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RNA interference (RNAi) is a natural biological pathway that inhibits gene expression by targeted degradation or translational inhibition of cytoplasmic messenger RNA (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 ultra-rare 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 which 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.

Background: About half of children with nephrolithiasis and/or nephrocalcinosis (NL/NC) have an underlying metabolic cause. Next-generation sequencing (NGS) is increasingly being used as a clinical tool in diagnosing inherited renal diseases. Objective: The objective of the study was to retrospectively analyze the utility of NGS in the diagnosis and management of children with NL/NC at a tertiary care referral nephrology center in western India. Methods: All children ?18 years with NL/NC, where an NGS was sent from September 2016 to September 2020, were included in the study. Clinical exome sequencing covering 8882 genes was done in 13 children. The test result was interpreted as per the American College of Medical Genetics classification: No pathogenic variant, a variant of unknown significance (VUS), and likely pathogenic and pathogenic variant. Results: The median age (IQR) of the cohort at the onset of disease was 11 months (4.25–102). History of consanguinity was present in 3 children (23%). Eight children had NC 7 had NL, 7 had the end-stage renal disease (ESRD) at presentation. Seven out of 8 children with NC had ESRD. Eleven children (84.6%) had an identifiable monogenic genetic cause: 9 had pathogenic, 2 had likely pathogenic variants detected in 5 genes: AGXT, GRHPR, HOGA1, CLDN16, and HPRT1. Two VUS were detected in two children in BBS4 and KCNJ1 gene. Primary hyperoxaluria (PH) Type 1 was the most common diagnosis in 6 children. Other diagnoses were Lesch–Nyhan syndrome in 2, PH 2, PH3, and FHHNC in 1 each. Conclusion: The yield of NGS in children with NL/NC was remarkably high. NGS was useful in diagnosis and management of children with NL/NC.

Purpose:The etiology of calcium-oxalate kidney stone formation remains elusive. Biallelic mutations in HOGA1 are responsible for primary hyperoxaluria type 3 and result in oxalate overproduction an...

Primary hyperoxaluria type 1 is an autosomal recessive disorder that causes overproduction and urinary excretion of oxalate. Liver transplant has been suggested as a treatment for primary hyperoxaluria type 1 since the defective enzyme is expressed in the liver. This study aimed to investigate results of combined liver and kidney, sequential, and preemptive livertransplantin patients with primary hyperoxaluria type 1.In this cohort study, we followed patients with primary hyperoxaluria type 1 who underwent liver transplant at our centerin Shiraz, Iran. Clinical and laboratory data of patients were gathered, and major outcomes, including renal failure after liver transplant, rejection, and mortality were recorded. Survival of patients was analyzed by the Kaplan-Meier method.Our study included 24 patients. There were 16 male (66.6%) and 8 female (33.33%) patients. Thirteen patients were in the pediatric age group (age18 y), and 11 patients were adults (age ≥ 18 y). Thirteen patients underwent sequential transplant, 8 patients underwent combined liver and kidney transplant, and 3 patients underwent preemptive transplant. All patients received organs from deceased donors. There were no statistically significant differences in mortality, rejection, and hemodialysis after transplant between those with sequential transplant and those with combined liver and kidney transplant (P.05).Liver transplant can be considered a treatment for patients with primary hyperoxaluria type 1. Combined liver and kidney transplant and preemptive liver transplant could be proper options for these patients.

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase. Methods: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. Results: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P

Fundus manifestations of primary hyperoxaluria include crystalline deposits, focal or diffuse macular hyperpigmentation, and subretinal fibrosis. Choroidal neovascularization has been hypothesized to underlie the pathogenesis of subretinal fibrosis, yet its manifestations are rarely observed. We report a case of infantile primary hyperoxaluria type 1 in a 17-month-old infant with macular subretinal fluid and subretinal hemorrhage that was associated with leakage on fluorescein angiography and responded to bevacizumab treatment, consistent with choroidal neovascularization. This case suggests that choroidal neovascularization may contribute to subretinal fibrosis and subsequent vision loss in infantile primary hyperoxaluria and may benefit from anti-vascular endothelial growth factor therapy.

