Clinical characterization of primary hyperoxaluria type 3 in comparison with types 1 and 2

Abstract

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 < 0.001) while urine calcium was highest in PH3 (112 versus 51 and 98 mg/day/1.73 m2 in PH1 and PH2, respectively, P < 0.001). Stone events per decade of life were similar across the age span and the three PH types. At 40 years of age, 97% of PH3 patients had not progressed to end-stage kidney disease compared with 36% PH1 and 66% PH2 patients. 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.

Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

“…7,9 More than one-third of patients with PH2 progress to kidney failure by age 40 years. 14 More than half of PH3 cases (50% to 89%) present with renal stones before age 5 years, 15,16 14% to 29% develop chronic renal disease, [16][17][18] and 3% to 4% develop kidney failure by age 40 years. 8,16 Novel therapeutic strategies focus on ribonucleic acid interference (RNAi) to decrease the levels of enzymes involved in the glyoxylate metabolic pathway and so reduce oxalate production.…”

“…14 More than half of PH3 cases (50% to 89%) present with renal stones before age 5 years, 15,16 14% to 29% develop chronic renal disease, [16][17][18] and 3% to 4% develop kidney failure by age 40 years. 8,16 Novel therapeutic strategies focus on ribonucleic acid interference (RNAi) to decrease the levels of enzymes involved in the glyoxylate metabolic pathway and so reduce oxalate production. One such RNAi therapeutic, lumasiran (Alnylam Pharmaceuticals, Inc.), depletes an enzyme (hydroxyacid oxidase 1) responsible for glyoxylate synthesis.…”

Primary hyperoxaluria in Italy: the past 30 years and the near future of a (not so) rare disease

“…PH type 2 (PH2) is caused by mutations in the gene glyoxylate reductase/hydroxypyruvate reductase ( GRHPR ), encoding the enzyme responsible for the reduction of glyoxylate to glycolate and hydroxypyruvate to D-glycerate. PH2 overall estimated frequency is 1:310,000 (carrier frequency 1:279) [ 3 ] and accounts for 10% of PH cases [ 13 ]. Most PH2-associated mutations produce an aberrant protein or affect catalytic activity [ 14 ].…”

“…HOGA1 is responsible for the conversion of 4-hydroxy-oxoglutarate to pyruvate and glyoxylate in mitochondria. PH3 accounts for 8–10% of PHs [ 13 ] and is characterized by recurrent nephrolithiasis, in some cases accompanied by hypercalciuria, that usually decreases with age [ 16 , 17 ]. Kidney function is preserved in most patients, although progressive impairment over decades is observed [ 13 ] and Martin-Higueras et al reported that 21.4% of patients had chronic kidney disease (CKD) stages 2 or higher [ 18 ].…”

“…PH3 accounts for 8–10% of PHs [ 13 ] and is characterized by recurrent nephrolithiasis, in some cases accompanied by hypercalciuria, that usually decreases with age [ 16 , 17 ]. Kidney function is preserved in most patients, although progressive impairment over decades is observed [ 13 ] and Martin-Higueras et al reported that 21.4% of patients had chronic kidney disease (CKD) stages 2 or higher [ 18 ]. PH3 overall estimated frequency is 1:135,000 (carrier frequency 1:185) [ 3 ].…”