Matthew K. Abramowitz

Treatment of chronic kidney disease

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.

Association of glucocorticoid use and low 25-hydroxyvitamin D levels: Results from the National Health and Nutrition Examination Survey (NHANES): 2001-2006

CONTEXT 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 Cross-sectional analysis was performed using NHANES 2001-2006. SETTING We analyzed a nationally representative sample of U.S. children and adults. PARTICIPANTS 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 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 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.

Serum Alkaline Phosphatase and Phosphate and Risk of Mortality and Hospitalization

BACKGROUND AND OBJECTIVES Elevated alkaline phosphatase (AlkPhos) and phosphate levels are associated with cardiovascular morbidity and mortality in patients receiving dialysis. A retrospective cohort study was conducted to test these associations in outpatients with an estimated GFR > or =60 ml/min/1.73 m(2). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients with serum AlkPhos and phosphate levels measured between 2000 and 2002 (n = 10,743) at Montefiore Medical Center (MMC) clinics were followed through September 11, 2008 (median 6.8 years). Mortality data were obtained via Social Security Administration records (n = 949 deaths). Hospitalization data were obtained from MMC records. RESULTS The mean age was 51 years, 64% were women, 22% were white, 26% were non-Hispanic black, 16% were Hispanic, 13% had a diagnosis of hypertension, 9% had diabetes mellitus, and 8% had cardiovascular disease at baseline. AlkPhos and phosphate were independently associated with mortality and cardiovascular-related hospitalization after multivariable adjustment. Comparing patients in the highest (> or =104 U/L) versus lowest quartile of AlkPhos (< or =66 U/L), the adjusted hazard ratio (HR) for mortality was 1.65 (P trend across quartiles <0.001). For the highest compared with the lowest quartile of serum phosphate (> or =3.8 mg/dl versus < or =3.0 mg/dl), the adjusted HR for mortality was 1.29 (P trend across quartiles = 0.008). High AlkPhos but not phosphate levels were also associated with all-cause, infection-related, and fracture-related hospitalization. CONCLUSIONS Higher levels of serum AlkPhos and phosphate were associated with increased mortality and cardiovascular-related hospitalization in an inner-city clinic population. Further studies are needed to elucidate mechanisms underlying these associations.

Effects of Oral Sodium Bicarbonate in Patients with CKD

BACKGROUND AND OBJECTIVES 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 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.

Association of sarcopenia with eGFR and misclassification of obesity in adults with CKD in the United States.

BACKGROUND AND OBJECTIVES Muscle wasting is common among patients with ESRD, but little is known about differences in muscle mass in persons with CKD before the initiation of dialysis. If sarcopenia was common, it might affect the use of body mass index for diagnosing obesity in people with CKD. Because obesity may be protective in patients with CKD and ESRD, an accurate understanding of how sarcopenia affects its measurement is crucial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Differences in body composition across eGFR categories in adult participants of the National Health and Nutrition Examination Survey 1999-2004 who underwent dual-energy x-ray absorptiometry were examined. Obesity defined by dual-energy x-ray absorptiometry versus body mass index and sarcopenia as a contributor to misclassification by body mass index were examined. RESULTS Sarcopenia and sarcopenic obesity were more prevalent among persons with lower eGFR (P trend <0.01 and P trend <0.001, respectively). After multivariable adjustment, the association of sarcopenia with eGFR was U-shaped. Stage 4 CKD was independently associated with sarcopenia among participants ≥60 years old (adjusted odds ratio, 2.58; 95% confidence interval, 1.02 to 6.51 for eGFR=15-29 compared with 60-89 ml/min per 1.73 m(2); P for interaction by age=0.02). Underestimation of obesity by body mass index compared with dual-energy x-ray absorptiometry increased with lower eGFR (P trend <0.001), was greatest among participants with eGFR=15-29 ml/min per 1.73 m(2) (71% obese by dual-energy x-ray absorptiometry versus 41% obese by body mass index), and was highly likely among obese participants with sarcopenia (97.7% misclassified as not obese by body mass index). CONCLUSIONS Sarcopenia and sarcopenic obesity are highly prevalent among persons with CKD and contribute to poor classification of obesity by body mass index. Measurements of body composition beyond body mass index should be used whenever possible in the CKD population given this clear limitation.