Oxalate is a metabolite promoting the formation of calcium oxalate crystals in urine. Hyperoxaluria is a feature of genetic diseases, known as primary hyperoxaluria, leading to chronic kidney disease. Ethylene glycol poisoning induces the crystallization of calcium oxalate crystals in renal tubules, promoting acute renal failure. Urine oxalate results from glyoxylate transformation to oxalate in the liver, due to lactate dehydrogenase (LDH) activity, especially the LDH-5 isoenzyme. Genetic RNA interference therapy targeting lactate dehydrogenase lowers urine oxalate excretion in murine models. Stiripentol is a drug inhibiting neuronal LDH-5 isoenzyme activity. We hypothesized that stiripentol would also reduce hepatic oxalate production and urine oxalate excretion. In vitro Stiripentol decreases oxalate synthesis by hepatocytes. In vivo, stiripentol decreases urine oxalate excretion in rats and protects kidney tissue and function against ethylene glycol intoxication and hydroxyproline-induced calcium oxalate crystalline nephropathy. The use of stiripentol in clinical practice deserves further clinical studies.

Primary hyperoxalurias are rare disease with autosomal recessive inheritance; they often lead to kidney failure and can lead to life-threatening conditions, especially in early onset forms. There are three types, responding to distinct enzyme deficits. Type 1 represents 85% of cases and results from an enzyme deficiency (alanine-glyoxylate aminotransferase) in the peroxisomes of the liver, causing hyperoxaluria leading to urolithiasis with or without nephrocalcinosis. As glomerular filtration decreases, a systemic overload appears and spares no organ. Treatment has hitherto been based on combined liver and kidney transplantation, with significant mortality and morbidity. The recent introduction of interfering RNA treatments opens up new perspectives. By blocking an enzymatic synthesis (glycolate oxidase or lacticodehydrogenase a) upstream of the deficit that causes the disease, oxaluria normalizes and the tolerance of the drug (administered by injection every 1 to 3 months) is good. This strategy will help prevent kidney failure in patients treated early and avoid liver transplantation in those who are diagnosed at an advanced stage of kidney failure.

Primary hyperoxaluria (PH) is a group of diseases due to mutations in genes coding for enzymes involved in oxalate metabolism. Three types of PH are identified depending on the gene mutated. Type 1 is the most frequent with 80% of the cases, while PH2 and PH3 are rarer. The severity of renal involvement varies between the three types. Indeed, between 60% and 80% of PH1 but only 20% of PH2 patients will reach end‐stage kidney disease. In PH3 patients, dialysis is uncommon. Because oxalate clearance is impaired in CKD patients, oxalate can precipitate in various organs leading to systemic oxalosis. We report an uncommon presentation of bone oxalosis associated with hypercalcemia in a dialyzed patient. This report emphasizes the difficulties to diagnose primary hyperoxaluria and the challenge of treating dialyzed patients.

Kidney transplant is the best therapy to manage end-stage kidney failure. The main barriers limiting this therapy are scarcity of cadaveric donors and the comorbidities of the patients with end-stage kidney failure, which prevent the transplant. Living kidney donor transplant makes it possible to obviate the problem of scarcity of cadaveric donor organs and also presents better results than those of cadaveric transplant. The principal indication of living kidney donor transplant is preemptive transplant. This allows the patient to avoid the complications of dialysis and it has also been demonstrated that it has better results than the transplant done after dialysis has been initiated. Priority indications of living donor transplant are also twins and HLA identical siblings. We also have very favorable conditions when the donor is young and male. On the contrary, the living donor transplant will have worse results if the donors are over 60-65 years and the recipients are young, and this can be a relative contraindication. There is an absolute contraindication for the living donation when the recipient has diseases with high risk of aggressive relapse in the grafts: focal and segmental hyalinosis that had early relapse in the first transplant; atypical hemolytic uremic syndrome due to deficit or malfunction of the complement regulatory proteins; early development of glomerulonephritis due to anti-glomerular basement membrane antibody in patients with Alport syndrome; primary hyperoxaluria. Extreme caution should also be taken in the evaluation of the kidney donors. The risks of developing renal failure or other complications are low if an adequate pre-donation evaluation has been made according to the international guidelines.

