Urinary Titratable Acid Research Articles

The Effects of Acid on Calcium and Phosphate Metabolism.

A variety of changes in mineral metabolism aiming to restore acid-base balance occur in acid loading and metabolic acidosis. Phosphate plays a key role in defense against metabolic acidosis, both as an intracellular and extracellular buffer, as well as in the renal excretion of excess acid in the form of urinary titratable acid. The skeleton acts as an extracellular buffer in states of metabolic acidosis, as the bone matrix demineralizes, leading to bone apatite dissolution and the release of phosphate, calcium, carbonate, and citrate into the circulation. The renal handling of calcium, phosphate and citrate is also affected, with resultant hypercalciuria, hyperphosphaturia and hypocitraturia.

Association between obstructive sleep apnea and 24-h urine chemistry risk factors for urinary stone disease

The effect of obstructive sleep apnea (OSA) on 24-h urine parameters and resultant kidney stone risk is unknown. We sought to compare urinary lithogenic risk factors among patients with kidney stone disease with and without OSA. We performed a retrospective cohort study of adult patients with nephrolithiasis undergoing both polysomnography and 24-h urine analysis. Measures of acid load including gastrointestinal alkali absorption, urinary titratable acid, and net acid excretion were calculated from 24-h urine. We performed univariable comparisons of 24-h urine parameters between those with and without OSA and fit a multivariable linear regression model adjusting for age, sex, and BMI. Overall, there were 127 patients who underwent both polysomnography and a 24-h urine analysis from 2006 to 2018. There were 109 (86%) patients with OSA and 18 (14%) without. Patients with OSA were more commonly male, had greater BMI and had higher rates of hypertension. Patients with OSA had significantly higher levels of 24-h urinary oxalate, uric acid, sodium, potassium, phosphorous, chloride, and sulfate; higher supersaturation of uric acid; higher titratable acid, and net acid excretion; and lower urinary pH and supersaturation of calcium phosphate (p < 0.05). The difference in urinary pH and titratable acid, but not net acid excretion, remained significant when adjusting for BMI, age, and gender (both p = 0.02). OSA is associated with changes in urinary analytes that promote kidney stone formation, similar to those observed with obesity. After accounting for BMI, OSA is independently associated with lower urine pH and increased urinary titratable acid.

Anti-carbonic anhydrase II antibody reflects urinary acidification defect especially in proximal renal tubules in patients with primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is a systemic autoimmue disease featured by excessive autoantibody production. It has been demonstrated that anti-carbonic anhydrase II (anti-CA II) antibody is correlated with renal tubular acidosis in pSS; however, no further details about urinary acidification defect have been reported, and the antibody's relationship with other organ impairments remains unknown. This case-control study aimed to examine anti-CA II antibody levels in relation to various systemic complications in pSS, and evaluate its potential role as a organ-specific biomarker in a Chinese cohort. Serum anti-CA II antibody levels were determined using ELISA in 123 patients with pSS and 72 healthy controls. The medical records of the patients were collected, and the correlation between serum anti-CA II antibody and clinical/immunological parameters was investigated. Serum anti-CA II antibody level and its positive rate were significantly increased in pSS patients compared with controls, and ANA-positive patients presented even higher titers of the antibody. In anti-CA II positive group, remarkably higher urine pH and bicarbonate, as well as lower urine titratable acid and serum potassium were observed, which indicated renal tubular acidification dysfunction both involving bicarbonate reabsorption and acid secretion. In addition, platelet count and complement 3, complement 4 levels decreased, whereas serum IgG, IgA and γ-globulin levels increased notably in accord with a higher EULAR SS disease activity index score in these patients. Further analysis showed that anti-CA II antibody was most elevated in patients with defect in bicarbonate reabsorption, reflecting proximal renal tubular injury, rather than in patients with distal renal tubular acidosis as previously reported. In conclusion, anti-CA II antibody reflects renal (especially proximal renal tubular) and hematologic impairment as well as increased disease activity in pSS. It may act as a serum biomarker of systemic damage of pSS.

