Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Incremental Hemodialysis: The University of California Irvine Experience.

Incremental hemodialysis has been examined as a viable hemodialysis regimen for selected end-stage renal disease (ESRD) patients. Preservation of residual kidney function (RKF) has been the driving impetus for this approach given its benefits upon the survival and quality of life of dialysis patients. While clinical practice guidelines recommend an incremental start of dialysis in peritoneal dialysis patients with substantial RKF, there remains little guidance with respect to incremental hemodialysis as an initial renal replacement therapy regimen. Indeed, several large population-based studies suggest that incremental twice-weekly vs. conventional thrice-weekly hemodialysis has favorable impact upon RKF trajectory and survival among patients with adequate renal urea clearance and/or urine output. In this report, we describe a case series of 13 ambulatory incident ESRD patients enrolled in a university-based center's Incremental Hemodialysis Program over the period of January 2015 to August 2016 and followed through December 2016. Among five patients who maintained a twice-weekly hemodialysis schedule vs. eight patients who transitioned to thrice-weekly hemodialysis, we describe and compare patients' longitudinal case-mix, laboratory, and dialysis treatment characteristics over time. The University of California Irvine Experience is the first systemically examined twice-weekly hemodialysis practice in North America. While future studies are needed to refine the optimal approaches and the ideal patient population for implementation of incremental hemodialysis, our case-series serves as a first report of this innovative management strategy among incident ESRD patients with substantial RKF, and a template for implementation of this regimen.

Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND).

BACKGROUND: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample. RESULTS: A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy. CONCLUSIONS: The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment.

Chronic kidney disease (CKD) results in systemic inflammation and oxidative stress which play a central role in CKD progression and its adverse consequences. Although many of the causes and consequences of oxidative stress and inflammation in CKD have been extensively explored, little attention had been paid to the intestine and its microbial flora as a potential source of these problems. Our recent studies have revealed significant disruption of the colonic, ileal, jejunal and gastric epithelial tight junction in different models of CKD in rats. Moreover, the disruption of the epithelial barrier structure and function found in uremic animals was replicated in cultured human colonocytes exposed to uremic human plasma in vitro We have further found significant changes in the composition and function of colonic bacterial flora in humans and animals with advanced CKD. Together, uremia-induced impairment of the intestinal epithelial barrier structure and function and changes in composition of the gut microbiome contribute to the systemic inflammation and uremic toxicity by accommodating the translocation of endotoxin, microbial fragments and other noxious luminal products in the circulation. In addition, colonic bacteria are the main source of several well-known pro-inflammatory uremic toxins such as indoxyl sulfate, p-cresol sulfate, trimethylamine-N-oxide and many as-yet unidentified retained compounds in end-stage renal disease patients. This review is intended to provide an overview of the effects of CKD on the gut microbiome and intestinal epithelial barrier structure and their role in the pathogenesis of systemic inflammation and uremic toxicity. In addition, potential interventions aimed at mitigating these abnormalities are briefly discussed.

Successful Conversion From Parenteral Paricalcitol to Pulse Oral Calcitriol for the Management of Secondary Hyperparathyroidism in Hemodialysis Patients.

