When delays could lead to ESKD. Identifying and managing primary hyperoxaluria in clinical practice – Organised by ALNYLAM PHARMACEUTICALS

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Welcome & introduction

Felix Knauf, Germany

Primary hyperoxaluria (PH) is a group of rare metabolic disorders caused by recessive gene mutations. There are three main types, PH1, PH2 and PH3, all characterized by oxalate overproduction in the liver. PH1 is the most severe form and the most frequent, accounting for 70% of cases. Delayed diagnosis is common, and there may be five years between presentation and diagnosis. At a virtual symposium held during the 2021 ERA-EDTA 2021 fully virtual congress, Professor Felix Knauf, Professor Rezan Topaloglu, and Professor Daniel Fuster discussed the importance of early diagnosis, current approaches to management, and new therapeutic innovations designed to improve outcomes in PH1.

The clock is ticking: When and how to evaluate a referral for potential hyperoxaluria

Rezan Topaloglu, Turkey

In North America and Europe, estimated diagnosed prevalence of PH1 is 1-3 per million population, though it is likely underdiagnosed due to its heterogeneous clinical presentation, and it accounts for about 1% of paediatric end-stage kidney disease (ESKD) in registries in Europe, USA and Japan. Prevalence is higher in areas of Middle East, North Africa and other countries where consanguineous marriages are common.

Professor Topaloglu reported that nephrocalcinosis and ESKD occur most frequently in PH1 compared to PH2 and PH3. Adults with PH1 present with recurrent kidney stones, while children present with recurrent kidney stones and progressive chronic kidney disease (CKD). Infantile oxalosis has the worst prognosis: 50% have ESKD at diagnosis and 80% progress within three years.

According to OxalEurope recommendations, PH1 should be considered in any child with a first kidney stone, in adults with recurrent stone disease, and in any patient with nephrocalcinosis, particularly when associated with decreased GFR. Investigation for PH is also recommended if there are oxalate crystals (calcium oxalate monohydrate) in any biological fluid or tissue. Screening is recommended in relatives of index cases, but not in the general population. Genetic testing is recommended in subjects with phenotypic characteristics of PH1, with mutation analysis extended to siblings and parents. Prenatal diagnosis using mutation analysis should be offered to parents of an affected child.

In biochemical and enzymological assessment, OxalEurope recommends measuring 24-hour urine oxalate, creatinine and glycolate in any patient with a possible diagnosis of PH1 and preserved renal function. Plasma oxalate (POx) should be measured in CKD patients. If genetic testing is inconclusive, measurement of AGT enzyme activity is recommended.

According to Professor Topaloglu, diagnostic delay is a key challenge in PH1, and is due to a low index of suspicion because of the condition’s rarity and nonspecific clinical presentation, and variability in age of onset and severity. There is also limited access to urinary metabolic and genetic screening in some countries. Diagnosis may also appear less urgent in adults, because symptoms are not as overt as in infant and paediatric patients. Adults may have a sudden and rapid progression if PH1 is not addressed adequately. Diagnostic delay—and its consequences for patients—may be avoided by greater awareness of the signs and symptoms of PH1 and by facilitating testing of appropriate patients.

Reducing oxalate to reduce the risk of ESKD

Felix Knauf, Germany

Professor Knauf agreed that early diagnosis of PH1 is essential, as delay increases the risk of oxalos-related complications, including urolithiasis with/without nephrocalcinosis and its recurrence post-renal transplantation. Even before there is substantial loss of kidney function (CKD stages 1-3a), there is a significant inverse correlation between eGFR and POx in patients with PH. Rate of disease progression is variable, but almost all patients experience kidney failure by age 60. At eGFR <45 ml/min/1.732 urinary excretion of oxalate cannot match the rate of oxalate production, and oxalate accumulates in the plasma and tissues, resulting in systemic effects on major organs, skin, blood vessels, nerves, muscles, bones and eyes.

PH1 patients require lifelong surveillance. At eGFR >60 ml/min/1.732, kidney function should be tested at least annually, together with renal ultrasound, fundoscopy and urinalysis to identify urinary oxalate (UOx). These investigations, plus POx, are recommended annually or more frequently when eGFR is 30-60 ml/min/1.732. At <30 ml/min/1.732, patients require frequent monitoring of POx and kidney function, together with X-ray of long bones, electrocardiogram, echocardiogram, haemoglobin, physical examination, and thyroid function testing.

Professor Knauf noted that most current management approaches do not target the cause of PH1. Dietary restrictions aim to minimize oxalate absorption but have limited impact. Non-surgical management includes hyperhydration targeted at preventing urinary calcium oxalate (CaOx) supersaturation, minimizing CaOx crystallization and stone formation in the kidney, with alkali citrate to reduce UOx saturation to inhibit crystallization. Pyridoxine can reduce hepatic oxalate production in patients with some mutations, normalizing oxalate production in a small subset of such patients.