Increasing Vegetable Intake Decreases Urinary Acidity and Bone Resorption Marker in Overweight and Obese Adults: An 8-Week Randomized Controlled Trial

BackgroundControlled intervention trials are needed to confirm a positive association from epidemiological studies between vegetable consumption and bone health. ObjectiveWe investigated whether providing vegetables at the Dietary Guidelines for Americans (DGA) recommended amount affects excretion of acid and calcium in urine and bone turnover markers in serum in adults with low vegetable intake. MethodsIn total, 102 adults (19 males and 83 females, age 18–65 y, BMI ≥25 kg/m2) consuming ≤1 serving of vegetables (128 g raw leafy or 64 g cooked vegetables) per d were recruited in a 2-arm, parallel, randomized, controlled, and community-based 8-wk feeding intervention trial. The 2 arms included a vegetable intervention (VI) during which participants received extra vegetables (∼270 g/d) and an attention control (CON) group that conducted only the testing visits. Measurements included nutrient intake, plasma carotenoids, and bone-related markers in serum and urine. Differences between CON and VI at week 8 were tested using the ANCOVA with baseline values as a covariate. ResultsCompared with CON, carotenoid intake (mean ± SD) was higher (6.4 ± 3.4 compared with 2.0 ± 1.2 mg/d) (P < 0.01) and dietary potential renal acid load was lower (20 ± 13 compared with 3.4 ± 14 mEq/d) (P < 0.01) in VI. Compared with CON at week 8, urine titratable acid and Mg were 24 and 26% lower, respectively, while urine pH was 3% greater (P < 0.05) and serum C-terminal telopeptide of type I collagen (CTX) was 19% lower in VI. There were no group differences in serum concentrations of propeptide of type 1 procollagen and tartrate-resistant acid phosphatase or urinary excretion of deoxypyridinoline and CTX. ConclusionsConsumption of vegetables at the DGA-recommended amount by adults with low vegetable intake potentially benefits bone health. This trial was registered at http://clinicaltrials.gov as NCT02585102.

Value of monitoring urine ammonia at time of biopsy in patients with lupus nephritis

ObjectiveAlthough lupus nephritis (LN) is mostly characterized by glomerular involvement, tubular injury is indispensable in its pathogenesis and progression. The purpose of this study is to examine associations between urinary acidification function and clinical and pathological features in LN.MethodsA total of 103 patients with renal biopsy-proven LN were included, and clinical parameters and laboratory data were obtained from the medical records. Plasma samples, 24-h urine samples and the urinary acidification function, including urine pH, titratable acid, and ammonia, were collected within 3 days before the day of renal biopsy. The correlations between defects of acid excretion and clinical and pathological features were then assessed. Logistic regression analysis was used to assess factors associated with the presence of nephrotic range proteinuria.ResultsThe urine ammonia level was inversely correlated with SLEDAI-2 K scores, rSLEDAI scores, serum creatinine levels and proteinuria, while it was positively correlated with eGFR. And urine titratable acid was only inversely correlated with rSLEDAI scores and proteinuria. Moreover, urine ammonia had significant negative correlations with AI scores, interstitial inflammatory cell infiltration, CI scores, glomerular sclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis. And urine titratable acid was mainly inversely correlated with CI scores. Furthermore, univariate logistic analyses identified that both urine titratable acid and ammonia were correlated with the presence of nephrotic range proteinuria. After the adjustment for chronicity index and eGFR in a multivariate logistic analysis, only urine titratable acid was still identified as an independent risk factor for the occurrence of nephrotic range proteinuria.ConclusionsUrine ammonia was associated with clinical and pathological features of chronicity and tubulointerstitial disease activity among patients with lupus nephritis. Furthermore, the strong association between urinary protein and titratable acid excretion at the time of kidney biopsy is significant even after adjusting for the chronicity index and eGFR at biopsy.

