Urine Anion Gap to Predict Urine Ammonium and Related Outcomes in Kidney Disease.

BACKGROUND AND OBJECTIVES: Low urine ammonium excretion is associated with ESRD in CKD. Few laboratories measure urine ammonium, limiting clinical application. We determined correlations between urine ammonium, the standard urine anion gap, and a modified urine anion gap that includes sulfate and phosphate and compared risks of ESRD or death between these ammonium estimates and directly measured ammonium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured ammonium, sodium, potassium, chloride, phosphate, and sulfate from baseline 24-hour urine collections in 1044 African-American Study of Kidney Disease and Hypertension participants. We evaluated the cross-sectional correlations between urine ammonium, the standard urine anion gap (sodium + potassium - chloride), and a modified urine anion gap that includes urine phosphate and sulfate in the calculation. Multivariable-adjusted Cox models determined the associations of the standard urine anion gap and the modified urine anion gap with the composite end point of death or ESRD; these results were compared with results using urine ammonium as the predictor of interest. RESULTS: The standard urine anion gap had a weak and direct correlation with urine ammonium (r=0.18), whereas the modified urine anion gap had a modest inverse relationship with urine ammonium (r=-0.58). Compared with the highest tertile of urine ammonium, those in the lowest urine ammonium tertile had higher risk of ESRD or death (hazard ratio, 1.46; 95% confidence interval, 1.13 to 1.87) after adjusting for demographics, GFR, proteinuria, and other confounders. In comparison, participants in the corresponding standard urine anion gap tertile did not have higher risk of ESRD or death (hazard ratio, 0.82; 95% confidence interval, 0.64 to 1.07), whereas the risk for those in the corresponding modified urine anion gap tertile (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.68) approximated that of directly measured urine ammonium. CONCLUSIONS: Urine anion gap is a poor surrogate of urine ammonium in CKD unless phosphate and sulfate are included in the calculation. Because the modified urine anion gap merely estimates urine ammonium and requires five measurements, direct measurements of urine ammonium are preferable in CKD.

Association between Urine Ammonium and Urine TGF-ß1 in CKD.

BACKGROUND AND OBJECTIVES: Urinary ammonium excretion increases in response to nonvolatile acids to maintain normal systemic bicarbonate and pH. However, enhanced ammonia production promotes tubulointerstitial fibrosis in animal models. Therefore, a subset of individuals with CKD and normal bicarbonate may have acid-mediated kidney fibrosis that might be better linked with ammonium excretion than bicarbonate. We hypothesized that urine TGF-ß1, as an indicator of kidney fibrosis, would be more tightly linked with urine ammonium excretion than serum bicarbonate and other acid-base indicators. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured serum bicarbonate and urinary ammonium, titratable acids, pH, and TGF-ß1/creatinine in 144 persons with CKD. Multivariable-adjusted linear regression models determined the cross-sectional association between TGF-ß1/creatinine and serum bicarbonate, urine ammonium excretion, urine titratable acids excretion, and urine pH. RESULTS: Mean eGFR was 42 ml/min per 1.73 m2, mean age was 65 years old, 78% were men, and 62% had diabetes. Mean urinary TGF-ß1/creatinine was 102 (49) ng/g, mean ammonium excretion was 1.27 (0.72) mEq/h, mean titratable acids excretion was 1.14 (0.65) mEq/h, mean urine pH was 5.6 (0.5), and mean serum bicarbonate was 23 (3) mEq/L. After adjusting for eGFR, proteinuria, and other potential confounders, each SD increase of urine ammonium and urine pH was associated with a statistically significant 1.22-fold (95% confidence interval, 1.11 to 1.35) or 1.11-fold (95% confidence interval, 1.02 to 1.21) higher geometric mean urine TGF-ß1/creatinine, respectively. Each SD increase of serum bicarbonate and urine titratable acids was associated with a nonsignificant 1.06-fold (95% confidence interval, 0.97 to 1.16) or 1.03-fold (95% confidence interval, 0.92 to 1.14) higher geometric mean urine TGF-ß1/creatinine, respectively. CONCLUSIONS: Urinary ammonium excretion but not serum bicarbonate is associated with higher urine TGF-ß1/creatinine.

