Urinary Ammonia Research Articles

Dietary effects on urinary physicochemistry in Navy bottlenose dolphins (Tursiops truncatus) for the prevention of ammonium urate kidney stones.

Bottlenose dolphins are susceptible to developing ammonium urate (NH4U) kidney stones. The current study was designed to test the hypothesis that diet influences the urinary physicochemistry risk factors associated with nephrolithiasis in dolphins. A comprehensive nutrient analysis was performed revealing that the baseline diet (BD) commonly fed to dolphins under professional care had a greater purine content and a more negative dietary cation-anion difference (DCAD) when compared with a model diet consumed by free-ranging dolphins. A modified diet (MD) was formulated to include free-ranging diet fish species and achieve a more positive DCAD. The BD had a more negative DCAD (-52 mEq/Mcal metabolizable energy) when compared with the MD (+51 mEq/Mcal ME), which more closely approximated the DCAD of the free-ranging model diet (+152 mEq/Mcal ME). Six dolphins (with stones) were fed the BD followed by the MD for a minimum of 4 wk. At the end of each feeding trial, a 6-h continuous urine collection was performed to compare urine parameters of dolphins fed the BD versus MD. Dolphins consuming the MD demonstrated a significant decrease in urinary ammonium, net acid excretion, saturation index of ammonium urate, and phosphorous, and a significant increase in urinary citrate and net gastrointestinal (GI) alkali absorption, as compared with urine parameters assessed when fed the BD. Increasing the proportion of free-ranging diet fish species and optimizing the DCAD positively influenced some of the risk factors believed to be associated with NH4U kidney stone development in bottlenose dolphins under professional care.

Net Endogenous Acid Excretion and Kidney Allograft Outcomes.

High dietary acid load may accelerate a decline in kidney function. We prospectively investigated whether dietary acid load is associated with graft outcomes in kidney transplant recipients, and whether venous bicarbonate mediates this association. We used data from 642 kidney transplant recipients with a functioning graft ≥1 year after transplantation. Net endogenous acid production was estimated using food frequency questionnaires and, alternatively, 24-hour urinary urea and potassium excretion to estimate net endogenous acid production. We defined the composite kidney end point as a 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 the kidney end point. We evaluated potential mediation effects of venous bicarbonate, urinary bicarbonate excretion, urinary ammonium excretion, titratable acid excretion, and net acid excretion on the association between net endogenous acid production and the kidney end point. The median net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion were 40 (interquartile range, 35-45) and 54 (interquartile range, 44-66) mEq/day, respectively. During a median follow-up of 5.3 years (interquartile range, 4.1-6.0), 121 (19%) participants reached the kidney end point. After multivariable adjustment, net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion (per SD higher) were independently associated with higher risk for kidney end point (hazard ratio, 1.33; 95% confidence interval, 1.12 to 1.57, P=0.001 and hazard ratio, 1.44; 95% confidence interval, 1.24 to 1.69, P<0.001, respectively). Baseline venous bicarbonate mediated 20% of the association between net endogenous acid production using food frequency questionnaires and the kidney end point. Baseline venous bicarbonate, urinary ammonium excretion, and net acid excretion mediated 25%, -14%, and -18%, respectively, of the association between net endogenous acid production using urinary excretion and the kidney end point. 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 bicarbonate, urinary ammonium, and net acid excretion.

PD21-08 OVER-THE-COUNTER ALKALI AGENTS TO RAISE URINE PH AND CITRATE EXCRETION: A PROSPECTIVE CROSSOVER STUDY IN HEALTHY ADULTS