Patients with kidney failure need frequent, intensive dialysis, initially haemodialysis (HD) 6-7 hours daily. If this is insufficient, patients may need 6-8 hours daily six times per week plus continuous daily peritoneal dialysis, or nocturnal dialysis 8-10 hours daily. Combined liver-kidney transplant (LKTx), preferably simultaneously, is the optimal treatment for patients on dialysis, and results in better graft survival compared to kidney-alone transplantation (KTx). Pre-emptive LTx normalizes oxalate production before advanced CKD, but short- and long-term complications must be considered. Although it restores renal function, isolated KTx does not address the underlying metabolic defect, though it may be an option when there is a full response to pyridoxine.

Professor Knauf concluded that the complications, fear of disease progression, and burdens of intensive monitoring and treatment can have a psychological and emotional impact on patients with PH1 and their family and caregivers and causes considerable medical and financial burdens for families. Fortunately, a therapeutic revolution is underway. Innovative drugs are being tested in clinical trials, with preliminary data showing impressive efficacy in reducing hepatic overproduction of oxalate.

RNAi Therapeutics: A new approach to managing primary hyperoxaluria

Daniel Fuster, Switzerland

Lumasiran (approved by the European medicines Agency in November 2020) and Nedosiran (still in clinical development) are two new PH treatments that use a new approach: RNA interference (RNAi). Professor Fuster explained that RNAi is a natural pathway regulating the level of gene production by interfering with messenger RNA (mRNA), which carries the instructions for making new protein. The process is post-transcriptional but pre-translational, so there is no change at the genome level, and it differs from other therapeutic approaches that generally target proteins.

The RNAi pathway can be exploited pharmaceutically by delivering small interfering RNAs (siRNAs) to cells to target and degrade specific mRNA in, for example, liver cells. Lumasiran is a subcutaneously delivered, double-stranded siRNAI, that inhibits glycolate oxidase (GO) production by targeting HAO1 RNA. Reducing hepatic GO levels lowers the levels of glyoxylate, so decreasing oxalate production.

The phase III, double-blind, placebo-controlled ILLUMINATE-A study included 39 adults and children aged  ≥ 6 years with PH1 and eGFR  ≥ 30 ml/min/1.732. Patients were randomized to either Lumasiran (3 mg/kg body weight) given once monthly for three doses, followed by maintenance doses given once every three months beginning one month after the last loading dose, or matching placebo. During the 54-month extension period, all patients received Lumasiran 3.0 mg every six months.

Professor Fuster reported that on the primary endpoint of percentage change in 24-hour UOx secretion from baseline, the least-squares mean difference (Lumasiran minus placebo) was -53.5 percentage points (p<0.001), with a reduction in the Lumasiran group of 65.4%, an effect seen as early as Month 1. Between-group differences for all tested secondary endpoints were also significant. The difference in the percent change in the POx level (Lumasiran minus placebo) was -39.5 percentage points (p<0.001). In the Lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at Month 6, compared with 0% of the placebo group (p<0.001).

At 6 months, nephrocalcinosis grade improved in 3 of 22 patients in the Lumasiran group as compared with 0 of 12 in the placebo group. Kidney stone event rates decreased during the treatment period in the Lumasiran arm, while remained stable in the placebo group.

All adverse events (AE) were mild or moderate, most commonly mild and transient injection site reactions. There was 1 discontinuation not drug related (fatigue and disturbance in attention), no adverse event leading to withdrawal from the trial, no clinically relevant changes in laboratory measures, vital signs or ECG, or deaths related to Lumasiran.

Based on the results ILLUMINATE A and B trials, Lumasiran has been granted European marketing authorization for the treatment of PH1 in all age groups. Nedosiran is the second RNAi agent in development. It targets mRNA encoding the enzyme LDH, the last step in hepatic oxalate production, and has the potential to treat PH2 and PH3 in addition to PH1. In the PHYOX1 phase 1 study, Nedosiran was well tolerated and associated with approximately reduction of 70% in UOx. Clinical trials PHYOX2 and PHYO3 are ongoing.

Further reading

Early diagnosis and diagnostic delay

Cochat P & Rumsby G. Primary hyperoxaluria. N Engl J Med 2013;369(7):649-58

Hopp K, et al. Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. J Am Soc Nephrol 2015;26(10):2559-70

Lieske JC, et al. International registry for primary hyperoxaluria. Am J Nephrol 2005;25(3):290-6

Cochat P, et al. Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant 2012;27(5):1729-36

Reducing oxalate: current treatment

Milliner DS, et al. Plasma oxalate and eGFR are correlated in primary hyperoxaluria patients with maintained kidney function-data from three placebo-controlled studies. Pediatr Nephrol 2021;36(7):1785-1793

Sas DJ, et al. Recent advances in the identification and management of inherited hyperoxalurias. Urolithiasis 2019;47(1):79–89

Lawrence JE & Wattenberg DJ. Primary Hyperoxaluria: The Patient and Caregiver Perspective. Clin J Am Soc Nephrol 2020;15(7):909–911

Metry EL, et al. Transplantation outcomes in patients with primary hyperoxaluria: a systematic review. Pediatr Nephrol 2021 Apr 8. Online ahead of print

A new approach: RNAi therapeutics

Liebow et al. An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria, J Am Soc Nephrol 2017;28(2):494-503

Garrelfs SF, et al. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1 N Engl J Med 2021;384(13):1216-1226