Increasing Consumption of Vegetables Decreases Acid Excretion and Bone Turnover Among Adults with Overweight and Obesity: An 8-Wk Randomized Controlled Trial

Abstract Objectives To investigate the extent to which increased vegetable consumption affects urinary acid excretion and serum bone markers. Epidemiological studies suggest vegetable intake is positively associated with bone health through several mechanisms such as reducing oxidative stress and inflammation or diet-induced metabolic acidosis. We hypothesized that increasing intake of vegetables to the amounts and types recommended by the Dietary Guidelines for Americans (DGA) is beneficial to bone health by suppressing bone turnover. Methods One-hundred and ten adults with overweight or obesity were recruited in a two-arm, parallel-designed, randomized controlled community-based 8-wk feeding intervention trial. The two arms included (1) attention control arm, and (2) active intervention arm during which participants received a variety of pre-packaged, minimally prepared fresh or frozen vegetables. Blood and urine samples were collected. One hundred-two participants completed the study. Results At baseline, there were no differences in urine pH (6.17 ± 0.42 vs 6.18 ± 0.41), urine titratable acid (21.0 ± 7.3 vs 20.7 ± 9.0 mEq/d), urine ammonia (324 ± 197 vs 348 ± 175 mg/d), serum N-terminal propeptide of type I procollagen (PINP, a bone formation marker, 27.8 ± 8.9 vs 26.3 ± 10.5 ng/ml), serum C-terminal telopeptide of type I collagen (CTX, a bone resorption marker, 0.36 ± 0.18 vs 0.34 ± 0.15 ng/ml), between the control and the intervention groups, respectively. There were no differences in the above parameters between the baseline and at the end of 8-wk for the control group. Compared to the baseline, increased intake of vegetables increased urine pH (6.33, P &amp;lt; 0.05) and serum PINP (29.7 ± 13.6 ng/ml, P &amp;lt; 0.05), and decreased urine titratable acid (17.0 ± 9.4 mEq/d, P &amp;lt; 0.05), urine ammonia (279 ± 151 mg/d, P &amp;lt; 0.05), and serum CTX (0.29 ± 0.11 ng/ml, P &amp;lt; 0.01). Conclusions These data demonstrate that increased vegetable consumption of the types and amounts recommended by the DGA decreases urinary acidity and has positive effects on bone turnover markers. Funding Sources This work was supported by the Agricultural Research Service of the United States Department of Agriculture, #3062–51,000-053–00D.

Sodium Bicarbonate Supplementation and Urinary TGF-β1 in Nonacidotic Diabetic Kidney Disease: A Randomized, Controlled Trial.

In early-phase studies of individuals with hypertensive CKD and normal serum total CO2, sodium bicarbonate reduced urinary TGF-β1 levels and preserved kidney function. The effect of sodium bicarbonate on kidney fibrosis and injury markers in individuals with diabetic kidney disease and normal serum total CO2 is unknown. We conducted a randomized, double-blinded, placebo-controlled study in 74 United States veterans with type 1 or 2 diabetes mellitus, eGFR of 15-89 ml/min per 1.73 m2, urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, and serum total CO2 of 22-28 meq/L. Participants received oral sodium bicarbonate (0.5 meq/kg lean body wt per day; n=35) or placebo (n=39) for 6 months. The primary outcome was change in urinary TGF-β1-to-creatinine from baseline to months 3 and 6. Secondary outcomes included changes in urinary kidney injury molecule-1 (KIM-1)-to-creatinine, fibronectin-to-creatinine, neutrophil gelatinase-associated lipocalin (NGAL)-to-creatinine, and UACR from baseline to months 3 and 6. Key baseline characteristics were age 72±8 years, eGFR of 51±18 ml/min per 1.73 m2, and serum total CO2 of 24±2 meq/L. Sodium bicarbonate treatment increased mean total CO2 by 1.2 (95% confidence interval [95% CI], 0.3 to 2.1) meq/L, increased urinary pH by 0.6 (95% CI, 0.5 to 0.8), and decreased urinary ammonium excretion by 5 (95% CI, 0 to 11) meq/d and urinary titratable acid excretion by 11 (95% CI, 5 to 18) meq/d. Sodium bicarbonate did not significantly change urinary TGF-β1/creatinine (difference in change, 13%, 95% CI, -10% to 40%; change within the sodium bicarbonate group, 8%, 95% CI, -10% to 28%; change within the placebo group, -4%, 95% CI, -19% to 13%). Similarly, no significant effect on KIM-1-to-creatinine (difference in change, -10%, 95% CI, -38% to 31%), fibronectin-to-creatinine (8%, 95% CI, -15% to 37%), NGAL-to-creatinine (-33%, 95% CI, -56% to 4%), or UACR (1%, 95% CI, -25% to 36%) was observed. In nonacidotic diabetic kidney disease, sodium bicarbonate did not significantly reduce urinary TGF-β1, KIM-1, fibronectin, NGAL, or UACR over 6 months.

