Association of Urine Findings with Metabolic Syndrome Traits in a Population of Patients with Nephrolithiasis

Background: The odds of nephrolithiasis increase with more metabolic syndrome (met-s) traits. We evaluated associations of metabolic and dietary factors from urine studies and stone composition with met-s traits in a large cohort of stone-forming patients. Methods: Patients >18 years, who were evaluated for stones with 24 h urine collections, July 2009-December 2018, had records reviewed retrospectively. Patient factors, laboratory values and diagnoses were identified within 6 months of urine collection and stone composition within 1 year. Four groups with 0, 1, 2, > 3 met-s traits (hypertension, obesity, dyslipidemia, diabetes) were evaluated. Trends across groups were tested using linear contrasts in analysis of variance and analysis of covariance. Results: 1473 patients met inclusion criteria (835 with stone composition). Met-s groups were 0=684, 1=425, 2=211, 3 and 4 =153. There were no differences among groups for urine volume, calcium or ammonium excretion. There was a significant trend (p<0.001) for more met-s traits being associated with decreasing urine pH, increasing age, calculated dietary protein, urine uric acid, oxalate, citrate, titratable acid phosphate, net acid excretion and uric acid supersaturation. The ratio of ammonium to net acid excretion did not differ among the groups. After adjustment for protein intake, the fall in urine pH remained strong, while the upward trend in acid excretion was lost. Calcium oxalate stones were most common, but there was a trend for more uric acid (p<0.001) and fewer calcium phosphate (p=0.09) and calcium oxalate stones (p=0.01) with more met-s traits. Conclusions: Stone forming patients with met-s have a defined pattern of metabolic and dietary risk factors that contribute to an increased risk of stone formation including higher acid excretion, largely the result of greater protein intake, and lower urine pH.

Net Endogenous Acid Excretion and Kidney Allograft Outcomes

Background and objectives: High dietary acid load may accelerate kidney function decline. We prospectively investigated whether dietary acid load is associated with graft outcomes in kidney transplant recipients and whether venous bicarbonate (HCO3−) mediates this association. Design, setting, participants and measurements: We used data from 642 kidney transplant recipients with a functioning graft ≥1 year after transplantation. Net endogenous acid production (NEAP) was estimated using food frequency questionnaires (FFQ) and, alternatively, 24-hour urinary urea and potassium excretion to estimate NEAPUrine. We defined composite kidney endpoint as doubling of plasma creatinine or graft failure. Multivariable Cox regression analyses, adjusted for potential confounders, were used to study the associations of dietary acid load with kidney endpoint. We evaluated potential mediation effects of venous HCO3− , urinary HCO3− excretion, urinary ammonium (NH4+) excretion, titratable acid excretion, and net acid excretion on the association between NEAP and kidney endpoint. Results: Median NEAPFFQ and NEAPUrine were 40 (Interquartile range [IQR] 35-45) and 54 (IQR 44-66) mEq/day, respectively. During a median follow-up time of 5.3 (IQR 4.1-6.0) years, 121 (19%) participants reached kidney endpoint. After multivariable adjustment, NEAPFFQ and NEAPUrine (per SD higher) were independently associated with higher risk for kidney endpoint (hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.12-1.57, P=0.001 and HR 95%CI, 1.44 [1.24-1.69], P<0.001 resp.). Baseline venous HCO3− mediated 20% of the association between NEAPFFQ and kidney endpoint. Baseline venous HCO3−, urinary NH4+ excretion and net acid excretion mediated 25%, -14% and -18% resp. of the association between NEAPUrine and kidney endpoint. Conclusion: Higher dietary acid load was associated with a higher risk of doubling of plasma creatinine or graft failure, and this association was partly mediated by venous HCO3−, urinary NH4+ and net acid excretion.

