Kidney Stones in the Pediatric Patient

Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.

Low-carbohydrate high-protein (LCHP) diets are used commonly for weight reduction. This study explores the relationship between such diets and acid-base balance, kidney-stone risk, and calcium and bone metabolism. Ten healthy subjects participated in a metabolic study. Subjects initially consumed their usual non-weight-reducing diet, then a severely carbohydrate-restricted induction diet for 2 weeks, followed by a moderately carbohydrate-restricted maintenance diet for 4 weeks. Urine pH decreased from 6.09 (Usual) to 5.56 (Induction; P < 0.01) to 5.67 (Maintenance;P < 0.05). Net acid excretion increased by 56 mEq/d (Induction; P < 0.001) and 51 mEq/d (Maintenance; P < 0.001) from a baseline of 61 mEq/d. Urinary citrate levels decreased from 763 mg/d (3.98 mmol/d) to 449 mg/d (2.34 mmol/d; P < 0.01) to 581 mg/d (3.03 mmol/d; P < 0.05). Urinary saturation of undissociated uric acid increased more than twofold. Urinary calcium levels increased from 160 mg/d (3.99 mmol/d) to 258 mg/d (6.44 mmol/d; P < 0.001) to 248 mg/d (6.19 mmol/d; P < 0.01). This increase in urinary calcium levels was not compensated by a commensurate increase in fractional intestinal calcium absorption. Therefore, estimated calcium balance decreased by 130 mg/d (3.24 mmol/d; P < 0.001) and 90 mg/d (2.25 mmol/d; P < 0.05). Urinary deoxypyridinoline and N-telopeptide levels trended upward, whereas serum osteocalcin concentrations decreased significantly (P < 0.01). Consumption of an LCHP diet for 6 weeks delivers a marked acid load to the kidney, increases the risk for stone formation, decreases estimated calcium balance, and may increase the risk for bone loss. Copyright 2002 by the National Kidney Foundation, Inc.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.