You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy (PD21)1 Sep 2021PD21-08 OVER-THE-COUNTER ALKALI AGENTS TO RAISE URINE PH AND CITRATE EXCRETION: A PROSPECTIVE CROSSOVER STUDY IN HEALTHY ADULTS Noah Canvasser, Marcelino Rivera, Seth Bechis, Johann Ingimarsson, John Knoedler, Karen Stern, Christa Stoughton, Daniel Wollin, Michael Borofsky, Naeem Bhojani, Marawan El Tayeb, Guido Kamphuis, David Leavitt, Ryan Hsi, and Kymora Scotland Noah CanvasserNoah Canvasser More articles by this author , Marcelino RiveraMarcelino Rivera More articles by this author , Seth BechisSeth Bechis More articles by this author , Johann IngimarssonJohann Ingimarsson More articles by this author , John KnoedlerJohn Knoedler More articles by this author , Karen SternKaren Stern More articles by this author , Christa StoughtonChrista Stoughton More articles by this author , Daniel WollinDaniel Wollin More articles by this author , Michael BorofskyMichael Borofsky More articles by this author , Naeem BhojaniNaeem Bhojani More articles by this author , Marawan El TayebMarawan El Tayeb More articles by this author , Guido KamphuisGuido Kamphuis More articles by this author , David LeavittDavid Leavitt More articles by this author , Ryan HsiRyan Hsi More articles by this author , and Kymora ScotlandKymora Scotland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002010.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Urinary citrate is a potent inhibitor of kidney stones; hypocitraturia is a common abnormality in the recurrent stone former. The American Urological Association guidelines specifically recommend potassium citrate for urinary alkalization based on the significant improvement in urinary parameters, and the reduced risk of recurrent stone disease. However, there is poor adherence to prescribed potassium citrate therapy. More recently, patients have had increased access to alternative over-the-counter alkali preparations. Our goal was to assess the effect of two over-the-counter alkalizing agents on 24-hour urinary parameters in healthy adults without a history of kidney stones. METHODS: Ten healthy volunteers without a history of kidney stones were recruited to complete a baseline 24-hour urinalysis with a four-day diet inventory. Participants were randomized 1:1 to take LithoLyte® (20 mEq two times per day) or KSPtabsTM (1 tablet two times per day) while maintaining the same diet and submit another 24-hour urinalysis. The process was repeated with the other supplement. Urinary parameters including citrate, pH and ammonium were compared to baseline. Side effects of each supplement were elicited with a questionnaire after each urine collection. RESULTS: LithoLyte® intake resulted in a non-significant increase in citrate (597 to 758 mg/day, p=0.058, an increase in urine pH (6.46 to 6.66, p=0.028), and a decrease in urine ammonium (41 to 36 mmol/day, p=0.005) compared to baseline (table 1). KSPtabsTM resulted in an increase in citrate (597 to 797 mg/day, p=0.037) and urine pH (6.46 to 6.86, p=0.037), with a non-significant decrease in ammonium (41 to 34 mmol/day, p=0.059). No significant differences were seen comparing urinary analytes between LithoLyte® and KSPtabsTM supplements. With Litholyte®, no side effects, mild, moderate, and severe side effects were seen in 50%, 40%, 10%, and 0%, respectively. With KSPtabsTM, rates were 60%, 20%, 10%, and 10%, respectively. CONCLUSIONS: In healthy participants without a history of kidney stones, LithoLyte® and KSPtabsTM are effective over-the-counter alkali supplements. Their side effect profiles appear similar to prescription potassium citrate. Source of Funding: This was an investigator-initiated project where the protocol, data collection, statistical analysis and drafting of the manuscript was performed by the authors. The study supplements, Litholyte® and KSPtabsTM, and 24-hour urine testing were funded by the manufacturers © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e377-e377 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Noah Canvasser More articles by this author Marcelino Rivera More articles by this author Seth Bechis More articles by this author Johann Ingimarsson More articles by this author John Knoedler More articles by this author Karen Stern More articles by this author Christa Stoughton More articles by this author Daniel Wollin More articles by this author Michael Borofsky More articles by this author Naeem Bhojani More articles by this author Marawan El Tayeb More articles by this author Guido Kamphuis More articles by this author David Leavitt More articles by this author Ryan Hsi More articles by this author Kymora Scotland More articles by this author Expand All Advertisement Loading ...

Integrated Sensing Systems for Monitoring Interrelated Physiological Parameters in Young and Aged Adults

Acute injury to aged individuals represents a significant challenge to the global healthcare community as these injuries are frequently treated in a reactive method due to the infeasibility of frequent visits to the hospital for biometric monitoring. However, there is potential to prevent a large number of these cases through passive, at-home monitoring of multiple physiological parameters related to various causes that are common to aged adults in general. This research strives to implement wearable devices, ambient “smart home” devices, and minimally invasive blood and urine analysis to test the feasibility of implementation of a multitude of research-level (i.e. not yet clinically validated) methods simultaneously in a “smart system”. The system comprises measures of balance, breathing, heart rate, metabolic rate, joint flexibility, hydration, and physical performance functions in addition to lab testing related to biological aging and mechanical cell strength. A proof-of-concept test is illustrated for two adult males of different ages: a 22-year-old and a 73-year-old matched in body mass index (BMI). The integrated system is test in this work, a pilot study, demonstrating functionality and age-related clinical relevance. The two subjects had physiological measurements taken in several settings during the pilot study: seated, biking, and lying down. Balance measurements indicated changes in sway area of 45.45% and 25.44%, respectively for before/after biking. The 22-year-old and the 73-year-old saw heart rate variabilities of 0.11 and 0.02 seconds at resting conditions, and metabolic rate changes of 277.38% and 222.23%, respectively, in comparison between the biking and seated conditions. A smart camera was used to assess biking speed and the 22- and 73-year-old subjects biked at 60 rpm and 28.5 rpm, respectively. The 22-year-old subject saw a 7 times greater electrical resistance change using a joint flexibility sensor inside of their index finger in comparison with the 73-year-old male. The 22 and 73-year-old males saw respective 28% and 48% increases in their urine ammonium concentration before/after the experiment. The average lengths of the telomere DNA from the two subjects were measured to be 12.1 kb (22-year-old) and 6.9 kb (73-year-old), consistent with their biological ages. The study probed feasibility of 1) multi-metric assessment under free living conditions, and 2) tracking of the various metrics over time.

