outcomes.

• Anaesthesia for combined solid organ transplants
• combined liver-kidney transplantation
• intraoperative renal replacement therapy
• primary hyperoxaluria
• simultaneous liver-kidney transplantation

• autosomal recessive polycystic kidney disease
• children
• combined liver and kidney transplantation
• kidney after liver transplantation
• primary hyperoxaluria type 1