PH is a genetic disorder of oxalate metabolism. There is accumulation of oxalate initially in the kidneys and subsequently in bones, heart, eyes, and other tissues. This disease where there is systemic accumulation of oxalate is called as OXALOSIS.
The enzyme glycolate oxidase is needed to convert glycolate to glyoxalate and then to oxalate. Glyoxalate is acted upon by Alanine Glyoxalate aminoTransferase (AGT) to glycine in the liver. When AGT is going to be deficient, all the glycolate gets converted to oxalate.
Figure 1 : Oxalate metabolism
Increase in oxalate levels could result in formation of renal stones. In aggressive disease states, children start manifesting recurrent renal stone formation and develop nephrocalcinosis and renal failure. In less severe forms, the disease manifestations could be later. Since there is no enzyme that can metabolise oxalate, it has to be excreted through the kidneys. And if the filtered oxalate load is going to be higher, then it starts forming renal stones and later gets accumulated in renal parenchyma, causing renal failure and systemic deposition.
Figure 2 : renal biopsy in 4 month old child with oxalate deposition.
Figure 3 – oxalate deposition in the retina.
Figure 4 – oxalate deposition in bones.
Till recently, there is no treatment available, but for liver transplantation towards replenishing the enzyme defect followed by renal transplantation. Recently, there is lumasiran – double- stranded small interfering RiboNucleic Acid (siRNA) that reduces the levels of the enzyme glycolate oxidase by targeting the HAO1 messenger RNA in hepatocytes through RNA interface. This decreases the production of glyoxalate that is a precursor of oxalate formation.
Illuminate -A and B trials tested the effect of lumasiran and proved that it reduces the urinary excretion of oxalate compared to placebo significantly, and it got approved by the USFDA, This drug is administered at 3 to 6 mg /kg initially for 3 consecutive months and at once in 3 months as a maintenance dose. This drug may not be useful once renal failure and systemic oxalosis has developed. Lumasiran is an excellent drug that will decrease the need for liver and renal transplantation.
Dr. Balasubramaniam Raju Chief Nephrologist Kauvery Hospital