Effects of Bacillus megatherium 1259 on Growth Performance, Nutrient Digestibility, Rumen Fermentation, and Blood Biochemical Parameters in Holstein Bull Calves.

Simple SummaryThis study was conducted to investigate the effects of dietary supplementation with Bacillus megaterium 1259 (BM1259) on growth performance, nutrient digestibility, rumen fermentation, and blood biochemical parameters in Holstein bull calves. The results demonstrated that the addition of BM1259 to the diets can significantly improve the growth performance and elevate the apparent digestibility of crude protein and neutral detergent fiber. Moreover, supplementation with BM1259 ameliorated rumen fermentation and reduced the emission of both ammoniacal nitrogen and sulfuretted hydrogen in feces and urine. In addition, adding 12 g/head/day of BM1259 had no adverse effect on blood biochemical parameters and the health status of Holstein bull calves. This study demonstrates that BM1259 can be applied as a potential microecologics to improve production performance and nitrogen utilization in Holstein bull calves.Bacillus megaterium is an ideal microecologics in the feed industry. BM1259 was already isolated from chicken manure and the whole-genome sequencing was also analyzed in our previous study. However, few studies concentrated on dietary supplementation with BM1259 in young ruminants and especially its effect on Holstein bull calves have not been reported. Hence, this experiment was conducted with the aim to evaluate the effects of BM1259 on growth performance, nutrient digestibility, rumen fermentation, and blood biochemical parameters in Holstein bull calves. Twenty-four healthy Holstein bull calves with the initial age of 90 days old and a similar body weight (115 ± 6.5 kg) were selected and randomly allocated into two groups with one Holstein bull calf in each pen (2.5 m × 2.2 m). Holstein bull calves in the control group (COG) were fed a basal total mixed ration (TMR), while experimental treatments (BMG) were fed with the TMR diet supplemented with 12 g/head/day of BM1259 powder (1 × 1010 cfu/g) separately. Results showed that (1) the average daily gain and dry matter intake of the BMG were significantly higher than those of the COG (p < 0.01), increased by 12.5% and 8.79%, respectively, during the 4–8 weeks after the addition of 12 g/head/day of BM1259; from 0 to 8 weeks, ADG (p < 0.05) and DMI (p < 0.05) in the BMG were significantly higher than those in the COG, increased by 14.9% and 6.04%, respectively. (2) At the end of the fourth week, the apparent digestibility of crude protein and neutral detergent fiber in the BMG was significantly higher than that in the COG (p < 0.05), increased by 5.97% and 6.70%, respectively; at the end of the eighth week, the apparent digestibility of crude protein and neutral detergent fiber was significantly higher than that of the COG (p < 0.01), increased by 5.88% and 10.26%, respectively. (3) At the end of the eighth week, the rumen fluid pH (p < 0.05), MCP (p < 0.05), and acetate (p < 0.05) in the BMG were significantly higher than those in the COG, increased by 9.03%, 19.68%, and 12.74%, respectively; at the end of the fourth and eighth week, NH3-N concentration in the BMG was significantly lower than that in the COG, with a decrease of 21.81% and 16.40%, respectively. (4) At the end of the fourth (p < 0.05) and eighth week (p < 0.05), the glutamate content of the rumen fluid of the Holstein bull calves in the BMG was significantly higher than that in the COG, increased by 13.21% and 14.32%, respectively; at the end of the fourth week, the contents of glutamate in the serum (p < 0.05), urine (p < 0.05), and feces (p < 0.05) of the Holstein bull calves in the BMG were significantly lower than those in the COG, decreased by 25.76%, 33.87%, and 9.23%, respectively; at the end of the eighth week, the contents of glutamate in the serum, urine, and feces of the Holstein bull calves in the BMG were significantly lower than those in the COG (p < 0.01), decreased by 26.69%, 27.94%, and 11.11%, respectively. (5) After adding 12 g/head/day of BM1259, the urine ammonia–nitrogen content of the BMG was extremely significantly lower than that of the COG at the end of the fourth and eighth week (p < 0.01), decreased by 54.60% and 40.31%, respectively. (6) After adding 12 g/head/day of BM1259, there was no significant effect on the level of blood biochemical parameters of the Holstein bull calves. This study demonstrates that BM1259 can be applied as a potential microecologics to improve growth performance, nutrient digestibility, rumen fermentation, and nitrogen utilization in Holstein bull calves.

Critical flux on a submerged membrane bioreactor for nitrification of source separated urine

Membrane fouling is the biggest challenge in membrane based technology operation. Studies on critical flux mainly focused on membrane bioreactor for municipal wastewater and/or greywater treatment, which can significantly differ from the ultrafiltration membrane bioreactor (UF-MBRs) to treat source separated urine. In this work, the inhibitory factors on nitrifying bacteria activity were investigated for fast acclimation of nitrifying bacteria with high ammonium concentration and optimization of a high-rate partial nitrification MBR. The maximum nitrification rate of 447 ± 50 mgN L–1 d–1 was achieved when concentration of ammonia in feed urine is approximately 4006.3 ± 225.8 mg N L–1 by maintaining desired pH around 6.2 and FA concentrations below 0.5 mgL−1. Furthermore, for the first time, the impact of different operational and filtration conditions (i.e. aeration intensity, filtration method, imposed flux, intermittent relaxation, biomass concentration) on the reversibility of membrane fouling was carried out for enhancement of membrane flux and fouling mitigation. Fouling mechanisms for minor irreversible fouling observed under sub-critical condition were pore blocking and polarization. To mitigate membrane fouling, the UF module with effective membrane surface area of 0.02 m2 is recommended to be operated at the aeration intensity of 0.4 m3 h−1, intermittent relaxation of 15 min, biomass concentration of 3.5 g L−1.