OBJECTIVE: The management of hyperparathyroidism in hemodialysis patients involves the administration of phosphate binders, vitamin D receptor activators, and calcimimetics. Intravenous paricalcitol has been preferred over oral calcitriol as it may cause less hypercalcemia and hyperphosphatemia. However, there is little data looking at the efficacy and tolerability of oral calcitriol in the calcimimetic era particularly in a real practice-based experience. The University of California, Irvine free-standing dialysis center converted from routine intravenous paricalcitol to oral calcitriol due to pharmacy purchasing preferences. We report the efficacy, safety, and cost of such a change. SUBJECTS: Ninety-three preconversion intravenous paricalcitol and 91 postconversion oral calcitriol. INTERVENTION: Conversion to in-center, pulse, oral calcitriol (0.25 mcg = 1 mcg paricalcitol) 3 times a week from intravenous paricalcitol. Additional dose adjustments were made by the nephrologists based on clinical indications. MAIN OUTCOME MEASURE: Five-month average serum calcium, phosphorous, and intact parathyroid hormone levels and cardiovascular events pretransition and posttransition. RESULTS: There were 93 patients on intravenous paricalcitol between April 2013 and August 2013, of which 74 converted to oral calcitriol and were included in the postconversion group evaluated between October 2013 and February 2014. An additional 17 new patients had initiated calcitriol such that 91 patients were on oral therapy in the postconversion period. Sevelamer use increased from 41 (44.1%) patients preconversion to 48 (52.7%) postconversion, whereas calcium acetate use significantly dropped from 62 (66.7%) to 46 (50.5%) (P = .026). Cinacalcet use dropped slightly from 37 (39.7%) patients preconversion to 35 (38.4%) postconversion. Average serum calcium, phosphorus, and intact parathyroid hormone levels remained unchanged after conversion. Percent of values within Kidney Disease Outcome Quality Initiative guidelines were similarly maintained. Estimated vitamin D cost savings were $564 per person/year. No increase in the incidence of cardiovascular events was observed. CONCLUSIONS: We conclude that in-center distributed pulse oral calcitriol may be an effective, safe, and economical treatment option for the management of hyperparathyroidism in hemodialysis patients.

Association of serum lipids with outcomes in Hispanic hemodialysis patients of the West versus East Coasts of the United States.

BACKGROUND: Paradoxical associations exist between serum lipid levels and mortality in patients on maintenance hemodialysis (MHD) including those of Hispanic origin. However, there are significant racial and ethnic variations in patients of 'Hispanic' background. We hypothesized that clinically meaningful differences existed in the association between lipids and survival in Hispanic MHD patients on the West versus East Coast. METHODS: We examined the survival impact of serum lipids in a 2-year cohort of 15,109 MHD patients of Hispanic origin being treated in California, Texas, representing the West versus New York, New Jersey and Florida representing the East Coast, using Cox models with various degrees of adjustments. RESULTS: The association of serum total and HDL cholesterol with mortality follows a U-shaped pattern in Hispanic patients residing in the West. This is in contrast to Hispanic patients in the East Coast whose survival seems to improve with increasing total and HDL cholesterol levels. Elevated serum LDL levels in Hispanic patients on the West Coast are associated with a significant increase in mortality, while this association is not observed in patients residing on the East Coast. CONCLUSIONS: Substantial differences exist in the association of serum lipids with mortality in MHD patients of Hispanic background depending on whether they reside on the West or East Coast of the United States. These geographical variances most likely reflect ethnic, racial and genetic distinctions, which are usually ignored. Future studies should take into account these critical variations in a population of patients who make up a significant portion of our society.

The Chronic Kidney Disease - Colonic Axis.

Chronic kidney disease (CKD) has long been known to cause significant gastrointestinal and colonic pathology. Recent advances in understanding of the role of colonic bacterial microbiome and its function and composition in health and disease have revealed previously unappreciated effects of CKD-associated colonic pathology on the development of uremic complications. CKD can result in profound changes in the microbiome composition and biosynthetic pattern, and the structure and function of the colon. Increases in bacteria that produce urease, uricase, p-cresol- and indole-forming enzymes and the depletion of bacteria that possess short chain fatty acid forming enzymes have been described in human and animal models. Disruption of the colonic epithelial tight junction in different animal models of CKD has been reported and is largely due to the conversion of luminal urea to ammonia by urease possessing bacteria. Together, these changes contribute to the pathogenesis of systemic inflammation and uremic toxicity by allowing the translocation of endotoxin and microbial fragments into the circulation. Additionally, colonic bacteria are the main source of several well-known pro-inflammatory uremic toxins such as indoxyl sulfate, P-cresol sulfate. This review is intended to provide an overview of the effects of CKD on the colonic microbiome and the intestinal epithelial barrier structure and function and their role in the pathogenesis the systemic inflammation and uremic toxicity.

Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD.

