We investigated chronic renal failure (CRF) in 166 Iranian children (95 boys and 71 girls) from July 1991 to June 1999. The mean age at onset of CRF was 7.9+/-4.5 years. The most common cause of CRF was congenital urological malformations (78 cases). The second most common cause of CRF was hereditary nephropathy (21%). Glomerular diseases accounted for only 10% of children who later went on to develop renal failure. High rates of cystinosis and primary hyperoxaluria were seen, and these elevated rates could be due to a high prevalence of parental consanguinity. Eighty-six patients required renal replacement therapy, of whom the majority underwent hemodialysis. The prevalence of primary reflux as a cause of CRF was high compared with reports from western countries. Earlier diagnosis and management of urinary tract infections in this group could reduce the prevalence of reflux as a cause of CRF in this population.

Abstract. Hypercalciuria is the major risk factor promoting stone formation in Dent's disease, also known as X-linked recessive nephrolithiasis, but the effects of diuretics on calcium excretion and other stone risk factors in this disease are unknown. This study examined urine composition in eight male patients with Dent's disease, ages 6 to 49 yr, all of whom were hypercalciuric and had inactivating mutations of CLCN5. Eight males, ages 7 to 34 yr, with idiopathic hypercalciuria (IH) served as controls. Patients were instructed to maintain a consistent intake of sodium, potassium, calcium, and protein.Two consecutive 24-h urine collections were obtained after a baseline period and after 2 wk of chlorthalidone (25 mg), amiloride (5 mg), and the two diuretics in combination, with a week off drug separating the treatment periods in a randomized crossover design. Doses were reduced by half in boys under age 12 yr. Chlorthalidone alone (P Ͻ 0.002) and the combination of chlorthalidone and amiloride (P Ͻ 0.003) reduced calcium excretion significantly in either patient group. With chlorthalidone, calcium excretion fell to normal (Ͻ4.0 mg/kg per d) in all but one patient in each group. Amiloride alone had no significant effect on urinary calcium excretion, in either patient group. In patients with Dent's disease during chlorthalidone therapy, the supersaturation ratios for calcium oxalate and calcium phosphate fell by 25% and 35%, respectively. Mean citrate excretion was reduced by chlorthalidone (P Ͻ .04) and by chlorthalidone in combination with amiloride (P Ͻ .02). There were no significant differences in the responses to these diuretics between the patient groups in any of the urinary parameters. The intact hypocalciuric response to a thiazide diuretic indicates that inactivation of the ClC-5 chloride channel does not impair calcium transport in the distal convoluted tubule and indicates that thiazides should be useful in reducing the risk of kidney stone recurrence in patients with Dent's disease.

The molecular mechanisms associated with reestablishment of renal epithelial polarity after injury remain incompletely delineated. Stress proteins may act as molecular chaperones, potentially modulating injury or enhancing recovery. We tested whether overexpression of heat shock protein 70 (HSP70) would stabilize Na-K-ATPase attachment to the cytoskeleton, under conditions of ATP depletion, and whether a direct association existed between Na-K-ATPase and HSP70 in cultured renal epithelial cells. LLC-PK1 cells were transfected with a tagged HSP70 (70FLAG) or vector alone (VA). Detachment of Na-K-ATPase was detected in Triton soluble lysate after ATP depletion. 70FLAG cells demonstrated a significant (P < 0.01) decrease in detachment of Na-K-ATPase after either 2 or 4 h of ATP depletion. Interactions between HSP70 and Na-K-ATPase were determined by coimmunoprecipitation of 70FLAG and Na-K-ATPase, by direct and competitive binding assays and by immunocytochemical localization. Binding of HSP70 and Na-K-ATPase increased dramatically following injury. Interactions were: 1) reversible; 2) reciprocal to changes in the HSP70 binding protein clathrin; and 3) present only when ATP turnover was inhibited in cell lysate, an established characteristic of HSP binding. These studies indicate that 1) overexpression of HSP70 is associated with decreased detachment of Na-K-ATPase from the cytoskeleton following injury; 2) HSP70 binds to Na-K-ATPase; and 3) binding of HSP70 to Na-K-ATPase is dynamic and specific, increasing in response to injury and decreasing during recovery. Interaction between the molecular chaperone HSP70 and damaged or displaced Na-K-ATPase may represent a fundamental cellular mechanism underlying maintenance and recovery of renal tubule polarity following energy deprivation.