Association of urinary acidification function with the progression of diabetic kidney disease in patients with type 2 diabetes

ObjectiveAlthough diabetic kidney disease (DKD) has been considered as a glomerulocentric disease in the past few decades, growing evidence demonstrated that tubular damage was indispensable in its pathogenesis and progression. This study was designed to investigate the association of urinary acidification dysfunction with the progression of DKD in type 2 diabetic patients. MethodsHere the urinary acidification functions were measured from 80 participants with renal biopsy-proven DKD. The different kinds of renal tubular transportation dysfunction were analyzed, including the dysfunction of bicarbonate reabsorption, titratable acid secretion, and ammonium secretion. In addition, patients were followed up for 17 (interquartile range, 11–32) months to evaluate the effect of urinary acidification dysfunction in the progression of DKD. ResultsThe most common urinary acidification dysfunction was the disorder of ammonium secretion, accounting for 53.75%. The more proteinuria excretion and the lower glomerular filtration rate (GFR) were observed in the urinary titratable acid disorder group than the normal group, and the same results were obtained for ammonium secretion disorder. Urine titratable acid was positively correlated with eGFR whereas it was inversely correlated with proteinuria, serum creatinine, and BUN. Moreover, 24 h urine protein, serum creatinine, BUN and cystatin C increased from DKD stage II to stage IV, whereas the eGFR and urine titratable acid decreased in the same way. Furthermore, Kaplan-Meier analysis and Cox regression showed that the disorder of titratable acid was an independent risk factor for DKD progression. ConclusionsThe dysfunction of urinary titratable acid is a potential biomarker for the severity of proteinuria, eGFR and glomerular lesions in patients with DKD. Moreover, the titratable acid disorder is an independent risk factor of the DKD progression.

Acid Load and Phosphorus Homeostasis in CKD

The kidneys maintain acid-base homeostasis through excretion of acid as either ammonium or as titratable acids that primarily use phosphate as a buffer. In chronic kidney disease (CKD), ammoniagenesis is impaired, promoting metabolic acidosis. Metabolic acidosis stimulates phosphaturic hormones, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) invitro, possibly to increase urine titratable acid buffers, but this has not been confirmed in humans. We hypothesized that higher acid load and acidosis would associate with altered phosphorus homeostasis, including higher urinary phosphorus excretion and serum PTH and FGF-23. Cross-sectional. 980 participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Net acid excretion as measured in 24-hour urine, potential renal acid load (PRAL) estimatedfrom food frequency questionnaire responses, and serum bicarbonate concentration< 22 mEq/L. 24-hour urine phosphorus and calcium excretion and serum phosphorus, FGF-23, and PTH concentrations. Using linear and log-linear regression adjusted for demographics, kidney function, comorbid conditions, body mass index, diuretic use, and 24-hour urine creatinine excretion, we found that 24-hour urine phosphorus excretion was higher at higher net acid excretion, higher PRAL, and lower serum bicarbonate concentration (each P<0.05). Serum phosphorus concentration was also higherwith higher net acid excretion and lower serum bicarbonate concentration (each P=0.001). Only higher net acid excretion associated with higher 24-hour urine calcium excretion (P<0.001). Neither net acid excretion nor PRAL was associated with FGF-23 or PTH concentrations. PTH, but notFGF-23, concentration (P=0.2) was 26% (95% CI, 13%-40%) higher in participants with a serumbicarbonate concentration<22 versus≥22 mEq/L (P<0.001). Primary results were similar if stratified by estimated glomerular filtration rate categories or adjusted for iothalamate glomerular filtration rate (n=359), total energy intake, dietary phosphorus, or urine urea nitrogen excretion, when available. Possible residual confounding by kidney function or nutrition; urine phosphorus excretion was included in calculation of the titratable acid component of net acid excretion. In CKD, higher acid load and acidosis associate independently with increased circulating phosphorus concentration and augmented phosphaturia, but not consistently with FGF-23 or PTH concentrations. This may be an adaptation that increases titratable acid excretion and thus helps maintain acid-base homeostasis in CKD. Understanding whether administration of base can lower phosphorus concentrations requires testing in interventional trials.

