Primary Hyperoxaluria Type 1

Marion B Coulter-Mackie, PhD, Colin T White, MD, Dirk Lange, PhD, and Ben H Chew, MD, MSc, FRCSC.

Summary

Clinical characteristics.

Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium salts that accumulate in the kidney and other organs. Individuals with PH1 are at risk for recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis/urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), or end-stage renal disease (ESRD) with a history of renal stones or calcinosis. Age at onset of symptoms typically ranges from one to 25 years. Approximately 19% of affected individuals present before age four to six months with severe disease, often associated with failure to thrive, nephrocalcinosis, anemia, and metabolic acidosis. Approximately 54% of affected individuals present in late childhood or early adolescence, usually with symptomatic nephrolithiasis. The remainder of affected individuals present in adulthood with recurrent renal stones. The natural history of untreated PH1 is one of inexorable decline in renal function as a result of progressive nephrolithiasis/nephrocalcinosis, with eventual progression to oxalosis (widespread tissue deposition of calcium oxalate) and death from ESRD.

Diagnosis/testing.

The diagnosis of PH1 is suspected in an individual with an elevated oxalate to creatinine ratio in urine and an elevated plasma oxalate concentration. The diagnosis can be confirmed by detection of biallelic pathogenic variants in AGXT on molecular genetic testing. Failure to detect at least one common, known, or otherwise provenAGXT pathogenic variant requires consideration of liver biopsy to assay the activity of the enzyme alanine:glyoxylate-aminotransferase (AGT).

Management.

Treatment of manifestations: Reduction of calcium oxalate supersaturation and oxalate biosynthesis; organ transplantation as either preemptive liver transplantation or combined liver/kidney transplantation. For kidney stones: consider shockwave lithotripsy, percutaneous nephrolithotomy, or ureteroscopy.

Prevention of primary manifestations: Maintenance of high fluid intake; pyridoxine supplements for those who are pyridoxine responsive; use of potassium or sodium citrate, pyrophosphate-containing solutions, or thiazides to minimize stone formation.

Surveillance: Regular renal ultrasound and fundoscopic eye examinations; ongoing urinalysis; regular measurement of glomerular filtration rate (GFR). Additionally:

In those with reduced GFR: regular measurement of plasma oxalate.

In patients with greatly reduced GFR or rapid deterioration in function: multi-system testing prior to initiation of dialysis

Agents/circumstances to avoid: Dehydration; foods high in oxalate (e.g., chocolate, rhubarb, and starfruit); megadoses of vitamins C and D; loop diuretics.

Evaluation of relatives at risk: Early diagnosis of at-risk relatives enables early institution of treatment and preventive measures.

Genetic counseling.

PH1 is inherited in an autosomal recessive manner. At conception, each sib of a proband with PH1 has a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants have been identified in a family. Assay of AGT enzymatic activity prenatally is not generally offered because it requires a fetal liver biopsy.

http://www.ncbi.nlm.nih.gov/books/NBK1283/

I have had an experience with a young boy whose parents were cousin. I obtained some response with high dose piridoxine. I found oxalate crystal in the bone marrow also . The renal transplant unfortunately was uneventful,

I have a pt.who had ESRD ,then renal transplant done which failed then resume HD

TRACP 5b als ein alternativer Marker für Schwere und Fortschreiten der Erkrankung an primärer Hyperoxalurie Typ 1

K.-O. Stenger1, M. Sterneck2 und A. Kromminga3,4,5

1Hamburg (vormals Phv-Dialyse Sinstorf, Hamburg), 2Transplantations-Zentrum, Universitätskrankenhaus Eppendorf, Hamburg, 3Labor Lademannbogen, Hamburg, 4IPM Biotech GmbH, Hamburg, 5Institut für Immunforschung, Universität Kiel

Nieren- und Hochdruckkrankheiten, Jahrgang 43, Nr. 5/2014, S. 217–228

Aim / Background. Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by alanine:glyoxylate-aminotransferase (AGT) deficiency in the liver. In the absence of AGT activity, calcium oxalate accumulates in tissues, ultimately causing a decline in renal function. Although plasma oxalate levels are easily monitored, they do not always accurately reflect disease severity and progression. Therefore, there is a need to explain the hypercalcemia in advanced disease and to develop a method to accurately estimate total body burden of oxalate.

Materials / Methods. We studied two adult hemodialysis patients homozygous for AGT mutations and confirmed their PH1 status by enzymological and molecular analysis. We collected histological and biochemical data, including oxalate and tartrate-resistant acid phosphatase 5b (TRACP 5b) levels.

Results. An unusual elevation of TRACP 5b in the male patient before he underwent combined liver and kidney transplantation (CLKT) was observed. The activity of macrophages and giant cells was compared in bone histology of both patients. In the female patient, a parallel decline in TRACP 5b activity and plasma oxalate concentration was observed following CLKT for more than 8 years.

Conclusions. The correlation to the enhanced activity of macrophages and giant cells surrounding calcium oxalate crystals in the bone marrow space may have clinical implications. We propose the measurement of TRACP 5b activity as a marker of oxalate burden in adult PH1 patients.

No, I haven`t.