Machine Learning Prediction of Kidney Stone Composition Using Electronic Health Record-Derived Features.

Objectives: To assess the accuracy of machine learning models in predicting kidney stone composition using variables extracted from the electronic health record (EHR). Materials and Methods: We identified kidney stone patients (n = 1296) with both stone composition and 24-hour (24H) urine testing. We trained machine learning models (XGBoost [XG] and logistic regression [LR]) to predict stone composition using 24H urine data and EHR-derived demographic and comorbidity data. Models predicted either binary (calcium vs noncalcium stone) or multiclass (calcium oxalate, uric acid, hydroxyapatite, or other) stone types. We evaluated performance using area under the receiver operating curve (ROC-AUC) and accuracy and identified predictors for each task. Results: For discriminating binary stone composition, XG outperformed LR with higher accuracy (91% vs 71%) with ROC-AUC of 0.80 for both models. Top predictors used by these models were supersaturations of uric acid and calcium phosphate, and urinary ammonium. For multiclass classification, LR outperformed XG with higher accuracy (0.64 vs 0.56) and ROC-AUC (0.79 vs 0.59), and urine pH had the highest predictive utility. Overall, 24H urine analyte data contributed more to the models' predictions of stone composition than EHR-derived variables. Conclusion: Machine learning models can predict calcium stone composition. LR outperforms XG in multiclass stone classification. Demographic and comorbidity data are predictive of stone composition; however, including 24H urine data improves performance. Further optimization of performance could lead to earlier directed medical therapy for kidney stone patients.

Assessing urine ammonium concentration by urine osmolal gap in chronic kidney disease.

Acidemia is one of the risk factors for end-stage kidney disease and increases the mortality rate of patients with chronic kidney disease (CKD). Although urinary ammonium (U-NH4 + ) is the crucial component of renal acid excretion, U-NH4 + concentration is not routinely measured. To estimate U-NH4 + , urine osmolal gap (UOG=urine osmolality - [2(Na+ + K+ ) + urea + glucose]) is calculated and the formula (U-NH4 + =UOG/2) has traditionally been used. However, the usefulness of this formula is controversial in CKD patients. We assessed the relationship between U-NH4 + and UOG in patients with CKD. Blood and spot urine samples were collected in 36 patients who had non-dialysis-dependent CKD. The mean ± SD age of patients was 72.0 ± 14.8 years, and the mean ± SD serum creatinine and U-NH4 + were 2.7 ± 2.3mg/dl and 9.3 ± 9.2 mmol/L, respectively. A significant relationship was found between UOG/2 and U-NH4 + (r=.925, p < .0001). U-NH4 + estimated using the UOG was on average higher by 4.7 mmol/L than the measured one. Our results suggested that UOG could be a useful tool in clinical settings, especially in patients with moderate to severe CKD.

A Pilot Study of the Safety and Efficacy of Alkali Therapy on Vascular Function in Kidney Transplant Recipients

IntroductionMetabolic acidosis is associated with cardiovascular events, graft function, and mortality in kidney transplant recipients (KTRs). We examined the effect of alkali therapy on vascular endothelial function in KTRs.MethodsWe performed an 18-week, randomized, double-blind, placebo-controlled crossover pilot study examining the effect of sodium bicarbonate therapy versus placebo on vascular function in 20 adult KTRs at least 1 year from transplant with an estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m2 and a serum bicarbonate level of 20 to 26 mEq/L. Each treatment period was 8 weeks in duration with a 2-week washout period between treatments. The primary outcome was change in brachial artery flow-mediated dilation (FMD) between sodium bicarbonate treatment and placebo.ResultsTwenty patients completed the study and were included in the primary analysis. The mean (SD) baseline eGFR of participants was 75 (22) ml/min per 1.73 m2, respectively. Serum bicarbonate levels did not increase significantly with treatment (0.3 [1.5] mEq/L, P = 0.37). Sodium bicarbonate therapy was not associated with worsening blood pressure, weight gain, or hypokalemia. There was no significant increase in FMD after 8 weeks of sodium bicarbonate therapy compared to placebo (mean change in FMD 2.2%, 95% CI –0.1 to 4.6, P = 0.06). There were no significant changes in high-sensitivity C-reactive protein, interleukin-6, eGFR, or urinary albumin-to-creatinine ratio during treatment. Urinary ammonium excretion decreased by 9 mmol/d (P=0.003), with sodium bicarbonate.ConclusionsSodium bicarbonate therapy is safe and feasible in KTRs, and our results strengthen the need for a larger randomized controlled trial.