Hyperkalemia and Hypokalemia in CKD: Prevalence, Risk Factors, and Clinical Outcomes.

Abnormalities of serum potassium are common in patients with CKD. Although hyperkalemia is a well-recognized complication of CKD, the prevalence rates of hyperkalemia (14%-20%) and hypokalemia (12%-18%) are similar. CKD severity, use of medications such as renin-angiotensin-aldosterone system inhibitors and diuretics, and dietary potassium intake are major determinants of serum potassium concentration in CKD. Demographic factors, acid-base status, blood glucose, and other comorbidities contribute as well. Both hyperkalemia and hypokalemia are associated with similarly increased risks of death, cardiovascular disease, and hospitalization. On the other hand, limited evidence suggests a link between hypokalemia, but not hyperkalemia, and progression of CKD. This article reviews the prevalence rates and risk factors for hyperkalemia and hypokalemia, and their associations with adverse outcomes in CKD.

Exenatide improves diastolic function and attenuates arterial stiffness but does not alter exercise capacity in individuals with type 2 diabetes.

BACKGROUND: Exercise is recommended as a cornerstone of treatment for type 2 diabetes mellitus (T2DM), however, it is often poorly adopted by patients. Even in the absence of apparent cardiovascular disease, persons with T2DM have an impaired ability to carry out maximal and submaximal exercise and these impairments are correlated with cardiac and endothelial dysfunction. Glucagon-like pepetide-1 (GLP-1) augments endothelial and cardiac function in T2DM. We hypothesized that administration of a GLP-1 agonist (exenatide) would improve exercise capacity in T2DM. METHODS AND RESULTS: Twenty-three participants (64±4years; mean±SE) with uncomplicated T2DM were randomized in a double-blinded manner to receive either 10µg BID of exenatide or matching placebo after baseline measurements. Treatment with exenatide did not improve VO2peak (P=0.1464) or VO2 kinetics (P=0.2775). Diastolic function, assessed via resting lateral E:E', was improved with administration of exenatide compared with placebo (Placebo Pre: 7.6±1.0 vs. Post: 8.4±1.2 vs. Exenatide Pre: 8.1±0.7 vs. Post: 6.7±0.6; P=0.0127). Additionally, arterial stiffness measured by pulse wave velocity, was reduced with exenatide treatment compared with placebo (Placebo Pre: 10.5±0.8 vs. Post: 11.5±1.1s vs. Exenatide Pre: 11.4±1.8 vs. Post: 10.2±1.4s; P=0.0373). Exenatide treatment did not improve endothelial function (P=0.1793). CONCLUSIONS: Administration of exenatide improved cardiac function and reduced arterial stiffness, however, these changes were not accompanied by improved functional exercise capacity. In order to realize the benefits of this drug on exercise capacity, combining exenatide with aerobic exercise training in participants with T2DM may be warranted.

Sex differences in cardiovascular disease risk and exercise in type 2 diabetes.

Diabetes currently affects approximately 14% of the US population, and cardiovascular disease (CVD) is a leading cause of morbidity and mortality in those with diabetes. Although in the general population women are at lower risk than men for CVD, women have a disproportionately greater increase in risk for CVD than do men in the context of diabetes. Physical activity is considered a cornerstone in the prevention and treatment of CVD and its risk factors, but greater barriers to physical activity may exist for women with diabetes compared to their male counterparts. In this article, we review sex differences in CVD incidence and risk among diabetics, sex differences in physical activity behaviors, cardiovascular abnormalities and impaired exercise capacity in women living with diabetes, and the effects of exercise on prevention and treatment of CVD in diabetic women. Finally, we discuss future research needed to clarify potential sex differences in the cardiovascular effects of diabetes and to establish ways to reduce the barriers to exercise in women with diabetes.