Association of Urine Findings with Metabolic Syndrome Traits in a Population of Patients with Nephrolithiasis

Background and objectives: The odds of nephrolithiasis increase with more metabolic syndrome (met-s) traits. We evaluated associations of metabolic and dietary factors from urine studies and stone composition with met-s traits in a large cohort of stone-forming patients. Design, setting, participants & measurements: Patients >18 years, who were evaluated for stones with 24 h urine collections, July 2009-December 2018, had records reviewed retrospectively. Patient factors, laboratory values and diagnoses were identified within 6 months of urine collection and stone composition within 1 year. Four groups with 0, 1, 2, > 3 met-s traits (hypertension, obesity, dyslipidemia, diabetes) were evaluated. Trends across groups were tested using linear contrasts in analysis of variance and analysis of covariance. Results: 1473 patients met inclusion criteria (835 with stone composition). Met-s groups were 0=684, 1=425, 2=211, 3 and 4 =153. There were no differences among groups for urine volume, calcium or ammonium (NH4) excretion. There was a significant trend (p<0.001) for more met-s traits being associated with decreasing urine pH, increasing age, calculated dietary protein, urine uric acid, oxalate, citrate, titratable acid (TAP), net acid excretion (eNAE) and uric acid supersaturation. The ratio of ammonium to net acid excretion did not differ among the groups. After adjustment for protein intake, the fall in urine pH remained strong, while the upward trend in TAP excretion was attenuated and NH4 decreased. Calcium oxalate stones were most common, but there was a trend for more uric acid (p<0.001) and fewer calcium phosphate (p=0.09) and calcium oxalate stones (p=0.01) with more met-s traits. Conclusions: Stone forming patients with met-s have a defined pattern of metabolic and dietary risk factors that contribute to an increased risk of stone formation including higher acid excretion, largely the result of higher protein intake, and lower urine pH.

NBCn1 Increases NH4+ Reabsorption Across Thick Ascending Limbs, the Capacity for Urinary NH4+ Excretion, and Early Recovery from Metabolic Acidosis

BackgroundThe electroneutral Na+/HCO3− cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking.MethodsMetabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH4+ transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH4+] was measured in renal biopsies, NH4+ excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice.ResultsBasolateral Na+/HCO3− cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na+/HCO3− cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH4+ reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH4+ gradient, reduced the capacity for urinary NH4+ excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO3−] from their initial decline.ConclusionsDuring metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO3− uptake and transepithelial NH4+ reabsorption in mTALs, renal medullary NH4+ accumulation, urinary NH4+ excretion, and early recovery of arterial blood pH and standard [HCO3−]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H+ released during NH4+ reabsorption across mTALs.

Urinary Lithogenic Risk Profile in ADPKD Patients Treated with Tolvaptan

Background and objectivesNephrolithiasis is a common health problem in autosomal dominant polycystic kidney disease (ADPKD) and significantly contributes to patient morbidity. Recently, Tolvaptan has been introduced for the treatment of ADPKD, but whether it is associated with alterations of the urinary lithogenic risk profile remains unknown.Design, setting, participants, & measurementsWe conducted an analysis of participants enrolled in the Bern ADPKD registry, a prospective observational cohort study. Twenty-four-hour urine analyses were performed at baseline and then at yearly follow-ups. Relative supersaturation ratios for calcium oxalate, brushite, and uric acid were calculated with the program EQUIL2. Unadjusted and multivariable mixed-effects linear regression models, adjusted for age, sex, body mass index, eGFR, net acid excretion, and height-adjusted total kidney volume, were used to assess the association of Tolvaptan with urinary parameters relevant for kidney stone formation. The maximum individual follow-up time was 3 years, median follow-up time 1.9 years, and cumulative follow-up time 169 years.ResultsIn total, 125 participants (38 with and 87 without Tolvaptan treatment) were included in the analysis. In multivariable analysis, Tolvaptan treatment was associated [adjusted estimate of the difference between Tolvaptan and no Tolvaptan; 95% confidence interval (CI)] with lower urine relative supersaturation ratios for calcium oxalate (−0.56; 95% CI, −0.82 to −0.3; P<0.001), brushite (−0.33; 95% CI, −0.54 to −0.11; P=0.004), and uric acid (−0.62; 95% CI, −0.88 to −0.37; P<0.001), and with higher urine citrate in mmol/mmol creatinine per day (0.25; 95% CI, 0.05 to 0.46; P=0.02) and calcium in mmol/mmol creatinine per day (0.31; 95% CI, 0.09 to 0.53; P=0.006) excretion. In addition, Tolvaptan treatment was associated with lower net acid excretion in mEq/mmol creatinine per day (−0.54; 95% CI, −0.90 to −0.17; P=0.004) and higher net gastrointestinal alkali absorption in mEq/mmol creatinine per day (0.57; 95% CI, 0.26 to 0.88; P<0.001).ConclusionsTolvaptan treatment is associated with a significantly improved urinary lithogenic risk profile in patients with ADPKD.