MO443EFFECTS OF SHORT-TERM POTASSIUM CHLORIDE SUPPLEMENTATION IN PATIENTS WITH CHRONIC KIDNEY DISEASE*

Abstract Background and Aims A high potassium (K+) diet is part of a healthy lifestyle and reduces blood pressure. Indeed, salt substitution (replacing NaCl by KCl) reduces the incidence of hypertension. Furthermore, emerging data show that high urinary K+ excretion in patients with chronic kidney disease (CKD) is associated with better kidney outcomes. This suggests that higher dietary K+ intake is also beneficial for patients with CKD, but a potential concern is hyperkalemia. Thus, there is a need for data on the effects of KCl supplementation in patients with CKD. Methods The effect of KCl supplementation (40 mEq/day) was studied by analyzing the 2-week open-label run-in phase of an ongoing randomized clinical trial studying the renoprotective effects of 2-year K+ supplementation in patients with progressive CKD and hypertension. The aims were to (1) analyze the effects of KCl supplementation on whole-blood K+ (WBK+) and acid-base balance, (2) identify factors associated with a rise in WBK+, and (3) identify risk factors for hyperkalemia (WBK+ &amp;gt; 5.5 mEq/L) . Results In 200 patients (68 ± 11 years, 74% males, eGFR 32 ± 9 mL/min/1.73 m2, 84% on renin-angiotensin inhibitors, 39% with diabetes mellitus), KCl supplementation increased urinary K+ excretion from 73 ± 24 to 106 ± 29 mEq/day, urinary chloride excretion from 144 ± 63 to 174 ± 60 mEq/day, WBK+ from 4.3 ± 0.5 to 4.7 ± 0.6 mEq/L, and plasma aldosterone from 294 to 366 ng/L (P &amp;lt; 0.01 for all). Plasma chloride increased from 104 ± 4 to 106 ± 4 mEq/L, while plasma bicarbonate decreased from 24.4 ± 3.4 to 23.6 ± 3.5 mEq/L and venous pH from 7.36 ± 0.03 to 7.34 ± 0.04 (P &amp;lt; 0.001 for all); urinary ammonium excretion did not increase (stable at 17.2 mEq/day). KCl supplementation had no significant effect on plasma renin (33 to 39 pg/mL), urinary sodium excretion (156 ± 63 to 155 ± 65 mEq/day), systolic blood pressure (134 ± 16 to 133 ± 17 mm Hg), eGFR (32 ± 9 to 31 ± 8 mL/min/1.73 m2) or albuminuria (stable at 0.2 g/day). Multivariable linear regression identified that age, female sex, and renin-angiotensin inhibitor use were associated with an increase in WBK+, while diuretic use, baseline WBK+, and baseline bicarbonate were inversely associated with a change in WBK+ after KCl supplementation (Table 1). The majority of patients (n = 181, 91%) remained normokalemic (WBK+ 4.6 ± 0.4 mEq/L). The 19 patients who did develop hyperkalemia (WBK+ 5.9 ± 0.4 mEq/L) were older (75 ± 8 vs. 67 ± 11 years), had lower eGFR (24 ± 8 vs. 32 ± 8 mL/min/1.73 m2), lower baseline bicarbonate (22.3 ± 3.6 vs. 24.6 ± 3.3 mEq/L), higher baseline WBK+ (4.8 ± 0.4 vs. 4.2 ± 0.4 mEq/L), and lower baseline urinary K+ excretion (64 ± 16 vs. 73 ± 25 mEq/day, P &amp;lt; 0.05 for all). Conclusions The majority of patients with advanced CKD remains normokalemic upon KCl supplementation, despite low eGFR, diabetes mellitus, or the use of renin-angiotensin inhibitors. This short-term study illustrates the feasibility of investigating the renoprotective potential of increased K+ intake or KCl-enriched salt in patients with CKD and provides the characteristics of patients in whom this is safe. Our study also shows that KCl supplementation causes a tendency towards metabolic acidosis, possibly by preventing an increase in ammoniagenesis. Longer-term studies are required to study the anti-hypertensive and renoprotective potential of K+ supplementation.

A Mathematical Model of the Rat Kidney: Ammonia Transport

Ammonia generated within the kidney is partitioned into a urinary fraction (the key buffer for net acid excretion), and an aliquot delivered to the systemic circulation. The physiology of this partitioning has yet to be examined in a kidney model, and that is undertaken in this work. This involves explicit representation of the cortical labyrinth, so that cortical interstitial solute concentrations are computed, rather than assigned. A detailed representation of cortical vasculature has been avoided by making the assumption that solute concentrations within interstitium and peritubular capillaries are likely to be identical, and that there is little to no modification of venous composition as blood flows to the renal vein. The model medullary ray has also been revised to include a segment of proximal straight tubule, which supplies ammonia to this region. The principal finding of this work is that cortical labyrinth interstitial ammonia concentration is likely to be several-fold higher than systemic arterial ammonia. This elevation of interstitial ammonia enhances ammonia secretion in both PCT and DCT, with uptake by Na,K-ATPases of both segments. Model prediction of urinary ammonia excretion is concordant with measured values, but at the expense of greater ammoniagenesis, with high rates of renal venous ammonia flux. This derives from a limited capability of the model medulla to replicate the high interstitial ammonia concentrations that are required to drive collecting duct ammonia secretion. Thus, renal medullary ammonia trapping appears key to diverting ammonia from renal vein to urine, but capturing the underlying physiology remains a challenge.

