Current status of bicarbonate in CKD Dobre, Mirela; Rahman, Mahboob; Hostetter, Thomas H
Journal of the American Society of Nephrology,
03/2015, Letnik:
26, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Metabolic acidosis was one of the earliest complications to be recognized and explained pathologically in patients with CKD. Despite the accumulated evidence of deleterious effects of acidosis, ...treatment of acidosis has been tested very little, especially with respect to standard clinical outcomes. On the basis of fundamental research and small alkali supplementation trials, correcting metabolic acidosis has a strikingly broad array of potential benefits. This review summarizes the published evidence on the association between serum bicarbonate and clinical outcomes. We discuss the role of alkali supplementation in CKD as it relates to retarding kidney disease progression, improving metabolic and musculoskeletal complications.
Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline ...free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients.
We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA.
Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses.
Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.
Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. ...We determined the association of the proatherogenic metabolite trimethylamine N-oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3-6 months after randomization from a total of 1232 white and black patients of the Hemodialysis Study, and analyzed the association of TMAO with cardiovascular outcomes using Cox models adjusted for potential confounders (demographics, clinical characteristics, comorbidities, albumin, and residual kidney function). Mean age of the patients was 58 years; 35% of patients were white. TMAO concentration did not differ between whites and blacks. In whites, 2-fold higher TMAO associated with higher risk (hazard ratio 95% confidence interval) of cardiac death (1.45 1.24 to 1.69), sudden cardiac death 1.70 (1.34 to 2.15), first cardiovascular event (1.15 1.01 to 1.32), and any-cause death (1.22 1.09 to 1.36). In blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentrations below the median (1.58 1.03 to 2.44). Compared with blacks in the same quintile, whites in the highest quintile for TMAO (≥135 μM) had a 4-fold higher risk of cardiac or sudden cardiac death and a 2-fold higher risk of any-cause death. We conclude that TMAO concentration associates with cardiovascular events in hemodialysis patients but the effects differ by race.
Metabolic acidosis associated with chronic kidney disease (CKD) may contribute to muscle dysfunction and bone disease. We aimed to test whether treatment with sodium bicarbonate improves muscle and ...bone outcomes.
Multicenter, randomized, placebo-controlled, clinical trial.
149 patients with CKD stages 3 and 4 between July 2011 and April 2016 at 3 centers in Cleveland, OH, and the Bronx, NY.
Sodium bicarbonate (0.4 mEq per kg of ideal body weight per day) (n=74) or identical-appearing placebo (n=75).
Dual primary outcomes were muscle function assessed using sit-to-stand test and bone mineral density. Muscle biopsies were performed at baseline and 2 months. Participants were seen at baseline and 2, 6, 12, and 24 months.
Mean baseline serum bicarbonate level was 24.0±2.2 (SD) mEq/L and mean baseline estimated glomerular filtration rate was 36.3±11.2mL/min/1.73m2. Baseline characteristics did not differ between groups. Mean serum bicarbonate levels in the intervention arm during follow-up were 26.4±2.2, 25.5±2.3, 25.6±2.6, and 24.4±2.8 mEq/L (at 2, 6, 12, and 24 months). These were significantly higher than in the placebo group (P<0.001). Compared to the placebo group, participants randomly assigned to sodium bicarbonate treatment had no significant differences in sit-to-stand time (5 repetitions: P=0.1; and 10 repetitions P=0.07) or bone mineral density (P=0.3). Sodium bicarbonate treatment caused a decrease in serum potassium levels that was of borderline statistical significance (P=0.05). There were no significant differences in estimated glomerular filtration rates, blood pressure, weight, serious adverse events, or levels of muscle gene expression between the randomly assigned groups.
Initial mean serum bicarbonate level was in the normal range.
Sodium bicarbonate therapy in patients with CKD stages 3 and 4 significantly increases serum bicarbonate and decreases potassium levels. No differences were found in muscle function or bone mineral density between the randomly assigned groups. Larger trials are required to evaluate effects on kidney function.
National Institutes of Health grant.
Registered at ClinicalTrials.gov with study number NCT01452412
Numerous uremic solutes are derived from the action of colon microbes. Two such solutes, indoxyl sulfate and p-cresol sulfate, have been associated with adverse outcomes in renal failure. This study ...tested whether increasing dietary fiber in the form of resistant starch would lower the plasma levels of these solutes in patients on hemodialysis.
