Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0392525 (nephrolithiasis)
 2,669 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although gout and hyperuricaemia are usually thought of as conditions of indulgent male middle age, in addition to the well-known uricosuria of the newborn, there is much of importance for the paediatric nephrologist in this field. Children and infants may present chronically with stones or acutely with renal failure from crystal nephropathy, as a result of inherited deficiencies of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or of the catabolic enzyme xanthine dehydrogenase (XDH). Genetic purine overproduction in phosphoribosylpyrophosphate synthetase superactivity, or secondary to glycogen storage disease, can also present in infancy with renal complications. Children with APRT deficiency may be difficult to distinguish from those with HPRT deficiency because the insoluble product excreted, 2,8-dihydroxyadenine (2,8-DHA), is chemically very similar to uric acid. Moreover, because of the high uric acid clearance prior to puberty, hyperuricosuria rather than hyperuricaemia may provide the only clue to purine overproduction in childhood. Hyperuricaemic renal failure may be seen also in treated childhood leukaemia and lymphoma, and iatrogenic xanthine nephropathy is a potential complication of allopurinol therapy in these conditions. The latter is also an under-recognised complication of treatment in the Lesch-Nyhan syndrome or partial HPRT deficiency. The possibility of renal complications in these three situations is enhanced by infection, the use of uricosuric antibiotics and dehydration consequent upon fever, vomiting or diarrhoea. Disorders of urate transport in the renal tubule may also present in childhood. A kindred with X-linked hereditary nephrolithiasis, renal urate wasting and renal failure has been identified, but in general, the various rare types of net tubular wasting of urate into the urine are recessive and relatively benign, being found incidentally or presenting as colic from crystalluria. However, the opposite condition of a dominantly inherited increase in net urate reabsorption is far from benign, presenting as familial renal failure, with hyperuricaemia either preceding renal dysfunction or disproportionate to it. Paediatricians need to be aware of the lower plasma urate concentrations in children compared with adults when assessing plasma urate concentrations in childhood and infancy, so that early hyperuricosuria is not missed. This is of importance because most of the conditions mentioned above can be treated successfully using carefully controlled doses of allopurinol or means to render urate more soluble in the urine. Xanthine and 2,8-DHA are extremely insoluble at any pH. Whilst 2,8-DHA formation can also be controlled by allopurinol, alkali is contraindicated. A high fluid, low purine intake is the only possible therapy for XDH deficiency.
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PMID:Gout, uric acid and purine metabolism in paediatric nephrology. 843 71

In humans, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency can manifest as nephrolithiasis, interstitial nephritis, and chronic renal failure. APRT catalyzes synthesis of AMP from adenine and 5-phosphoribosyl-1-pyrophosphate. In the absence of APRT, 2,8-dihydroxyadenine (DHA) is produced from adenine by xanthine dehydrogenase (XDH) and can precipitate in the renal interstitium, resulting in kidney disease. Treatment with allopurinol controls formation of DHA stones by inhibiting XDH activity. Kidney disease in APRT-deficient mice resembles that seen in humans. By age 12 wk, APRT-deficient male mice are, on average, mildly anemic and smaller than normal males. They have extensive renal interstitial damage (assessed by image analysis) and elevated blood urea nitrogen (BUN), and their creatinine clearance rates, which measure excretion of infused creatinine as an estimate of glomerular filtration rate (GFR), are about half that of wild-type males. APRT-deficient males treated with allopurinol in the drinking water had normal BUN and less extensive visible renal damage, but creatinine clearance remained low. Throughout their lifespans, homozygous null female mice manifested significantly less renal damage than homozygous null males of the same age. APRT-deficient females showed no significant impairment of GFR at age 12 wk. Consequences of APRT deficiency in male mice are more pronounced than in females, possibly due to differences in rates of adenine or DHA synthesis or to sex-determined responses of the kidneys.
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PMID:Chronic renal failure in a mouse model of human adenine phosphoribosyltransferase deficiency. 968 17

Adenine phosphoribosyltransferase (APRT) deficiency is an autosomal recessive purine enzyme defect that results in the inability to utilize adenine, which consequently is oxidized by xanthine dehydrogenase to 2,8-dihydroxyadenine (2,8-DHA), an extremely insoluble substance eventually leading to crystalluria, nephrolithiasis, and kidney injury. We describe a case of APRT deficiency not diagnosed until the evaluation of a poorly functioning kidney transplant in a 67-year-old white woman. After the transplant, there was delayed transplant function, urine specimens showed crystals with unusual appearance, and the transplant biopsy specimen showed intratubular obstruction by crystals identified as 2,8-DHA using infrared spectroscopy. APRT enzymatic activity was undetectable in red blood cell lysates, and analysis of the APRT gene showed 1 heterozygous sequence variant, a duplication of T at position 1832. The patient was treated with allopurinol, 300 mg/d, and transplant function progressively normalized. Because patients with undiagnosed APRT deficiency who undergo kidney transplant may risk losing the transplant because of an otherwise treatable disease, increased physician awareness may hasten the diagnosis and limit the morbidity associated with this disease.
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PMID:Decreased kidney function and crystal deposition in the tubules after kidney transplant. 2030 34

Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive disorder of uric acid metabolism that leads to formation and excretion of 2,8-dihydroxyadenine into urine. The low solubility of 2,8-dihydroxyadenine results in precipitation and formation of urinary crystals and renal stones. Patients with this disorder usually have recurrent nephrolithiasis and can develop nephropathy secondary to crystal precipitation in the renal parenchyma. The disease is most often underdiagnosed and can recur in renal transplant, causing graft failure. Lack of specific clinical manifestations, chemical and radiologic features identical to those shown with uric acid stones, and lack of awareness among clinicians are among the causes for the underdiagnoses of this treatable disease. Allopurinol, a xanthine dehydrogenase inhibitor, is the mainstay of treatment, supported by high fluid intake and dietary modifications. The possibility of adenine phosphoribosyl transferase deficiency should be considered in all cases of urolithiasis in children, patients with recurrent urolithiasis, and patients with urolithiasis associated with renal failure of unknown cause, including patients with end-stage renal disease and renal transplant recipients. Here, we report a case of a 41-year-old female patient who had a late diagnosis of 2,8-dihydroxyadenine nephropathy-induced end-stage renal disease, made on the native nephrectomy that accompanied the renal transplant, and who had a timely intervention that prevented recurrence in the graft.
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PMID:2,8-Dihydroxyadenine Nephropathy Identified as Cause of End-Stage Renal Disease After Renal Transplant. 2744 13

In recent years, the role of trace elements in lithogenesis has received steadily increasing attention. It is well documented that some trace elements can influence the morphology and speed of the crystallization process. Zinc has been found in significant amounts in calcium stones relative or organic stones (uric acid and cystine), probably substituting calcium in crystals because of their similarity in charge and size. High Zn levels are present in carbapatite of Randal's plaques suggesting that zinc could promote calcium phosphate deposition in the medullar interstitium. Large-scale epidemiological studies have found an association of increased dietary zinc intake with increased risk of nephrolithiasis in adults but not in adolescents. Most studies examining urinary zinc levels in adults have reported increased urinary Zn excretion in stone formers. In an experimental model of organic crystal formation produced by silencing xanthine dehydrogenase in Drosophila fly, maneuvers that reduce Zn excretion have shown to reduce crystal formation in the lumen of the Malpighian tubules. This is curious because this is not a model of calcium stone formation. Finally, zinc supplementation has been associated with increased admissions for urinary lithiasis in men, but no change in calcium stone formation in children. Perhaps, some of these contradicting findings can be explained in part by the in vitro effect of zinc on the type and amount of calcium phosphate formed: At low concentrations, Zn inhibited the crystal growth of dicalcium phosphate dihydrate, octacalcium phosphate, and apatite, and at higher concentrations, it promoted the formation of amorphous calcium phosphate. Thus, further studies are needed to see whether manipulation of Zn metabolism can inhibit calcium stone formation.
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PMID:The role of zinc in urinary stone disease. 2934 80

Nephrolithiasis has been reported in several aquatic mammals including bottlenose dolphins (Tursiops truncatus), small clawed otters (Amblonyx cinereus), European river otters (Lutra lutra), North American river otters (Lontra canadensis), northern elephant seals (Mirounga angustirostris), Florida manatees (Trichechus manatus latirostris), and California sea lions (Zalophus californianus). Compositions of calculi in previous cases were predominantly calcium oxalate or ammonium acid urate. Xanthine urolithiasis is rare in veterinary medicine. Primary cases (without exposure to xanthine dehydrogenase inhibitors) occur as a consequence of hereditary xanthinuria, although the causal mutation has only been discovered in a subset of cases. Five captive juvenile giant otters (Pteronura brasiliensis) from two facilities were diagnosed with nephrolithiasis: three siblings from one set of parents and two siblings from another pair. Serum analyte assays revealed renal compromise in affected individuals. Computed tomography (CT) confirmed the presence of nephrolithiasis in one individual. Postmortem evaluation identified extensive bilateral nephrolithiasis on gross necropsy in four of five cases. Calculus analyses identified 100% xanthine composition. Histologic examination revealed marked nephrolithiasis with associated tubular necrosis and gastric mineralization. Nutrient composition of the diet including mineral and purine content was assessed. No association between diet and nephroliths was found in this study. This is the first report of xanthine nephrolithiasis in aquatic mammals. The potential role of diet and genetics in xanthine nephrolithiasis in the small inbred population of giant otters under human care needs further investigation to assess the implications of this disease process for the long-term captive management of this species.
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PMID:XANTHINE NEPHROLITHIASIS IN JUVENILE CAPTIVE GIANT OTTERS (PTERONURA BRASILIENSIS). 3192 28