A retrospective statistical analysis of primary hyperoxaluria type 1 (PH1) in children from June 2016 to May 2019 was carried out to discover its clinical and molecular biological characteristics. Patients were divided into two groups (infant and noninfant) according to clinic type. There were 13 pediatric patients (male:female = 6:7) with PH1 in the cohort from 11 families (four of which were biological siblings from two families), whose median age of symptom onset was 12 months and median confirmed diagnosis age was 14 months. Infant type (6 patients) was the most common type. The infant type mortality rate (100%) was higher than the noninfant (14.3%) (p = 0.029). The incidence of renal failure in infant patients was 67%, while the noninfant was 14.3%. 8 of 10 patients with nephrocalcinosis (NC) (76.92%, 10/13) were diagnosed by radiological imaging examinations, including X-ray (3 patients), CT (4 patients) and MRI (1 patient). NC was an independent risk factor for renal insufficiency [OR 3.33, 95% CI (0.7–1.2)], p AGXT gene mutations were found; 1 type, c.190A > T, were first reported here. The most common AGXT gene mutation was c.679_680del, which occurred in exon 6 (5 patients). The infant type is the most common type of pediatric PH, with a relatively higher ratio of renal failure at symptom onset and poor prognosis. NC is an independent risk factor leading to renal failure, and radiological imaging examination is recommended for patients with abnormal ultrasound examination to identify NC. AGXT gene detection is important for the diagnosis and treatment of PH1 in children.

Systemic oxalosis is a severe complication seen in primary hyperoxaluria type I patients with kidney failure. Deposition of insoluble calcium oxalate crystals in multiple organs leads to significant morbidity and mortality. We describe a retrospective cohort of 11 patients with systemic oxalosis treated at our dialysis unit from 1982 to 1998 (group 1) and 2007–2019 (group 2). Clinical and demographic data were collected from medical records. Imaging studies were only available for patients in group 2 (n = 5). Median age at dialysis initiation was 6.1 months (IQR 4–21.6), 64% were male. Dialysis modality was mostly peritoneal dialysis in group 1 and daily hemodialysis in group 2. Bone disease was the first manifestation of systemic oxalosis, starting with the appearance of sclerotic bands (mean 166 days, range 1–235), followed by pathological fractures in long bones (mean 200.4 days, range 173–235 days). Advanced disease was characterized by vertebral fractures with resulting kyphosis, worsening splenomegaly, and adynamic bone disease. Two patients developed pulmonary hypertension, 4 and 8 months prior to their death. Four of 11 patients developed hypothyroidism 0–60 months after dialysis initiation. Only one patient survived after a successful liver–kidney transplantation. Four patients died after liver or liver–kidney transplantation. This is the first comprehensive description of the natural history of pediatric systemic oxalosis. We hope that our findings will provide basis for a quantitative severity score in future, larger studies.

