Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Metabolic acidosis contributes to muscle breakdown in patients with CKD, but whether its treatment improves functional outcomes is unknown. The choice of dose and tolerability of high doses remain unclear. In CKD patients with mild acidosis, this study evaluated the dose-response relationship of alkali with serum bicarbonate, its side effect profile, and its effect on muscle strength. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:In this single-blinded pilot study from March of 2009 to August of 2010, 20 adults with estimated GFR 15-45 ml/min per 1.73 m(2) and serum bicarbonate 20-24 mEq/L were treated during successive 2-week periods with placebo followed by escalating oral NaHCO3 doses (0.3, 0.6, and 1.0 mEq/kg per day). At each visit, handgrip strength and time required to complete 5 and 10 repetitions of a sit-to-stand test were measured. RESULTS:Each 0.1 mEq/kg per day increase in dose produced a 0.33 mEq/L (95% confidence interval=0.23-0.43 mEq/L) higher serum bicarbonate. Sit-to-stand time improved after 6 weeks of oral NaHCO3 (23.8±1.4 versus 22.2±1.6 seconds for 10 repetitions, P=0.002), and urinary nitrogen excretion decreased (-0.70 g/g creatinine [95% confidence interval=-1.11 to -0.30] per 0.1 mEq/kg per day higher dose). No statistically significant change was seen in handgrip strength (29.5±9.6 versus 28.4±9.4 kg, P=0.12). Higher NaHCO3 doses were not associated with increased BP or greater edema. CONCLUSIONS:NaHCO3 supplementation produces a dose-dependent increase in serum bicarbonate and improves lower extremity muscle strength after a short-term intervention in CKD patients with mild acidosis. Long-term studies are needed to determine if this finding translates into improved functional status.

Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p < 0.05, uremic serum vs. control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50 kDa showed significantly greater toxicity with the larger molecular weight fraction (83 ± 11 vs. 7 ± 17% survival, p < 0.05, <50 vs. >50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement.

It is well known that uremia causes an increase in the serum anion gap (AG); however, whether changes in the AG occur earlier in the course of chronic kidney disease is not known. Here we investigated whether different measures of the AG, as a marker of kidney function, are associated with mortality. To do this, we analyzed the available laboratory data of 11,957 adults in the National Health and Nutrition Examination Survey 1999-2004 to calculate AG using the traditional method, or one that was albumin-adjusted, as well as a full AG reflecting other electrolytes. A significant elevation in the traditional AG was seen only with an estimated glomerular filtration rate (eGFR) <45 ml/min per 1.73 m(2), whereas increases in the albumin-adjusted and full AG were found with eGFRs <60 or 90 ml/min per 1.73 m(2), respectively. Higher levels of each AG were associated with an increased risk of all-cause mortality after adjustment for age, gender, race/ethnicity, and eGFR. After adjustment for additional covariates including body mass index and comorbidities, higher levels of the albumin-adjusted and full AG were associated with mortality (relative hazard for the highest compared with the lowest quartile were 1.62 and 1.64, respectively). Thus, higher levels of AG are present in individuals with less advanced kidney disease than previously recognized, and are associated with increased risk of mortality. Further study is needed to identify the unmeasured anions and to determine their physiological significance.

Lower levels of serum bicarbonate and a higher anion gap have been associated with insulin resistance and hypertension in the general population. Whether these associations extend to other cardiovascular disease risk factors is unknown. To clarify this, we examined the association of serum bicarbonate and anion gap with cardiorespiratory fitness in 2714 adults aged 20-49 years in the 1999-2004 National Health and Nutrition Examination Survey. The mean serum bicarbonate was 24.6 mEq/l and the mean anion gap was 10.26 mEq/l, with fitness determined by submaximal exercise testing. After multivariable adjustment, gender, length of fasting, soft drink consumption, systolic blood pressure, serum phosphate, and hemoglobin were independently associated with both the serum bicarbonate and the anion gap. Low fitness was most prevalent among those in the lowest quartile of serum bicarbonate or highest quartile of anion gap. After multivariable adjustment, a 1 s.d. higher serum bicarbonate or anion gap was associated with an odds ratio for low fitness of 0.80 (95% CI 0.70-0.91) and 1.30 (95% CI 1.15-1.48), respectively. The association of bicarbonate with fitness may be mediated by differences in lean body mass. Thus, lower levels of serum bicarbonate and higher levels of anion gap are associated with lower cardiorespiratory fitness in adults aged 20-49 years in the general population.

OBJECTIVE:Deficient 25-hydroxyvitamin D (25[OH]D) levels are associated with cardiovascular disease (CVD) events and mortality. 25(OH)D deficiency and stroke are more prevalent in blacks. We examined whether low 25(OH)D contributes to the excess risk of fatal stroke in blacks compared with whites. METHODS:The Third National Health and Nutrition Examination Survey, a probability sample of U.S. civilians, measured 25(OH)D levels and CVD risk factors from 1988 through 1994. Vital status through December 2006 was obtained by a linkage with the National Death Index. In white and black adults without CVD reported at baseline (n = 7981), Cox regression models were fit to estimate hazard ratios (HR) for fatal stroke by 25(OH)D status and race. RESULTS:During a median of 14.1 y, there were 116 and 60 fatal strokes in whites and blacks, respectively. The risk of fatal stroke was greater in blacks compared with whites in models adjusted for socioeconomic status and CVD risk factors (HR 1.60, 95% confidence interval 1.01-2.53). Mean baseline 25(OH)D levels were significantly lower in blacks compared with whites (19.4 versus 30.8 ng/mL, respectively). In multivariable-adjusted models, deficient 25(OH)D levels lower than 15 ng/mL were associated with fatal stroke in whites (HR 2.13, 1.01-4.50) but not blacks (HR 0.93, 0.49-1.80). CONCLUSIONS:Vitamin D deficiency was associated with an increased risk of stroke death in whites but not in blacks. Although blacks had a higher rate of fatal stroke compared with whites, the low 25(OH)D levels in blacks were unrelated to stroke incidence. Therefore 25(OH)D levels did not explain this excess risk.

