FABRY DISEASE PRESENTING AS END-STAGE KIDNEY DISEASE

Fabry Disease is an X-linked disorder due to a pathogenic variant of the GLA gene that codes for the alpha-galctosidase enzyme. The reduced or absent activity of the enzyme results in lysosomal accumulation of globotriosylceramide, and its derivative, globotriaosylsphingosine in a variety of cells leading to a variety of complications including cardiac, renal, and cerebrovascular disorders. Early diagnosis is critically important for the selection of therapeutic treatments, which are essential for improving outcomes. Here we present a case of Fabry Disease diagnosed at the time of ESKD presentation. A 40-year-old man with a history of seizures, presented with increased serum creatinine, nephrotic rage proteinuria and new onset hypertension. A renal biopsy revealed numerous, whorled, and lamellated cytoplasmic inclusions in podocytes, glomerular peritubular capillary endothelial cells, mesangial cells, arterial myocytes and interstitial macrophages. Ultrastructural analysis confirmed the presence of glycosphingolipid inclusions and enlarged lysosomes packed with multi-lamellated structures ("zebra" bodies). The findings were suggestive of a lysosomal storage disorder and testing for alpha-galactosidase A levels revealed near-absent enzyme activity, confirming the diagnosis of advanced Fabry disease. The diagnosis of FD can be challenging as the manifestations of the disease are non-specific, and patients can present early with classical symptoms or late with non-classical patterns of involvement. We will discuss strategies to identify the disorder early by reviewing the classical and non-classical presentations and further outline currently available and potential future treatment options

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

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

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 XXX 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. SETTING: XXX dialysis center SUBJECTS: 93 pre conversion intravenous paricalcitol and 91 post conversion oral calcitriol INTERVENTION: Conversion to in-center, pulse, oral calcitriol (0.25 mcg =1 mcg paricalcitol) 3 times a week from intravenous paracalcitol. Additional dose adjustments were made by the nephrologists based on clinical indications. MAIN OUTCOME MEASURE: 5-month average serum calcium, phosphorous, and intact parathyroid hormone levels and cardiovascular events pre and post transition. 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 post-conversion 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 post-conversion period. Sevelamer use increased from 41 (44.1%) patients pre-conversion to 48 (52.7%) post-conversion, while calcium acetate use significantly dropped from 62 (66.7%) to 46 (50.5%) (p=0.026). Cinacalcet use dropped slightly from 37 (39.7%) patients pre- to 35 (38.4%) post-conversion. Average serum calcium, phosphorus and intact parathyroid hormone levels remained unchanged after conversion. Percent of values within KDOQI 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

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

Fabry Disease Presenting as End-Stage Kidney Disease.

BACKGROUND: Fabry disease (FD) is an X-linked disorder due to a pathogenic variant of the GLA gene that codes for the alpha-galactosidase enzyme. The reduced or absent activity of the enzyme results in lysosomal accumulation of globotriosylceramide and its derivative, globotriaosylsphingosine, in a variety of cells, leading to a variety of complications including cardiac, renal, and cerebrovascular disorders. Early diagnosis is critically important for the selection of therapeutic treatments, which are essential for improving outcomes. Here we present a case of FD diagnosed at the time of end-stage kidney disease presentation. SUMMARY: A 40-year-old man with a history of seizures presented with increased serum creatinine, nephrotic rage proteinuria, and new-onset hypertension. A renal biopsy revealed numerous, whorled, and lamellated cytoplasmic inclusions in podocytes, glomerular peritubular capillary endothelial cells, mesangial cells, arterial myocytes, and interstitial macrophages. Ultrastructural analysis confirmed the presence of glycosphingolipid inclusions and enlarged lysosomes packed with multi-lamellated structures (zebra bodies). The findings were suggestive of a lysosomal storage disorder, and testing for alpha-galactosidase A levels revealed near-absent enzyme activity, confirming the diagnosis of advanced FD. KEY MESSAGES: The diagnosis of FD can be challenging as the manifestations of the disease are nonspecific, and patients can present early with classical symptoms or late with non-classical patterns of involvement. We will discuss strategies to identify the disorder early by reviewing the classical and non-classical presentations and further outline currently available and potential future treatment options

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