The Urine Anion Gap: Common Misconceptions.

Two papers, one in 1986 and another one in 1988, reported a strong inverse correlation between urinary anion gap (UAG) and urine ammonia excretion (UNH4) in patients with metabolic acidosis and postulated that UAG could be used as an indirect measure of UNH4 This postulation has persisted until now and is widely accepted. In this review, we discuss factors regulating UAG and examine published evidence to uncover errors in the postulate and the design of the original studies. The essential fact is that, in the steady state, UAG reflects intake of Na, K, and Cl. Discrepancy between intake and urinary output of these electrolytes (i.e, UAG) indicates selective extrarenal loss of these electrolytes or nonsteady state. UNH4 excretion, which depends, in the absence of renal dysfunction, mainly on the daily acid load, has no consistent relationship to UAG either theoretically or in reality. Any correlation between UAG and UNH4, when observed, was a fortuitous correlation and cannot be extrapolated to other situations. Furthermore, the normal value of UAG has greatly increased over the past few decades, mainly due to increases in dietary intake of potassium and widespread use of sodium salts with anions other than chloride as food additives. The higher normal values of UAG must be taken into consideration in interpreting UAG.

Relative contributions of urine sulfate, titratable urine anion, and GI anion to net acid load and effects of age.

Models of acid–base balance include acid production from (1) oxidation of sulfur atoms on amino acids and (2) metabolically produced organic acid anions. Acid load is balanced by alkali from metabolism of GI anions; thus, net acid production is equivalent to the sum of urine sulfate and organic anion (measured by titration in urine), minus GI anion. However, the relative contributions of these three sources of acid production in people eating free choice diets, and presumably in acid–base balance, have not been well studied. We collected 26 urines from 18 normal subjects (10 male) and 43 urine samples from 34 stone formers (17 male) and measured sulfate, organic anion, and components of GI anion and acid excretion in each; values were expressed as mEq/mmol creatinine. Mean values of the urine components, except creatinine and pH, did not differ between the sexes or groups. Urine organic acid and acid production varied directly with age (p ≤ 0.03). In a general linear model of acid excretion, the coefficients for sulfate, organic anion, and GI anion were 0.34 ± 0.09, 0.49 ± 0.12, and −0.51 ± 0.06, respectively, p ≤ 0.005, and the model accounted for 54% of the variance. A model for urine ammonia gave similar results. Urine organic anion is a significant contributor to total acid production and may be responsible for an increase in acid production with age.

URINARY AMMONIUM EXCRETION BY ALDOSTERONE THROUGH THE REGULATION OF RH C GLYCOPROTEIN IN THE INTERCALATED CELLS OF THE RENAL COLLECTING DUCT

Objective: Aldosterone is a key hormone that regulates sodium reabsorption in the principal cells (PCs) of the renal collecting duct, maintaining blood pressure. Alternatively, aldosterone is involved in urinary acid excretion mainly via ammonia as ammonium ions in the intercalated cells (ICs) of the collecting duct, although its mechanisms are obscure. Rh C glycoprotein (Rhcg), an ammonia transporter, is expressed mainly in the intercalated cells. Direct regulation of ammonium excretion by aldosterone through the Rhcg in metabolic acidosis was investigated. Design and method: C57BL/6J mice were divided into four groups: 1) sham-operation, 2) sham and NH4Cl drinking (Sham-NH4Cl), 3) adrenalectomy and NH4Cl drinking (ADX-NH4Cl), and 4) adrenalectomy with continuous administration of aldosterone and NH4Cl drinking (ADX-Aldo-NH4Cl). Mice were sacrificed three days after NH4Cl drinking. Urinary ammonium excretion and localizations of Rhcg and ubiquitin were examined. For in vitro experiments, IN-IC cells, an intercalated cell-derived cell line, that stably express flag-tagged Rhcg (Rhcg-flag) were generated. The effects of aldosterone, spironolactone, Go6983 (a PKC inhibitor) and MG132 (a proteasome inhibitor) on the expression of Rhcg-flag were examined. Results: NH4Cl-induced urinary ammonium excretion was inhibited by adrenalectomy in ADX-NH4Cl mice. Aldosterone replacement restored ammonium excretion in ADX-Aldo-NH4Cl mice. Immunohistochemical study revealed that NH4Cl drinking increased the accumulation of Rhcg at apical and basolateral membranes and subapical sites of the ICs in sham-NH4Cl mice. Adrenalectomy and aldosterone replacement decreased and increased the accumulation of Rhcg at apical membrane of the ICs in ADX-NH4Cl and ADX-Aldo-NH4Cl mice, respectively. Ubiquitin expression was not changed between in PCs and ICs of sham-NH4Cl mice, while it was less in ICs than in PCs in ADX-NH4Cl mice. Aldosterone restored the ubiquitin expression in ICs. In IN-IC cells, Western blotting showed that aldosterone increased the expression of Rhcg-flag in the membrane fraction. Spironolactone and Go6983 each inhibited the expression of Rhcg-flag. Treatment with MG132 increased the expression of Rhcg-flag in whole cell lysate. Immunoprecipitation revealed the association of Rhcg with the ubiquitin. Conclusions: Aldosterone could directly regulate Rhcg expression through the mineralocorticoid receptor-PKC pathway. Furthermore, aldosterone could modulate Rhcg expression through the ubiquitin-proteasome pathway.

Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study

Patients with CKD are at elevated risk of metabolic acidosis due to impaired net acid excretion (NAE). Identifying early markers of acidosis may guide prevention in chronic kidney disease (CKD). This study compared NAE in participants with and without CKD, as well as the NAE, blood pressure (BP), and metabolomic response to bicarbonate supplementation. Randomized order, cross-over study with controlled feeding. Participants consisted of 8 patients with CKD (estimated glomerular filtration rate 30-59mL/min/1.73m2 or 60-70mL/min/1.73m2 with albuminuria) and 6 patients without CKD. All participants had baseline serum bicarbonate concentrations between 20 and 28 mEq/L; they did not have diabetes mellitus and did not use alkali supplements at baseline. Participants were fed a fixed-acid-load diet with bicarbonate supplementation (7 days) and with sodium chloride control (7 days) in a randomized order, cross-over fashion. Urine NAE, 24-hour ambulatory BP, and 24-hour urine and plasma metabolomic profiles were measured after each period. During the control period, mean NAE was 28.3±10.2 mEq/d overall without differences across groups (P=0.5). Urine pH, ammonium, and citrate were significantly lower in CKD than in non-CKD (P<0.05 for each). Bicarbonate supplementation reduced NAE and urine ammonium in the CKD group, increased urine pH in both groups (but more in patients with CKD than in those without), and increased; urine citrate in the CKD group (P< 0.2 for interaction for each). Metabolomic analysis revealed several urine organic anions were increased with bicarbonate in CKD, including 3-indoleacetate, citrate/isocitrate, and glutarate. BP was not significantly changed. Small sample size and short feeding duration. Compared to patients without CKD, those with CKD had lower acid excretion in the form of ammonium but also lower base excretion such as citrate and other organic anions, a potential compensation to preserve acid-base homeostasis. In CKD, acid excretion decreased further, but base excretion (eg, citrate) increased in response to alkali. Urine citrate should be evaluated as an early and responsive marker of impaired acid-base homeostasis. National Institute of Diabetes and Digestive and Kidney Diseases and the Duke O'Brien Center for Kidney Research. Registered atClinicalTrials.gov with study number NCT02427594.

Effects of emersion on acid-base regulation, osmoregulation, and nitrogen physiology in the semi-terrestrial mangrove crab, Helice formosensis.

Emersion limits water availability and impairs the gill function of water-breathing animals resulting in a reduced capacity to regulate respiratory gas exchange, acid-base balance, and nitrogenous waste excretion. Semi-terrestrial crustaceans such as Helice formosensis mitigate these physiological consequences by modifying and recycling urine and branchial water shifting some branchial workload to the antennal glands. To investigate how this process occurs, Helice formosensis were emersed for up to 160 h and their hemolymph and urinary acid-base, nitrogenous waste, free amino acids, and osmoregulatory parameters wereinvestigated. Upon emersion, crabs experienced a respiratory acidosis that is restored by bicarbonate accumulation and ammonia reduction within the hemolymph and urine after 24h. Prolonged emersion caused an overcompensatory metabolic alkalosis potentially limiting the crab's ability to remain emersed. During the alkalosis, hemolymph ammonia was maintained at control levels while urinary ammonia remained reduced by 60% of control values. During emersion, ammonia may be temporarily converted to alanine as part of the Cahill cycle until re-immersion where crabs can revert alanine to ammonia for excretion coinciding with the crabs' observed delayed ammonia excretion response. The presence of high hemolymph alanine concentrations even when immersed may indicate this cycle's use outside of emersion or in preparation for emersion. Furthermore, H. formosensis appears to be uniquely capable of actively suppressing its rate of desiccation in absence of behavioral changes, in part by creating hyperosmotic urine that mitigates evaporative water loss.

A chronic high phosphate intake in mice is detrimental for bone health without major renal alterations.