OBJECTIVES/OBJECTIVE:To test whether lower serum uric acid (UA) levels are associated with longevity independent of renal function. DESIGN/METHODS:Cross-sectional cohort study. SETTING/METHODS:Ashkenazi Jewish individuals with exceptional longevity (Longevity Genes Project at Albert Einstein College of Medicine). PARTICIPANTS/METHODS:Long-lived individuals (LLI) of Ashkenazi Jewish ethnicity (mean age ± standard deviation 97.7 ± 2.9, n = 365), their offspring (mean age ± standard deviation 68.2 ± 8.2, n = 593) and controls (without family history of longevity, mean age ± standard deviation 72.5 ± 9.9, n = 356). MEASUREMENTS/METHODS:Association between UA levels and estimated glomerular filtration rate (eGFR) as well as chronic kidney disease (CKD) stage, and correlation of UA levels of LLI and offspring were determined. Because LLI lack an appropriate control group, UA levels, eGFR, and prevalence of hyperuricemia and CKD stages were compared between offspring and controls. RESULTS:Offspring were less likely to have hyperuricemia and had lower UA levels than controls. Despite negative correlation between UA levels and eGFR and positive correlation between UA levels and CKD stages, eGFR and the prevalence of CKD stage III to V were not found to be different between offspring and controls. Furthermore, significant association between UA levels in LLI and their offspring (β estimate 0.1544, 95% confidence interval = 0.08-0.23, P < .001) has been observed. CONCLUSION/CONCLUSIONS:Offspring had lower UA levels than controls despite similar renal function, suggesting that other factors such as UA metabolism or renal tubular transport determine UA levels. The association between UA levels and longevity is particularly intriguing because UA levels are potentially modifiable with diet and drugs.

Treatment of chronic kidney disease (CKD) can slow its progression to end-stage renal disease (ESRD). However, the therapies remain limited. Blood pressure control using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) has the greatest weight of evidence. Glycemic control in diabetes seems likely to retard progression. Several metabolic disturbances of CKD may prove to be useful therapeutic targets but have been insufficiently tested. These include acidosis, hyperphosphatemia, and vitamin D deficiency. Drugs aimed at other potentially damaging systems and processes, including endothelin, fibrosis, oxidation, and advanced glycation end products, are at various stages of development. In addition to the paucity of proven effective therapies, the incomplete application of existing treatments, the education of patients about their disease, and the transition to ESRD care remain major practical barriers to better outcomes.

Vitamin D has garnered much research and debate about supplementation in recent years, not only as it pertains to patients with kidney disease but also to those in the general population. This review discusses observational and available clinical trial evidence about the effects of both calcitriol and vitamin D analogs (active) and ergocalciferol and cholecalciferol (nutritional) vitamin D in patients with CKD and ESRD.

CONTEXT/BACKGROUND:In many disorders requiring steroid therapy, there is substantial decrease in bone mineral density. The association between steroid use and 25-hydroxyvitamin D [25(OH)D] deficiency has not been confirmed in large population-based studies, and currently there are no specific vitamin D recommendations for steroid users. OBJECTIVE:The aim of the study was to evaluate the association of serum 25(OH)D deficiency [defined as 25(OH)D <10 ng/ml] with oral steroid use. DESIGN/METHODS:Cross-sectional analysis was performed using NHANES 2001-2006. SETTING/METHODS:We analyzed a nationally representative sample of U.S. children and adults. PARTICIPANTS/METHODS:The study sample consisted of children, adolescents, and adults from NHANES 2001-2006 (n = 22,650), representative of 286 million U.S. residents, with serum 25(OH)D levels and data on other potential confounders. MAIN OUTCOME MEASURE/METHODS:We measured serum 25(OH)D levels below 10 ng/ml. RESULTS:A total of 181 individuals (0.9% of the population) used steroids within the past 30 d. Overall, 5% of the population had 25(OH)D levels below 10 ng/ml. Among steroid users, 11% had 25(OH)D levels below 10 ng/ml, compared to 5% among steroid nonusers (P = 0.009). The odds of having 25(OH)D deficiency were 2-fold higher in those who reported steroid use compared to those without steroid use [odds ratio (OR), 2.36; 95% confidence interval (CI), 1.25, 4.45]. This association remained after multivariable adjustment (OR, 2.21; 95% CI, 1.01, 4.85) and in a multivariable model using NHANES III data (OR, 1.88; 95% CI, 1.01, 3.48). CONCLUSION/CONCLUSIONS:Steroid use is independently associated with 25(OH)D deficiency in this nationally representative cohort limited by cross-sectional data. It suggests the need for screening and repletion in patients on chronic steroids.