Dominic S. Raj

APOL1 risk variants, race, and progression of chronic kidney disease.

BACKGROUND Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. METHODS In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. RESULTS In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). CONCLUSIONS Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Advanced glycation end products: a Nephrologist's perspective.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules that accumulate in plasma and tissues with advancing age, diabetes, and renal failure. There is emerging evidence that AGEs are potential uremic toxins and may have a role in the pathogenesis of vascular and renal complications associated with diabetes and aging. AGEs are formed when a carbonyl of a reducing sugar condenses with a reactive amino group in target protein. These toxic molecules interact with specific receptors and elicit pleiotropic responses. AGEs accelerate atherosclerosis through cross-linking of proteins, modification of matrix components, platelet aggregation, defective vascular relaxation, and abnormal lipoprotein metabolism. In vivo and in vitro studies indicate that AGEs have a vital role in the pathogenesis of diabetic nephropathy and the progression of renal failure. The complications of normal aging, such as loss of renal function, Alzheimers disease, skin changes, and cataracts, may also be mediated by progressive glycation of long-lived proteins. AGEs accumulate in renal failure as a result of decreased excretion and increased generation resulting from oxidative and carbonyl stress of uremia. AGE-modified beta(2)-microglobulin is the principal pathogenic component of dialysis-related amyloidosis in patients undergoing dialysis. Available dialytic modalities are not capable of normalizing AGE levels in patients with end-stage renal disease. A number of reports indicated that restoration of euglycemia with islet-cell transplantation normalized and prevented further glycosylation of proteins. Aminoguanidine (AGN), a nucleophilic compound, not only decreases the formation of AGEs but also inhibits their action. A number of studies have shown that treatment with AGN improves neuropathy and delays the onset of retinopathy and nephropathy. N-Phenacylthiazolium bromide is a prototype AGE cross-link breaker that reacts with and can cleave covalent AGE-derived protein cross-links. Thus, there is an exciting possibility that the complications of diabetes, uremia, and aging may be prevented with these novel agents.

The Gut Microbiome, Kidney Disease, and Targeted Interventions

The human gut harbors >100 trillion microbial cells, which influence the nutrition, metabolism, physiology, and immune function of the host. Here, we review the quantitative and qualitative changes in gut microbiota of patients with CKD that lead to disturbance of this symbiotic relationship, how this may contribute to the progression of CKD, and targeted interventions to re-establish symbiosis. Endotoxin derived from gut bacteria incites a powerful inflammatory response in the host organism. Furthermore, protein fermentation by gut microbiota generates myriad toxic metabolites, including p-cresol and indoxyl sulfate. Disruption of gut barrier function in CKD allows translocation of endotoxin and bacterial metabolites to the systemic circulation, which contributes to uremic toxicity, inflammation, progression of CKD, and associated cardiovascular disease. Several targeted interventions that aim to re-establish intestinal symbiosis, neutralize bacterial endotoxins, or adsorb gut-derived uremic toxins have been developed. Indeed, animal and human studies suggest that prebiotics and probiotics may have therapeutic roles in maintaining a metabolically-balanced gut microbiota and reducing progression of CKD and uremia-associated complications. We propose that further research should focus on using this highly efficient metabolic machinery to alleviate uremic symptoms.

Fibroblast Growth Factor-23 and Cardiovascular Events in CKD

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

Association between Albuminuria, Kidney Function, and Inflammatory Biomarker Profile in CKD in CRIC

BACKGROUND AND OBJECTIVES Increased risk of mortality in patients with CKD has been attributed to inflammation. However, the association between kidney function, albuminuria, and biomarkers of inflammation has not been examined in a large cohort of CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study measured the plasma levels of IL-1β, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin in 3939 participants enrolled in the Chronic Renal Insufficiency Cohort study between June 2003 and September 2008. An inflammation score was established based on plasma levels of IL-1β, IL-6, TNF-α, hs-CRP, and fibrinogen. Estimated GFR (eGFR) and serum cystatin C were used as measures of kidney function. Albuminuria was quantitated by urine albumin to creatinine ratio (UACR). RESULTS Plasma levels of IL-1β, IL-1RA, IL-6, TNF-α, hs-CRP, and fibrinogen were higher among participants with lower levels of eGFR. Inflammation score was higher among those with lower eGFR and higher UACR. In regression analysis adjusted for multiple covariates, eGFR, cystatin C, and UACR were strongly associated with fibrinogen, serum albumin, IL-6, and TNF-α. Each unit increase in eGFR, cystatin C, and UACR was associated with a -1.2% (95% confidence interval, -1.4, -1), 64.9% (56.8, 73.3) and 0.6% (0.4, 0.8) change in IL-6, respectively (P<0.001). CONCLUSIONS Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria.

Fibroblast Growth Factor 23 and Inflammation in CKD

BACKGROUND AND OBJECTIVES Levels of fibroblast growth factor 23 (FGF23) and inflammatory markers are commonly elevated in CKD, and each is associated with adverse clinical outcomes. This study tested the hypothesis that FGF23 is independently associated with inflammation in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The association between levels of FGF23 and the inflammatory markers IL-6, C-reactive protein (CRP), TNF-α, and fibrinogen was assessed in a cross-sectional analysis of 3879 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study between June 2003 and September 2008. RESULTS FGF23 correlated directly with IL-6 (r=0.4), CRP (r=0.2), TNF-α (r=0.4), and fibrinogen (r=0.3; P<0.001 for each). In univariate and multivariable-adjusted linear regression analyses, natural log (ln) transformed FGF23 was significantly associated with lnIL-6, lnCRP, lnTNF-α, and fibrinogen (P<0.001 for each). Each unit higher lnFGF23 was associated with severe inflammation, defined as levels of all inflammatory markers in the highest 25th percentile, in univariate (odds ratio [OR], 2.4 [95% confidence interval (CI), 2.0-2.9]) and multivariable-adjusted (OR, 2.0 [95% CI, 1.6-2.5]) logistic regression analyses. Ascending FGF23 quartiles were independently associated with severe inflammation (OR, 5.6 for the highest versus lowest FGF23 quartile [95% CI, 2.3-13.9]; P for trend < 0.001). CONCLUSIONS Higher FGF23 levels are independently associated with higher levels of inflammatory markers in patients with CKD and with significantly greater odds of severe inflammation. Future studies should evaluate whether inflammation modifies the association between FGF23 and adverse outcomes in CKD.