Fifty-six patients on maintenance hemodialysis were randomly assigned to receive supplements containing resistant starch (n=28) or control starch (n=28) daily for 6 weeks in a study conducted between October 2010 and May 2013. Of these, 40 patients (20 in each group) completed the study and were included in the final analysis. Plasma indoxyl sulfate and p-cresol sulfate levels were measured at baseline and week 6.
Increasing dietary fiber for 6 weeks significantly reduced the unbound, free plasma level of indoxyl sulfate (median -29% 25th percentile, 75th percentile, -56, -12 for fiber versus -0.4% -20, 34 for control, P=0.02). The reduction in free plasma levels of indoxyl sulfate was accompanied by a reduction in free plasma levels of p-cresol sulfate (r=0.81, P<0.001). However, the reduction of p-cresol sulfate levels was of lesser magnitude and did not achieve significance (median -28% -46, 5 for fiber versus 4% -28, 36 for control, P=0.05).
Increasing dietary fiber in hemodialysis patients may reduce the plasma levels of the colon-derived solutes indoxyl sulfate and possibly p-cresol sulfate without the need to intensify dialysis treatments. Further studies are required to determine whether such reduction provides clinical benefits.
Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a ...molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 ± 26 vs 2±1 μM, mean ± SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45±11 mg/dl and 15±3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86±3 vs 74±6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine's. Also production rates were similar (533±272 vs 606 ± 220 μ moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219±78 ml/min) compared to the urinary urea and creatinine clearances (55±14 and 119±21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO's high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions.
Background Animal models of kidney disease have linked metabolic acidosis with renal damage. The role of low serum bicarbonate levels in kidney disease progression in humans has not been studied. ...Study Design Retrospective cohort study. Setting & Participants Adults visiting a medical clinic in the Bronx, NY, from January 1, 2001, to December 31, 2003, were included in the study (n = 5,422) and followed up until June 30, 2007. Predictor Serum bicarbonate level. Outcomes Kidney disease progression was defined as either a decrease in estimated glomerular filtration rate (eGFR) by 50% or reaching an eGFR less than 15 mL/min/1.73 m2 (n = 337). Measurements Patients' baseline demographics, comorbid conditions, laboratory data, and socioeconomic status were recorded. Serial outpatient serum creatinine levels were collected (median, 5 measurements/person). Results Mean age was 52 years, 69% were women, 45% were African American, 31% were Hispanic, 21% had diabetes mellitus, 41% had hypertension, and 9% had a baseline eGFR less than 60 mL/min/1.73 m2 . Kidney disease progressed as defined in 337 patients (6.2%). Compared with the reference group (bicarbonate level, 25 to 26 mEq/L), hazard ratios for progression after adjustment for potential confounders were 1.54 (95% confidence interval CI, 1.13 to 2.09) for bicarbonate levels of 22 mEq/L or less, 0.97 (95% CI, 0.70 to 1.35) for 23 to 24 mEq/L, and 1.14 (95% CI, 0.84 to 1.55) for 27 mEq/L or greater (global P for inclusion of serum bicarbonate level in the model = 0.01). These results were similar using different definitions of the outcome (eGFR decrease of 30%, 1,288 outcomes 24%; or doubling of serum creatinine level, 268 outcomes 4.9%). Limitations Data used in the study were collected for clinical, not research, purposes. Conclusions Low serum bicarbonate level is associated with progression of kidney disease independent of baseline eGFR and other clinical, demographic, and socioeconomic factors. Prospective studies are needed to confirm this relationship and evaluate the efficacy of alkali supplements for slowing progression.
Uremic solutes from colon microbes Meyer, Timothy W.; Hostetter, Thomas H.
Kidney international,
05/2012, Letnik:
81, Številka:
10
Journal Article
Recenzirano
Odprti dostop
There is renewed interest in identifying organic waste solutes that are normally excreted by the kidneys and must be removed by renal replacement therapy when the kidneys fail. A large number of ...these waste solutes are produced by colon microbes. Mass spectrometry is expanding our knowledge of their chemical identity, and DNA sequencing technologies are providing new knowledge of the microbes and metabolic pathways by which they are made. There is evidence that the most extensively studied of the colon-derived solutes, indoxyl sulfate and p-cresol sulfate, are toxic. Much more study is required to establish the toxicity of other solutes in this class. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than the production of other waste solutes. To the extent that they are toxic, suppressing their production could improve the health of renal failure patients without the need for more intensive or prolonged dialysis.
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