Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit.

Congenital distal renal tubular acidosis (RTA) from mutations of the B1 subunit of V-ATPase is considered an autosomal recessive disease. We analyzed a distal RTA kindred with a truncation mutation of B1 (p.Phe468fsX487) previously shown to have failure of assembly into the V1 domain of V-ATPase. All heterozygous carriers in this kindred have normal plasma HCO3- concentrations and thus evaded the diagnosis of RTA. However, inappropriately high urine pH, hypocitraturia, and hypercalciuria were present either individually or in combination in the heterozygotes at baseline. Two of the heterozygotes studied also had inappropriate urinary acidification with acute ammonium chloride loading and an impaired urine-blood Pco2 gradient during bicarbonaturia, indicating the presence of a H+ gradient and flux defects. In normal human renal papillae, wild-type B1 is located primarily on the plasma membrane, but papilla from one of the heterozygote who had kidney stones but not nephrocalcinosis showed B1 in both the plasma membrane as well as diffuse intracellular staining. Titration of increasing amounts of the mutant B1 subunit did not exhibit negative dominance over the expression, cellular distribution, or H+ pump activity of wild-type B1 in mammalian human embryonic kidney-293 cells and in V-ATPase-deficient Saccharomyces cerevisiae. This is the first demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of a mutant B1 subunit that cannot be attributable to negative dominance. We propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency. B1 heterozygosity should be considered in patients with calcium nephrolithiasis and urinary abnormalities such as alkalinuria or hypocitraturia.

Metabolic basis for low urine pH in type 2 diabetes.

BACKGROUND AND OBJECTIVES: Type 2 diabetes is associated with excessively low urine pH, which increases the risk for uric acid nephrolithiasis. This study was conducted to assess the metabolic basis responsible for the excessive urinary acidity of individuals with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Nine non-stone-forming patients who had type 2 diabetes and low urine pH and 16 age- and body mass index-matched non-stone-forming volunteers without type 2 diabetes were maintained on a constant metabolic diet for 7 days, and 24-hour urine was collected on the last 2 days of the diet. RESULTS: Urine dietary markers (potassium, sulfate, phosphorus, and urea nitrogen) were not different between the two groups. Patients with type 2 diabetes exhibited a significantly lower 24-hour urine pH (5.45+/-0.27 versus 5.90+/-0.42; P<0.01) and higher net acid excretion (NAE; 57+/-12 versus 38+/-18 mEq/d; P<0.01) compared with control subjects. The proportion of NAE excreted as ammonium (NH4+/NAE) was significantly lower in patients with type 2 diabetes than in control subjects (0.70+/-0.12 versus 0.94+/-0.36; P<0.01); however, the greater NAE in patients with type 2 diabetes was not accounted for by the differences in unmeasured urinary anions. CONCLUSIONS: The overly acidic urine in patients with type 2 diabetes persists after controlling for dietary factors, body size, and age. The lower pH is due to a combination of greater NAE and lower use of ammonia buffers in patients with diabetes, which predisposes them to uric acid urolithiasis.

Low urine pH: a novel feature of the metabolic syndrome.

BACKGROUND AND OBJECTIVES: The metabolic syndrome is associated with alterations in renal function. An overly acidic urine has been described as a renal manifestation of the metabolic syndrome in patients with kidney stone disease. This study examined the association between the metabolic syndrome and urine pH in individuals without a history of nephrolithiasis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 148 adults who were free of kidney stones were evaluated in this outpatient cross-sectional study. Height, weight, BP, fasting blood, and 24-h urine chemistries were obtained. Urine pH was measured by pH electrode. The following features of the metabolic syndrome were evaluated: BP; body mass index; and serum triglyceride, glucose, and HDL cholesterol concentrations. The degree of insulin resistance was assessed by the homeostasis model assessment of insulin resistance. RESULTS: Participants with the metabolic syndrome had a significantly lower 24-h urine pH compared with participants without the metabolic syndrome. Mean 24-h urine pH, adjusted for age, gender, creatinine clearance, and 24-h urine sulfate, decreased from 6.15, 6.10, 5.99, 5.85, to 5.69 with increasing number of metabolic syndrome abnormalities. An association was observed between 24-h urine pH and each metabolic feature. After adjustment for age, gender, creatinine clearance, urine sulfate, and body mass index, a significant inverse relationship was noted between 24-h urine pH and the degree of insulin resistance. CONCLUSIONS: An unduly acidic urine is a feature of the metabolic syndrome and is associated with the degree of insulin resistance.

Uric acid nephrolithiasis.