DIETARY EFFECTS OF MAGNESIUM ON HISTAMINE METABOLISM AND URINE ACIDITY IN DOMESTIC FELINES

Magnesium deficiency has been associated with increased histamine production in rats. Limitation of Mg with acidifying foods is common practice for management of urinary tract health in domestic cats. Nine healthy adult female shorthair cats were used in a 3 period random crossover experiment with fixed treatment sequences to test the effects of dietary Mg (0.06, 0.12 and 0.18% DM) on histamine in blood and urine. The dry-extruded test foods were fed in sufficient amounts to maintain ideal body weight and obtain a target urine pH of 6.3. Each experimental period was preceded by a 7d wash out period, in which the 0.06% Mg food was fed, followed by a 14d feeding period of the appropriate food. Two 24 h total urine collections were performed (d13: Acidified, d14: Un-acidified; immediately iced) and blood was collected on d14. Dry matter intake (p≥0.13) and BW (p≥0.13) were not affected by treatment. Plasma Mg concentration increased linearly with increasing dietary Mg (0.54, 0.56, 0.58 mM; p = 0.001). In contrast, plasma concentrations of threonine, histidine and tryptophan were lower in cats fed 0.12% Mg compare with 0.06 or 0.18% Mg (quadratic, p≤0.03). Urine output (p≥0.17), pH (p≥0.55), NH3 (p≥0.21) and titratable acidity of urine (p≥0.14) were similar across treatments. Urinary histamine excretion responded quadratically (p = 0.02) to treatment (3483, 3369, 3986 ng/d), whereas urinary histamine: Creatinine (p≥0.43) and plasma histamine concentration (p≥0.55) were unaffected. Differences were not detected among treatments in total histamine, cellular + noncellular histamine, (p≥0.11) or antigen-induced (p≥0.21) histamine release in whole blood. These data indicate that dietary Mg concentration, from 0.06-0.18%, does not affect urinary acidity or circulating histamine concentrations, however, supplying Mg at 0.18% may increase urinary histamine excretion.

Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR

Metabolic acidosis often accompanies low glomerular filtration rate and induces secretion of endothelin, which in turn might mediate kidney injury. Here we tested whether treatment of metabolic acidosis in patients with low glomerular filtration rate reduced the progression of kidney disease. Fifty-nine patients with hypertensive nephropathy and metabolic acidosis had their blood pressure reduced with regimens that included angiotensin-converting enzyme inhibition. Thirty patients were then prescribed sodium citrate, and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 24 months with maintenance of their blood pressure reduction. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower. The estimated glomerular filtration rate was statistically higher after 24 months of sodium citrate treatment compared to the control group. Hence it appears that sodium citrate is an effective kidney-protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition.

Alterations in renal sodium and acid‐base transport in H,K‐ATPase null mice

The kidney expresses two H,K‐ATPase isoforms in the collecting duct, HKα1 or HKα2, that function to transport potassium (K) in exchange for protons, particularly in states of K depletion. However, loss of either HKα1 or HKα2 H,K‐ATPase isoforms did not significantly effect either urinary K excretion or systemic acid‐base balance in mice (Spicer et al. J Biol Chem. 2000 275(28); Meneton et al. J Clin Invest. 1998 101(3)). Because another isoform is present in these single knockout animals, we hypothesized that the H,K‐ATPases compensated for each other. To test this hypothesis, the effect of dietary K depletion on renal electrolyte and acid‐base handling was evaluated in double‐knockout mice lacking both HKα1 or HKα2 (HKα1,2−/‐). Surprisingly, HKα1,2−/− mice efficiently conserved urinary K. However, the HKα1,2−/− mice excreted significantly more urinary titratable acid and ammonium, sodium (Na) and chloride (Cl) with no apparent change in blood Na, Cl, pH, or HCO3. With K depletion, HKα1,2−/− mice retained more urinary Na than wild type mice. The evidence suggests that renal H,K‐ATPases may not play an essential role in net renal K conservation. Instead, the pumps may participate directly or indirectly in both Na and acid‐base transport by the kidney.These studies were supported by an NIH grant (RO1‐DK‐049750).