Association of Serum Bicarbonate Levels With Gait Speed and Quadriceps Strength in Older Adults

BACKGROUND Metabolic acidosis is associated with skeletal muscle proteolysis, and alkali supplementation has shown improvements in lean body mass and urinary nitrogen wasting in several studies. However, the association of acidosis with functional outcomes has not been examined on a population-based level. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS 2,675 nationally representative adults 50 years or older in the National Health and Nutrition Examination Survey 1999-2002. FACTOR Serum bicarbonate level. OUTCOMES Low gait speed and low peak torque were defined as being in the lowest sex-specific quartile of gait speed and peak torque, respectively. MEASUREMENTS Serum bicarbonate was measured in all participants. Gait speed was determined from a 20-foot timed walk. Peak torque was calculated using peak isokinetic knee extensor force. RESULTS Serum bicarbonate level <23 mEq/L was present in 22.7% of the cohort. Compared with participants with bicarbonate levels ≥23 mEq/L, those with bicarbonate levels <23 mEq/L had higher body mass index and serum albumin levels; were more likely to have low socioeconomic status, a diagnosis of diabetes mellitus, or glomerular filtration rate <60 mL/min/1.73 m(2); and were less likely to use diuretics. Serum bicarbonate level <23 mEq/L compared with ≥23 mEq/L was associated with low gait speed (OR, 1.43; 95% CI, 1.04-1.95) and low peak torque (OR, 1.36; 95% CI, 1.07-1.74) after multivariable adjustment. The association with low peak torque was modified by race/ethnicity in women, but not men (ORs, 1.52 [95% CI, 1.08-2.13] for men, 2.33 [95% CI, 1.23-4.44] for nonwhite women, and 0.93 [95% CI, 0.47-1.82] for white women). LIMITATIONS Cross-sectional study using a single bicarbonate measurement. CONCLUSIONS Lower serum bicarbonate levels are associated with slower gait speed and decreased quadriceps strength in older adults. Further studies should examine the effect of alkali therapy on functional outcomes.

Lower serum bicarbonate and a higher anion gap are associated with lower cardiorespiratory fitness in young adults

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 one standard deviation 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.

The serum anion gap is altered in early kidney disease and associates with mortality

It is well known that uremia causes an increase in the serum anion gap; however, whether changes in the anion gap occur earlier in the course of chronic kidney disease is not known. Here we investigated whether different measures of the anion gap, 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 anion gap using the traditional method, or one that was albumin-adjusted, as well as a full anion gap reflecting other electrolytes. A significant elevation in the traditional anion gap was seen only with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73m2, whereas increases in the albumin-adjusted and full anion gap were found with eGFRs less than 60 or 90mL/min/1.73m2, respectively. Higher levels of each anion gap 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 anion gap were associated with mortality (relative hazard for highest compared to the lowest quartile were 1.62 and 1.64, respectively). Thus, higher levels of anion gap 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 physiologic significance.

Dietary Acid, Age, and Serum Bicarbonate Levels among Adults in the United States

BACKGROUND AND OBJECTIVES Greater dietary acid has been associated with lower serum bicarbonate levels in patients with CKD. Whether this association extends to the general population and if it is modified by age are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study examined the association of the dietary acid load, estimated by net endogenous acid production, with serum bicarbonate levels in adult participants in the National Health and Nutrition Examination Survey 1999-2004. RESULTS The mean serum bicarbonate was 24.9 mEq/L (SEM=0.1), and the mean estimated net endogenous acid production was 57.4 mEq/d (SEM=0.4). Serum bicarbonate was linearly associated with age, such that the oldest participants had the highest serum bicarbonate levels. After multivariable adjustment, participants in the highest quartile of net endogenous acid production had 0.40 mEq/L (95% confidence interval, -0.55 to -0.26) lower serum bicarbonate and a 33% (95% confidence interval, 3 to 72) higher likelihood of acidosis compared with those participants in the lowest quartile. There was a significant interaction by age of the association of net endogenous acid production with serum bicarbonate (P=0.005). Among participants 20-39, 40-59, and ≥60 years old, those participants in the highest net endogenous acid production quartile had 0.26 (95% confidence interval, -0.49 to -0.03), 0.60 (95% confidence interval, -0.92 to -0.29), and 0.49 (95% confidence interval, -0.84 to -0.14) mEq/L lower serum bicarbonate, respectively, compared with participants in the lowest quartile. CONCLUSION Greater dietary acid is associated with lower serum bicarbonate in the general US population, and the magnitude of this association is greater among middle-aged and elderly persons than younger adults.

Metabolic acidosis and the progression of chronic kidney disease

Metabolic acidosis is a common complication of chronic kidney disease. Accumulating evidence identifies acidosis not only as a consequence of, but as a contributor to, kidney disease progression. Several mechanistic pathways have been identified in this regard. The dietary acid load, even in the absence of overt acidosis, may have deleterious effects. Several small trials now suggest that the treatment of acidosis with oral alkali can slow the progression of kidney disease.