Background Oxalate nephropathy is a rare disorder that can result in acute kidney injury (AKI) and progresses to end-stage kidney disease (ESKD). The causes can be either primary or secondary. Primary hyperoxaluria includes a group of hereditary disorders with enzymatic defects in the glyoxylate pathway, resulting in decreased oxalate metabolism. Secondary hyperoxaluria, often overlooked can result from increased intestinal absorption, nutritional deficiencies, decreased fluid intake, impaired excretion, and increased dietary consumption of oxalate. Case presentation We present a Caucasian case of acute oxalate induced nephropathy associated with consumption of large quantities of green vegetables in a patient with chronic kidney disease (CKD). Imaging study showed no evidence of kidney stone, but a kidney biopsy revealed acute tubular injury, tubular atrophy, interstitial fibrosis, and dense tubular deposition of calcium oxalate crystals. Upon further questioning the patient, we learned that in the months prior to presentation, he had very significantly increased his consumption of green vegetables. Because of no clinical improvement, the patient was initiated and maintained on hemodialysis. Conclusion This report illustrates a case of acute oxalate nephropathy in the setting of very high dietary consumption of oxalate-rich foods in a patient with advanced CKD. Special attention should be given to the secondary causes of hyperoxaluria in patients with predisposing conditions such as CKD.

Primary hyperoxaluria are a group of rare genetic diseases caused by defective glyoxylate metabolism leading to excessive oxalate production and deposition into the tissues (oxalosis). Clinical manifestations include recurrent nephrolithiasis and nephrocalcinosis, rapidly progressive chronic kidney disease subsequently leading to end-stage renal disease, systemic oxalosis, PTH-independent hypercalcemia, pancytopenia, oxalate osteopathy with osteosclerosis, pathological fractures and endocrinopathy. Regardless of the type of primary hyperoxaluria any conservative therapy is palliative and can only slow the progression of the disease but not prevent it completely. We report the case of a young male patient with genetically confirmed primary hyperoxaluria type 1 complicated by severe oxalate osteopathy and hypercalcemia, who received a combined liver/ kidney transplant after 10 years from the disease. Treatment with human monoclonal antibody to the receptor activator of nuclear factor kappa B ligand (RANKL) — denosumab allowed achieving normalization of calcium-phosphorus metabolism, significantly reduce the activity of bone resorption and improve clinical performance. Knowledge of the features of clinical manifestations, timely diagnosis and treatment of primary hyperoxaluria are important prognostic value for patients.

Background Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2. Methods Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62). Results PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (P = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients, while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P Conclusions Patients with all forms of PH experience lifelong stone events, often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer-term follow-up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.

Introduction Primary hyperoxaluria (PH) is a family of 3 rare genetic disorders of hepatic glyoxylate metabolism that lead to overproduction and increased renal excretion of oxalate resulting in progressive renal damage. LDHA inhibition of glyoxylate-to-oxalate conversion by RNA interference (RNAi) has emerged as a potential therapeutic option for all types of PH. LDHA is mainly expressed in the liver and muscles. Methods Nonclinical data in mice and nonhuman primates show that LDHA inhibition by RNAi reduces urinary oxalate excretion and that its effects are liver-specific without an impact on off-target tissues, such as the muscles. To confirm the lack of unintended effects in humans, we analyzed data from the phase I randomized controlled trial of single-dose nedosiran, an RNAi therapy targeting hepatic LDHA. We conducted a review of the literature on LDHA deficiency in humans, which we used as a baseline to assess the effect of hepatic LDHA inhibition. Results Based on a literature review of human LDHA deficiency, we defined the phenotype as mainly muscle-related with no liver manifestations. Healthy volunteers treated with nedosiran experienced no drug-related musculoskeletal adverse events. There were no significant alterations in plasma lactate, pyruvate, or creatine kinase levels in the nedosiran group compared with the placebo group, signaling the uninterrupted interconversion of lactate and pyruvate and normal muscle function. Conclusion Phase I clinical data on nedosiran and published nonclinical data together provide substantial evidence that LDHA inhibition is a safe therapeutic mechanism for the treatment of all known types of PH., Graphical abstract