Renal Acid Excretion in Hypertensive Black Africans

Altered activity of the sodium-hydrogen exchanger (NHE) has been implicated in the development of hypertension. The aim of the study was to determine if the indices of urinary acid-base excretion (as markers of the NHE activity) are increased in hypertensives compared to normotensive black Africans. Sixty black African subjects (30 untreated hypertensives and 30 normotensives) were recruited for the study. All subjects collected timed 24 hour urine for quantification of the indices of acid excretion. There was no difference in all the measures of acid excretion between hyperten-sives and normotensive subjects: p=0.384 for urine pH, p=0.442 for urine ammonium, p=0.279 for urine titratable acidity and p=0.304 for total acid excretion. This suggests that there is no difference in urinary acid excretion between black hypertensives and normotensives and that the NHE may not be implicated in the genesis of hypertension in blacks.

Dietary Cation-Anion Difference and Dietary Protein Effects on Performance and Acid-Base Status of Dairy Cows in Early Lactation

Our objective was to examine the effects of dietary cation-anion difference (DCAD) with different concentrations of dietary crude protein (CP) on performance and acid-base status in early lactation cows. Six lactating Holstein cows averaging 44 d in milk were used in a 6×6 Latin square design with a 2×3 factorial arrangement of treatments: DCAD of −3, 22, or 47 milliequivalents (Na + K–Cl–S)/100g of dry matter (DM), and 16 or 19% CP on a DM basis. Linear increases with DCAD occurred in DM intake, milk fat percentage, 4% fat-corrected milk production, milk true protein, milk lactose, and milk solids-not-fat. Milk production itself was unaffected by DCAD. Jugular venous blood pH, base excess and HCO3− concentration, and urine pH increased, but jugular venous blood Cl− concentration, urine titratable acidity, and net acid excretion decreased linearly with increasing DCAD. An elevated ratio of coccygeal venous plasma essential AA to nonessential AA with increasing DCAD indicated that N metabolism in the rumen was affected, probably resulting in more microbial protein flowing to the small intestine. Cows fed 16% CP had lower urea N in milk than cows fed 19% CP; the same was true for urea N in coccygeal venous plasma and urine. Dry matter intake, milk production, milk composition, and acid-base status did not differ between the 16 and 19% CP treatments. It was concluded that DCAD affected DM intake and performance of dairy cows in early lactation. Feeding 16% dietary CP to cows in early lactation, compared with 19% CP, maintained lactation performance while reducing urea N excretion in milk and urine.

Causes of Hypocitraturia in Recurrent Calcium Stone Formers: Focusing on Urinary Potassium Excretion

Multiple factors associated with hypocitraturia have been identified. However, limited studies addressing the causal relationship to hypocitraturia are available. We therefore conducted this study to determine factors associated with hypocitraturia and show their causal relationship in recurrent calcium stone formers. Dietary review and 24-hour urine samples were obtained from all recurrent calcium stone formers referred for metabolic workup in the stone clinic. One month of oral potassium chloride supplementation was prescribed to stone formers to determine the causal relationship between urinary potassium and citrate levels. Eighty-three subjects, 44 men and 39 women, were recruited to participate in this study. Hypocitraturia (citrate < 300 mg/d [<1.43 mmol/d]) was found in 50.6% of subjects. Four independent urinary variables associated with hypocitraturia were identified, including potassium level, net gastrointestinal alkaline absorption, calcium level, and titratable acid. Urinary potassium level was the strongest predictor of urinary citrate level. Hypocitraturic subjects also had lower fruit intake compared with subjects with high urinary citrate levels. Potassium chloride supplementation to a subgroup of this population (n = 58) resulted in a significant increase in urinary citrate excretion (350.73 +/- 27.25 versus 304.15 +/- 30.00 mg/d [1.67 +/- 0.13 versus 1.45 +/- 0.14 mmol/d]; P < 0.02), but no alteration in fractional excretion of citrate (19.7% +/- 2.7% versus 23.1% +/- 2.4%; P > 0.05). Hypocitraturia was found to be a common risk factor associated with recurrent calcium stone formation and low urinary potassium level, low alkaline absorption, low urinary calcium level, and high titratable acid excretion. Hypocitraturia is predominantly of dietary origin. Estimation of fruit intake should be included in the metabolic evaluation for recurrent calcium stone formation.