BACKGROUND: Intestinal microbiome constitutes a symbiotic ecosystem that is essential for health, and changes in its composition/function cause various illnesses. Biochemical milieu shapes the structure and function of the microbiome. Recently, we found marked differences in the abundance of numerous bacterial taxa between ESRD and healthy individuals. Influx of urea and uric acid and dietary restriction of fruits and vegetables to prevent hyperkalemia alter ESRD patients' intestinal milieu. We hypothesized that relative abundances of bacteria possessing urease, uricase, and p-cresol- and indole-producing enzymes is increased, while abundance of bacteria containing enzymes converting dietary fiber to short-chain fatty acids (SCFA) is reduced in ESRD. METHODS: Reference sets of bacteria containing genes of interest were compiled to family, and sets of intestinal bacterial families showing differential abundances between 12 healthy and 24 ESRD individuals enrolled in our original study were compiled. Overlap between sets was assessed using hypergeometric distribution tests. RESULTS: Among 19 microbial families that were dominant in ESRD patients, 12 possessed urease, 5 possessed uricase, and 4 possessed indole and p-cresol-forming enzymes. Among 4 microbial families that were diminished in ESRD patients, 2 possessed butyrate-forming enzymes. Probabilities of these overlapping distributions were <0.05. CONCLUSIONS: ESRD patients exhibited significant expansion of bacterial families possessing urease, uricase, and indole and p-cresol forming enzymes, and contraction of families possessing butyrate-forming enzymes. Given the deleterious effects of indoxyl sulfate, p-cresol sulfate, and urea-derived ammonia, and beneficial actions of SCFA, these changes in intestinal microbial metabolism contribute to uremic toxicity and inflammation.

Chronic kidney disease alters intestinal microbial flora.

The population of microbes (microbiome) in the intestine is a symbiotic ecosystem conferring trophic and protective functions. Since the biochemical environment shapes the structure and function of the microbiome, we tested whether uremia and/or dietary and pharmacologic interventions in chronic kidney disease alters the microbiome. To identify different microbial populations, microbial DNA was isolated from the stools of 24 patients with end-stage renal disease (ESRD) and 12 healthy persons, and analyzed by phylogenetic microarray. There were marked differences in the abundance of 190 bacterial operational taxonomic units (OTUs) between the ESRD and control groups. OTUs from Brachybacterium, Catenibacterium, Enterobacteriaceae, Halomonadaceae, Moraxellaceae, Nesterenkonia, Polyangiaceae, Pseudomonadaceae, and Thiothrix families were markedly increased in patients with ESRD. To isolate the effect of uremia from inter-individual variations, comorbid conditions, and dietary and medicinal interventions, rats were studied 8 weeks post 5/6 nephrectomy or sham operation. This showed a significant difference in the abundance of 175 bacterial OTUs between the uremic and control animals, most notably as decreases in the Lactobacillaceae and Prevotellaceae families. Thus, uremia profoundly alters the composition of the gut microbiome. The biological impact of this phenomenon is unknown and awaits further investigation.

Timing of return to dialysis in patients with failing kidney transplants.

In the last decade, the number of patients starting dialysis after a failed kidney transplant has increased substantially. These patients appear to be different from their transplant-naïve counterparts, and so may be the timing of dialysis therapy initiation. An increasing number of studies suggest that in transplant-naïve patients, later dialysis initiation is associated with better outcomes. Very few data are available on timing of dialysis reinitiation in failed transplant recipients, and they suggest that an earlier return to dialysis therapy tended to be associated with worse survival, especially among healthier and younger patients and women. Failed transplant patients may also have unique issues such as continuation of immunosuppression versus withdrawal or the need for remnant allograft nephrectomy with regard to dialysis reinitiation. These patients may have a different predialysis preparation work-up, worse blood pressure control, higher or lower serum phosphorus levels, lower serum bicarbonate concentration, and worse anemia management. The choice of dialysis modality may also represent an important question for these patients, even though there appears to be no difference in mortality between patients starting peritoneal versus hemodialysis. Finally, failed transplant patients returning to dialysis appear to have a higher mortality rate compared with transplant-naïve incident dialysis patients, especially in the first several months of dialysis therapy. In this review, we will summarize the available data related to the timing of dialysis initiation and outcomes in failed kidney transplant patients after returning to dialysis.