Department of Nephrology, University Hospital Utrecht, Utrecht, The Netherlands
A 48-year-old man visited the urologist with a history of recurrent urolithiasis since childhood. The family history for urolithiasis was negative. At presentation he complained of loin pain and haematuria. Intravenous urography showed hydronephrosis and a concrement in the left ureter (Figure 1A and B). Furthermore, it demonstrated nephrocalcinosis, which had not been seen on urography 8 years ago (Figure 1C
). The obstruction was successfully treated with extracorporal wave lithotripsy. Nevertheless, renal function remained impaired (serum creatinine 280 µmol/l). The radiologist suggested a diagnosis of medullary sponge kidney and the patient was referred to our clinic. Calcium, phosphate, PTH and bicarbonate concentrations were all normal. Urine analysis demonstrated erythrocyturia, but no proteinuria. Urine pH was 5.0. Calcium excretion was low (<0.25 mmol/day) and uric acid excretion was normal (1.5 mmol/day). Abdominal ultrasound showed nephrocalcinosis but no signs of postrenal obstruction.
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This patient presented with a long term history of uro- and nephrolithiasis with development of nephrocalcinosis and finally a rapid deterioration of renal function.
In reviewing the X-rays the diagnosis of medullary sponge kidneys seemed unlikely as the abnormalities were not limited to the medullary pyramids. No specific cystic dilatations of the collecting ducts (`bunch of grapes') were seen and urography had been normal in 1990. Furthermore, medullary sponge kidneys are associated with hypercalciuria and impaired acidification of urine. These abonormalities were not found in our patient. The clinical course of medullary sponge kidneys is generally benign and does seldom lead to renal failure.
Analysis of the origin of his stone formation in earlier years showed no abnormalities, but urinary excretion of oxalate had not been measured. Oxalate excretion was markedly increased (4.5 mmol/day, normally <0.5 mmol/day) at the first presentation in our clinic. A diagnosis of hyperoxaluria was made.
Primary hyperoxaluria (PHO) is a rare metabolic disorder with autosomal recessive inheritance. Two different inborn errors of metabolism, leading to a defective conversion of glyoxalate, result in increased formation of oxalate. The normal metabolism of glyoxalate is demonstrated in Figure 2.
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In PHO type II (extremely rare) the conversion of glyoxalate to glycolate is disturbed because of deficient cytosolic D-glycerate dehydrogenase activity, resulting in hyperoxaluria and L-glyceric aciduria.
Clinical symptoms are similar in type I and type II PHO, although type II PHO usually has a milder course. The infantile form (<5 years of age) is characterized by massive parenchymal oxalosis with chronic renal insufficiency, but without renal calculi. The juvenile and most common variant occurs between 2 and 18 years. Our patient presented with a more indolent course and the less common adult form of hyperoxaluria. Patients present with recurrent calciumoxalate stones, often leading to obstruction, infection and renal damage. With declining glomerular filtration rate (GFR) the combination of oxalate retention and overproduction may lead to systemic oxalosis, resulting in digital gangrene, osteosclerosis, cardiac conduction defects and progressive renal failure.
The diagnosis is made by measurement of increased excretion of oxalate. Discrimination between type I and type II can be made by measurement of glycolic acid and L-glyceric acid in urine. However, this analysis is not reliable when GFR is seriously reduced (<10 ml/min). In that case measurement of plasma glycolic acid can be helpful. In our patient plasma glycolic acid was markedly elevated. A definitive diagnosis of PHO type I was confirmed by demonstration of AGT deficiency in liver biopsy. (In PHO type II the diagnosis can be confirmed by demonstration of deficient D-glycerate dehydrogenase activity in peripheral blood leucocytes). Discrimination between PHO type I and II is important because of different treatment strategies.
Treatment of PHO (both type I and type II) consists of the following general recommendations to minimize renal oxalate deposition before renal failure has occurred: (i) maintenance of a high urine output (>3 l/day), (ii) dietary restriction of high oxalate foods and (iii) prescription of crystallization inhibitors (orthophosphate, potassium citrate or magnesium oxide).
In PHO type I administration of high dose pyridoxine may be beneficial. Pyridoxine promotes the conversion of glyoxalate to glycine (Figure 2) by stimulating AGT. This treatment is most successful in symptomatic heterozygote patients.
As soon as renal failure has occurred the only beneficial treatment to prevent further systemic oxalosis in PHO type I is combined liverkidney transplantation. Kidney transplantation alone has a poor outcome (3-year survival of 30%). Dialysis treatment (both haemodialysis and peritoneal dialysis) is insufficient to remove oxalate, even with intensive daily dialysis. Until now, no specific therapy for PHO type II is known, but this form does rarely cause severe systemic oxalosis.
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