Uric acid nephrolithiasis may be the final manifestation of various pathophysiological processes. Recent advances in renal urate transport have elucidated mechanisms by which hyperuricosuria occurs. However, in most uric acid stone formers the primary pathophysiologic defect is an excessively acidic urine pH rather than hyperuricosuria. Insulin resistance may contribute to the development of acidic urine by augmenting endogenous acid production and decreasing renal ammonium excretion. Medical management strategies focus primarily on alkali treatment or decreasing hyperuricosuria.

Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis.

Type 2 diabetes is a risk factor for nephrolithiasis in general and has been associated with uric acid stones in particular. The purpose of this study was to identify the metabolic features that place patients with type 2 diabetes at increased risk for uric acid nephrolithiasis. Three groups of individuals were recruited for this outpatient study: patients who have type 2 diabetes and are not stone formers (n = 24), patients who do not have diabetes and are uric acid stone formers (UASF; n = 8), and normal volunteers (NV; n = 59). Participants provided a fasting blood sample and a single 24-h urine collection for stone risk analysis. Twenty-four-hour urine volume and total uric acid did not differ among the three groups. Patients with type 2 diabetes and UASF had lower 24-h urine pH than NV. Urine pH inversely correlated with both body weight and 24-h urine sulfate in all groups. Urine pH remained significantly lower in patients with type 2 diabetes and UASF than NV after adjustment for weight and urine sulfate (P < 0.01). For a given urine sulfate, urine net acid excretion tended to be higher in patients with type 2 diabetes versus NV. With increasing urine sulfate, NV and patients with type 2 diabetes had a similar rise in urine ammonium, whereas in UASF, ammonium excretion remained unchanged. The main risk factor for uric acid nephrolithiasis in patients with type 2 diabetes is a low urine pH. Higher body mass and increased acid intake can contribute to but cannot entirely account for the lower urine pH in patients with type 2 diabetes.

Nephrolithiasis in children.

A metabolic etiology is the most common cause for pediatric kidney stones. Appropriate evaluation of affected children should include assessment of stone type, if available, and assessment of predisposing factors in all cases. This review discusses the metabolic disorders that lead to nephrolithiasis with respect to the development of calcium, uric acid, struvite, and cystine stones. Environmental and hereditary factors are summarized to provide a guide in the evaluation of pediatric stone formers.

Minimal change disease with acute renal failure: a case against the nephrosarca hypothesis.

An unusual but well-documented presentation of minimal change disease is nephrotic proteinuria and acute renal failure. One pathophysiological mechanism proposed to explain this syndrome is nephrosarca, or severe oedema of the kidney. We describe a patient with minimal change disease who presented with heavy proteinuria and acute renal failure but had no evidence of renal interstitial oedema on biopsy. Aggressive fluid removal did not reverse the acute renal failure. Renal function slowly returned concomitant with resolution of the nephrotic syndrome following corticosteroid therapy. The time profile of the clinical events is not compatible with the nephrosarca hypothesis and suggests an alternative pathophysiological model for the diminished glomerular filtration rate seen in some cases of minimal change disease.

Novel insights into the pathogenesis of uric acid nephrolithiasis.

PURPOSE OF REVIEW: The factors involved in the pathogenesis of uric acid nephrolithiasis are well known. A low urinary pH is the most significant element in the generation of stones, with hyperuricosuria being a less common finding. The underlying mechanism(s) responsible for these disturbances remain poorly characterized. This review summarizes previous knowledge and highlights some recent developments in the pathophysiology of low urine pH and hyperuricosuria. RECENT FINDINGS: Epidemiological and metabolic studies have indicated an association between uric acid nephrolithiasis and insulin resistance. Some potential mechanisms include impaired ammoniagenesis caused by resistance to insulin action in the renal proximal tubule, or substrate competition by free fatty acids. The evaluation of a large Sicilian kindred recently revealed a putative genetic locus linked to uric acid stone disease. The identification of novel complementary DNA has provided an interesting insight into the renal handling of uric acid, including one genetic cause of renal uric acid wasting. SUMMARY: The recognition of metabolic, molecular, and genetic factors that influence urinary pH, and uric acid metabolism and excretion, will provide novel insights into the pathogenesis of uric acid stones, and open the way for new therapeutic strategies.

Recurrent calcium nephrolithiasis associated with primary aldosteronism.

Typical manifestations of hyperaldosteronism include salt retention, hypokalemia, and metabolic alkalosis. However, a consequence infrequently recognized and described is hypocitraturia. In combination with hypercalciuria, aldosterone-induced hypocitraturia can trigger calcium nephrolithiasis. The authors report a case of an individual with primary hyperaldosteronism from an adrenal adenoma that resulted in hypocitraturia. The patient had severe recurrent renal calcium calculi that corrected with adrenalectomy. The clinical physiology of renal calcium and citrate handling in hyperaldosteronism is reviewed.