Effect of Low-Carbohydrate High-Protein Diets on Acid-Base Balance, Stone-Forming Propensity, and Calcium Metabolism

Diets that restrict carbohydrate intake but allow unlimited fat and protein, such as the Atkins' diet, are much in vogue today. Whether a low-carbohydrate, high-protein (LCHP) diet increases the risk of bone loss or kidney stone formation was the question asked in this study of 10 healthy individuals ranging in age from 21 to 52 years. Initially they took their usual diet for 2 weeks and then an Atkins'-type induction diet (with severely restricted carbohydrate) for 2 weeks. An Atkins' maintenance diet then was consumed for 4 weeks in the maintenance phase. In the last week, the participants ate constant metabolic meals. Both the induction and maintenance LCHP diets contained nearly twice as much protein and fat as the subjects' usual diets but significantly less carbohydrate. Intakes of calcium, potassium, magnesium, sodium, and chloride did not differ significantly. Both weight loss and increased blood urea nitrogen levels attested to compliance with the diet. None of the 10 dieters developed clinically apparent metabolic acidosis. Serum sodium levels dropped slightly, but there were no changes in levels of potassium, chloride, calcium, or phosphorus. Urinary pH and citrate fell significantly with the induction and maintenance diets. Urinary ammonium, titratable acidity, and net acid excretion rose nearly 2-fold, as did urinary sulfate levels. Urinary calcium and phosphorus levels increased by about 2.25 mmol and 12.5 mmol/day, respectively, during the LCHP diet periods. Urinary magnesium decreased, but uric acid, oxalate, sodium, and potassium excretion did not change measurably levels measured during the baseline diet. The urinary content of undissociated uric acid doubled. Calcium balance decreased during both LCHP diets. Serum alkaline phosphatase decreased, but the bone-specific fraction did not change. Serum osteocalcin was significantly lower when subjects were on the LCHP diets. Urinary levels of deoxypyridinoline and N-telopeptide tended to increase, but not to a significant degree, and serum levels of calcitriol and parathyroid hormone did not change significantly. Endogenous creatinine clearance rose significantly during both LCH diets. This short-term study suggests that intake of a LCHP weight reduction diet, through delivering an exaggerated acid load, may heighten the risk of both kidney stone formation and bone loss. This possibility should be evaluated in a long-term prospective trial.

Abnormal urinary acidification in infants with hydronephrosis.

Distal renal tubular abnormalities have been observed in patients with dilated urinary tract disorders. The present study was undertaken to look for patterns in urinary acidification in infants with varying degrees of hydronephrosis due to either reflux or obstruction and occurring as unilateral or bilateral disease. Three groups of infants (mean age 3.7+/-3.8 months) were studied prospectively. Groups IA and IB included patients with hydronephrosis who were acidotic and non-acidotic, respectively. Group II served as controls and consisted of patients with diarrhea and secondary metabolic acidosis with no known renal disease. Serum electrolytes, creatinine, and urine pH were measured in all patients. Urinary titratable acidity, ammonium (NH4), and net acid excretion (NAE) were measured by the titrimetric method. Infants with hydronephrosis demonstrated lower urinary buffering capacity, reflected in low NAE in the face of acidosis. Deficiencies were noted in both titratable acid and NH4 excretion compared with control infants. Acidosis was as common in unilateral as in bilateral disease, regardless of severity score. These data confirm a defect in distal urinary acidification in infants with hydronephrosis, whether unilateral or bilateral. Immaturity and endogenous acid load may play a significant role in the manifestation of metabolic acidosis with unilateral disease.