We report a patient with homocystinuria and hyperoxaluria who was cured of homocystinuria-related disease following liver transplant. The patient was diagnosed with homocystinuria as a newborn and was treated with dietary modifications and supplements. At 22 months, he passed a calcium oxalate stone and was found to have numerous bilateral kidney stones. Genetic testing confirmed primary hyperoxaluria, type 1. He underwent preemptive liver transplant at age four to treat primary hyperoxaluria. Following transplant, his serum methionine and homocysteine levels normalized, thus, demonstrating resolution of homocystinuria. Methionine and homocysteine levels remained normal 6 years later. Homocystinuria is associated with ophthalmologic, skeletal, neurologic, and thromboembolic complications. As cystathionine beta-synthase resides in the liver, transplant was hypothesized to be an effective treatment. Primary hyperoxaluria generally progresses to chronic kidney disease and is treated with combined kidney-liver transplant at the time of end stage kidney disease. Given this patient's dual diagnoses, we proceeded with preemptive liver transplantation. Three prior cases of patients with homocystinuria treated with liver transplantation have been reported. In all cases, transplant resolved metabolic effects. However, our case represents a pediatric patient without disease-related complications prior to transplant. This case supports liver-targeted gene therapies as an effective treatment for homocystinuria.

Lumasiran (Oxlumo™) is a subcutaneously administered small interfering RNA (siRNA) targeting the mRNA for hydroxyacid oxidase 1 gene (HAO1; encodes glycolate oxidase) and was developed by Alnylam Pharmaceuticals for the treatment of primary hyperoxaluria type 1 (PH1). By silencing the gene encoding glycolate oxidase, lumasiran depletes glycolate oxidase and thereby inhibits the synthesis of oxalate, which is the toxic metabolite that is directly associated with the clinical manifestations of PH1. On 19 November 2020, lumasiran received its first global approval in the EU for the treatment of PH1 in all age groups. On 23 November 2020, lumasiran was approved in the USA for the treatment of adult and paediatric patients with PH1. This article summarizes the milestones in the development of lumasiran leading to this first approval.

Introduction: Current knowledge of risk factors and renal histologic patterns of oxalate nephropathy (ON) not due to primary hyperoxaluria (PH) has been limited to small case series and case reports. Thus, we analyzed and compared clinical risk factors, histologic characteristics, and renal outcomes of patients with biopsy-confirmed ON among a cohort of patients with enteric and nonenteric risk factors. Methods: A clinical data repository of native kidney pathology reports from 2009 to 2020 at all Mayo Clinic sites was used to identify 421 ON cases. Results: After excluding cases in transplanted kidneys or due to PH, 64 cases remained. Enteric risk factors were present in 30 and nonenteric in 34. Roux-en-Y gastric bypass (17) and pancreatic insufficiency (6) were most common in the enteric hyperoxaluria group. In the nonenteric group, vitamin C (7) and dietary oxalate (7) were common, while no apparent risk was noted in 16. Acute kidney injury (AKI) stage III at the time of diagnosis was present in 60%, and 40.6% required dialysis. Patients in the nonenteric group had more interstitial inflammation (p = 0.01), and a greater number of tubules contained intratubular calcium oxalate (CaOx) crystals (p = 0.001) than the nonenteric group. Patients in the enteric group were more likely to have baseline chronic kidney disease (CKD) (p = 0.02) and moderate-to-severe tubulointerstitial fibrosis and atrophy (IFTA) (OR 3.49, p = 0.02). After a median follow-up of 10 months, 39% were dialysis dependent, 11% received a kidney transplant, and 32% died. On univariate analysis, >10 tubules with CaOx crystals, baseline CKD, and AKI requiring dialysis correlated with the risk of dialysis, transplant, or death. On multivariate analysis, only AKI requiring dialysis correlated with adverse renal outcomes. Conclusion: This is the largest cohort study of ON not due to PH. Histologic features differ in patients with enteric versus nonenteric risks. Patients in the enteric group are more likely to have baseline CKD and significant IFTA, while patients in the nonenteric group were more likely to have a greater number of tubules with CaOx crystals and corresponding interstitial inflammation. AKI requiring dialysis at the time of diagnosis was the single most significant predictor of adverse renal outcome.