Wasting in chronic kidney disease

Wasting/cachexia is prevalent among patients with chronic kidney disease (CKD). It is to be distinguished from malnutrition, which is defined as the consequence of insufficient food intake or an improper diet. Malnutrition is characterized by hunger, which is an adaptive response, whereas anorexia is prevalent in patients with wasting/cachexia. Energy expenditure decreases as a protective mechanism in malnutrition whereas it remains inappropriately high in cachexia/wasting. In malnutrition, fat mass is preferentially lost and lean body mass and muscle mass is preserved. In cachexia/wasting, muscle is wasted and fat is relatively underutilized. Restoring adequate food intake or altering the composition of the diet reverses malnutrition. Nutrition supplementation does not totally reverse cachexia/wasting. The diagnostic criteria of cachexia/protein–energy wasting in CKD are considered. The association of wasting surrogates, such as serum albumin and prealbumin, with mortality is strong making them robust outcome predictors. At the patient level, longevity has consistently been observed in patients with CKD who have more muscle and/or fat, who report better appetite and who eat more. Although inadequate nutritional intake may contribute to wasting or cachexia, recent evidence indicates that other factors, including systemic inflammation, perturbations of appetite-controlling hormones from reduced renal clearance, aberrant neuropeptide signaling, insulin and insulin-like growth factor resistance, and metabolic acidosis, may be important in the pathogenesis of CKD-associated wasting. A number of novel therapeutic approaches, such as ghrelin agonists and melanocortin receptor antagonists are currently at the experimental level and await confirmation by randomized controlled clinical trials in patients with CKD-associated cachexia/wasting syndrome.

Diets and enteral supplements for improving outcomes in chronic kidney disease

Protein-energy wasting (PEW), which is manifested by low serum levels of albumin or prealbumin, sarcopenia and weight loss, is one of the strongest predictors of mortality in patients with chronic kidney disease (CKD). Although PEW might be engendered by non-nutritional conditions, such as inflammation or other comorbidities, the question of causality does not refute the effectiveness of dietary interventions and nutritional support in improving outcomes in patients with CKD. The literature indicates that PEW can be mitigated or corrected with an appropriate diet and enteral nutritional support that targets dietary protein intake. In-center meals or oral supplements provided during dialysis therapy are feasible and inexpensive interventions that might improve survival and quality of life in patients with CKD. Dietary requirements and enteral nutritional support must also be considered in patients with CKD and diabetes mellitus, in patients undergoing peritoneal dialysis, renal transplant recipients, and in children with CKD. Adjunctive pharmacological therapies, such as appetite stimulants, anabolic hormones, and antioxidative or anti-inflammatory agents, might augment dietary interventions. Intraperitoneal or intradialytic parenteral nutrition should be considered for patients with PEW whenever enteral interventions are not possible or are ineffective. Controlled trials are needed to better assess the effectiveness of in-center meals and oral supplements.

Soluble CD14 Levels, Interleukin-6, and Mortality Among Prevalent Hemodialysis Patients

BACKGROUND CD14 is a pattern-recognition receptor that has a central immunomodulatory role in proinflammatory signaling in response to a variety of ligands, including endotoxin. CD14 protein is present in 2 forms: soluble (sCD14) and membrane bound. Here, we studied the implications of increased sCD14 levels in hemodialysis patients. We hypothesized that sCD14 level increase may link to cytokine activation and protein-energy wasting, predisposing to increased mortality risk. STUDY DESIGN Prospective observational study of prevalent hemodialysis patients. SETTING & PARTICIPANTS 211 prevalent hemodialysis patients, median age of 65 years, with 29 months of vintage dialysis time followed up for mortality for a median of 31 months. PREDICTORS Tertiles of baseline circulating sCD14 levels corresponding to less than 2.84, 2.85 to 3.62, and greater than 3.63 microg/mL. OUTCOME The major outcome of interest was all-cause mortality. MEASUREMENTS sCD14 and endotoxin, together with other markers of inflammation and protein-energy wasting. RESULTS Median sCD14 level was 3.2 microg/mL (25th to 75th percentile, 2.7 to 3.9). sCD14 level correlated positively with C-reactive protein, interleukin 6, endotoxin, and pentraxin 3 levels and negatively with serum albumin level, muscle mass, and handgrip strength. Patients with increased sCD14 levels had lower body mass index and increased prevalence of muscle atrophy. Patients within the highest sCD14 tertile had a crude morality hazard ratio of 1.94 (95% confidence interval, 1.13 to 3.32) that persisted after adjustment for multiple confounders (hazard ratio, 3.11; 95% confidence interval, 1.49 to 6.46). In patients with persistent inflammation, the presence of a concurrent sCD14 level increase gradually increased mortality risk, but this effect was less than multiplicative and failed to show a statistical interaction. LIMITATIONS Those inherent to an observational study. CONCLUSIONS sCD14 level is associated with inflammation and protein-energy wasting in hemodialysis patients. It is a strong and independent predictor of mortality that warrants further assessment in the clinical setting regarding its usefulness as a complementary prognosticator to other general inflammatory markers.

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE study.