The Physiology of Gastrocystoplasty: Once a Stomach, Always a Stomach

To determine the physiology of acid secretion after gastrocystoplasty with the body of the stomach we performed a prospective standardized 3-day study in 13 children (median age 12.5 years) who had undergone bladder augmentation/replacement (median postoperative period 2 years). Urinary pH and titratable acid, and serum gastrin levels were measured after gastric distention with a meal and bladder distention with urethral filling at baseline and after medication with a histamine-2 receptor antagonist or an anticholinergic agent. Five children underwent cystoscopy and biopsy of the gastric and native segments of the gastrocystoplasty. In the fasting state pH was neutral, there was no titratable acid in the urine and serum gastrin level was normal in all cases. After a meal urinary acid secretion and serum gastrin level increased markedly. After each medication half of the patients demonstrated marked inhibition of urinary acid secretion after a meal while response was partial in the remainder. In none of the patients was there significant alteration in the pattern of gastrin secretion. Bladder distention did not result in urinary acid secretion or gastrin secretion. The cystoscopic and histological appearance of the native bladder and stomach segment of the gastrocystoplasty in the 5 patients was normal. We conclude that the gastric body segment used in gastrocystoplasty continues to secrete acid as though it were part of the stomach. The secretion of acid in the urine can be decreased with histamine-2 receptor antagonist or anticholinergic medication.

Comparison of Patients with Idiopathic Calcium Phosphate and Calcium Oxalate Stones

Our primary objective was to test the hypothesis that a defect in acidification is more common in patients who have idiopathic calcium phosphate kidney stones than in those whose stones are formed mainly of calcium oxalate. Additionally, other risk factors might differ for these 2 stone types. Urine pH was measured serially over 24 hours, and along with ammonium and titratable acid, it was measured before and serially after ingestion of ammonium chloride in 3 groups of subjects: 24 patients with predominantly calcium phosphate stones, 30 patients with calcium oxalate stones, and 15 health non-stone-formers. Twenty-six parameters potentially related to stone formation and acidification were assayed on urines collected over 24 hours, and 15 parameters on blood. The data base was a computerized list of 5900 analyses of stones from patients living in Newfoundland. Patients not known by their physician to have had urinary tract infection, anatomical abnormality, hyperparathyroidism, or renal tubular acidosis were asked to participate in the study. Differences between means were considered significant if p values were less than 0.05 for F by analysis of variance and also less than 0.01 by t-test. In all patients with calcium oxalate stones and all non-stone-formers, urine acidified to pH less than 5.25, but in 8 of the 23 phosphate stone formers who completed the ammonium chloride study urine failed to acidify to pH less than 5.25. As all 8 had normal values for venous pH, total CO2, and chloride, they were considered to have incomplete renal tubular acidosis (IRTA). The 8 phosphate stone formers with IRTA had greater mean values for urine pH on all 9 specimens collected serially over 24 hours (all means greater than 6.2), and after administration of ammonium chloride (p less than 0.01), as well as lower mean values for urine titratable acid excretion (p less than 0.01), both after administration of ammonium chloride and in 24-hour urine samples, compared with the remaining phosphate stone formers whose urine acidified and the oxalate and non-stone-forming control groups. Nearly all the phosphate stone formers had 1 or more risk factors for stone formation, but with frequencies not significantly higher than those found in the oxalate group. Hypercalciuria and hypocitruria were the commonest, but increased oxalate or urate also occurred. Thus, idiopathic calcium phosphate stone formation can be associated with 1 or more of several risk factors, and, with the possible exception of those with IRTA, treatment should be similar to that given to patients with calcium oxalate stones.

Metabolic Acidosis due to Inapparent Defects in Renal Acid Excretion in a Patient with Chronic Diarrhea

In a patient with persistent diarrhea, renal acid excretion was examined because fecal alkali loss was insufficient to account for chronic metabolic acidosis. Bicarbonate wasting did not occur at physiologic serum concentrations, and the patient's ability to lower urine pH after an acid load was within normal limits. Glomerular filtration rate and the maximal rate of distal hydrogen ion secretion were unequivocally reduced, however, and ammonium excretion ws consequently inadequate. Unanticipated hypophosphaturia limited urinary titratable acidity. This case demonstrates that renal dysfunction may contribute significantly to acidosis associated with diarrhea and shows that defects in renal acid excretion may be superficially inapparent.