Over the past several decades, the pathophysiologic mechanisms by which renal tubule cells are injured have been the subject of intensive investigation. Although it is clear that a number of factors contribute to the susceptibility and the degree of injury, the interrelationship between metabolic alterations and structural changes has provided some important new insights. A clear example of the way in which differences in cellular metabolism can effect injury is demonstrated by contrasting the straight (S,) segment of the proximal tubule and the medullary thick ascending limb (mTAL). Because of a dependence on oxidative phosphorylation for energy in the adult animal, the S, segment is particularly susceptible to renal ischemia and those nephrotoxins that disrupt mitochondrial function and energy supply (1,2). Even brief periods of ischemia result in structural changes such as sloughing of the brush border, whereas prolonged ischemia produces irreversible changes in some cells and sublethal alterations such as swelling and mitochondrial condensation in others (2, 3). These changes take place rapidly and, with mild injury, repair and restitution of cellular structure is quickly accomplished. In contrast, the mTAL is much more susceptible to hypoxia, an observation that was first made in isolated perfused kidneys when a cellfree perfusate was being used (4). The unique susceptibility of this segment to hypoxia can be prevented when red blood cells or Hb is added to the perfusate, indicating the crucial importance of a threshold for oxygen delivery in the renal medulla (5). The mitochondrial swelling and nuclear pyknosis that is characteristic of the mTAL lesion can be modified by inhibiting transport in this scgment with agents such as furosemide or ouabain (4). In contrast, maneuvers that increase the workload in the mTAL segment have been shown to cause more severe structural damage with complete cellular disruption (4). The differential response of these two nephron segments is a clear demonstration of the intricate relationship between metabolic factors and the cellular targets for renal epithelial injury. This review will focus on ischemic acute renal failure, which has been extensively studied and represents a model system in which alterations in cellular metabolism and consequent changes in renal cell structure can be readily appreciated. Three interrelated aspects of ischemic injury to renal epithelial cells will be discussed: adenine nucleotide metabolism, cellular structure and integrity, and response of heat shock proteins. ADENINE NUCLEOTIDE METABOLISMIn 1968, Voight and Farber (6) documented that, within 5-10 min of complete occlusion of the renal artery, cellular ATP levels fell by 85-9076. With the application of in I~I J O nuclear magnetic resonance spectroscopy, it has been possible to further delineate alterations in adenine nucleotide metabolism that occur as a consequence of renal hypoperfusion or ischemia (7,8). Three phases of this relationship have been found to be of particular importance (F...

Ischemia and reperfusion damage mitochondrial structure and impair respiratory function. In this study, 45 min of renal ischemia followed by varying periods of reflow profoundly depressed the activity of several respiratory complexes in mitochondria isolated from rat kidneys. The respiratory complexes are composed of subunits encoded by both the nuclear and mitochondrial genomes. To determine the role of mitochondrial gene expression in recovery of respiratory function, expression of mitochondrial RNA was examined during reperfusion. Both mature and incompletely processed cytochrome b mRNA levels were depressed after 45 min of ischemia and 15 min of reflow; levels rebounded to above normal after 2 h of reflow and then declined over the next 22 h. Another mitochondrial RNA showed a similar pattern; in contrast, the levels of a nuclear-encoded subunit mRNA for a respiratory enzyme and of 28S rRNA were unchanged. These data demonstrate that renal ischemia followed by reperfusion alters mitochondrial RNA expression. We speculate that mitochondrial RNA turnover is increased in response to continuing injury and that recovery is accompanied by enhanced RNA synthesis.