Phosphate intake has increased in the last decades due to a higher consumption of processed foods. This higher intake is detrimental for patients with chronic kidney disease, increasing mortality and cardiovascular disease risk and accelerating kidney dysfunction. Whether a chronic high phosphate diet is also detrimental for the healthy population is still under debate. We fed healthy mature adult mice over a period of one year with either a high (1.2% w/w) or a standard (0.6% w/w) phosphate diet, and investigated the impact of a high phosphate diet on mineral homeostasis, kidney function and bone health. The high phosphate diet increased plasma phosphate, parathyroid hormone (PTH) and calcitriol levels, with no change in fibroblast growth factor 23 levels. Urinary phosphate, calcium and ammonium excretion were increased. Measured glomerular filtration rate was apparently unaffected, while blood urea was lower and urea clearance was higher in animals fed the high phosphate diet. No change was observed in plasma creatinine levels. Blood and urinary pH were more acidic paralleled by higher bone resorption observed in animals fed a high phosphate diet. Total and cortical bone mineral density was lower in animals fed a high phosphate diet and this effect is independent of the higher PTH levels observed. A chronic high phosphate intake did not cause major renal alterations, but affected negatively bone health, increasing bone resorption and decreasing bone mineral density.

Electrochemical system for selective oxidation of organics over ammonia in urine

Low pH allows for selective oxidation of the organic fraction in urine while retaining nitrogen.

Effect of sodium bicarbonate supplementation on the renin-angiotensin system in patients with chronic kidney disease and acidosis: a randomized clinical trial

BackgroundAcidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate supplementation reduces urinary renin excretion in patients with chronic kidney disease (CKD) and metabolic acidosis.MethodsPatients with CKD stage G4 and plasma bicarbonate 15–24 mmol/l were randomized to receive sodium bicarbonate (3 × 1000 mg/day, ~ 0.5 mEq/kg), sodium chloride (2 × 1,00 mg/day), or no treatment for 4 weeks (n = 15/arm). The effects on urinary renin excretion (primary outcome), other plasma and urine parameters of the renin-angiotensin system, endothelin-1, and proteinuria were analyzed.ResultsForty-five patients were included (62 ± 15 years, eGFR 21 ± 5 ml/min/1.73m2, plasma bicarbonate 21.7 ± 3.3 mmol/l). Sodium bicarbonate supplementation increased plasma bicarbonate (20.8 to 23.8 mmol/l) and reduced urinary ammonium excretion (15 to 8 mmol/day, both P < 0.05). Furthermore, a trend towards lower plasma aldosterone (291 to 204 ng/L, P = 0.07) and potassium (5.1 to 4.8 mmol/l, P = 0.06) was observed in patients receiving sodium bicarbonate. Sodium bicarbonate did not significantly change the urinary excretion of renin, angiotensinogen, aldosterone, endothelin-1, albumin, or α1-microglobulin. Sodium chloride supplementation reduced plasma renin (166 to 122 ng/L), and increased the urinary excretions of angiotensinogen, albumin, and α1-microglobulin (all P < 0.05).ConclusionsDespite correction of acidosis and reduction in urinary ammonium excretion, sodium bicarbonate supplementation did not improve urinary markers of the renin-angiotensin system, endothelin-1, or proteinuria. Possible explanations include bicarbonate dose, short treatment time, or the inability of urinary renin to reflect intrarenal renin-angiotensin system activity.Graphic abstract

Serum bicarbonate is associated with kidney outcomes in autosomal dominant polycystic kidney disease.

BackgroundMetabolic acidosis accelerates progression of chronic kidney disease, but whether this is also true for autosomal dominant polycystic kidney disease (ADPKD) is unknown. MethodsPatients with ADPKD from the DIPAK (Developing Interventions to halt Progression of ADPKD) trial were included [n = 296, estimated glomerular filtration rate (eGFR) 50 ± 11 mL/min/1.73 m2, 2.5 years follow-up]. Outcomes were worsening kidney function (30% decrease in eGFR or kidney failure), annual eGFR change and height-adjusted total kidney and liver volumes (htTKV and htTLV). Cox and linear regressions were adjusted for prognostic markers for ADPKD [Mayo image class and predicting renal outcomes in ADPKD (PROPKD) scores] and acid–base parameters (urinary ammonium excretion). ResultsPatients in the lowest tertile of baseline serum bicarbonate (23.1 ± 1.6 mmol/L) had a significantly greater risk of worsening kidney function [hazard ratio = 2.95, 95% confidence interval (CI) 1.21–7.19] compared with patients in the highest tertile (serum bicarbonate 29.0 ± 1.3 mmol/L). Each mmol/L decrease in serum bicarbonate increased the risk of worsening kidney function by 21% in the fully adjusted model (hazard ratio = 1.21, 95% CI 1.06–1.37). Each mmol/L decrease of serum bicarbonate was also associated with further eGFR decline (−0.12 mL/min/1.73 m2/year, 95% CI −0.20 to −0.03). Serum bicarbonate was not associated with changes in htTKV or htTLV growth.ConclusionsIn patients with ADPKD, a lower serum bicarbonate within the normal range predicts worse kidney outcomes independent of established prognostic factors for ADPKD and independent of urine ammonium excretion. Serum bicarbonate may add to prognostic models and should be explored as a treatment target in ADPKD.