A paradigm shift from office to home-based blood pressure measurement approaches in kidney transplant recipients.

PURPOSE OF REVIEW: The unattended blood pressure (BP) readings from home blood pressure (HBP) monitoring should provide more accurate BP readings than attended BP obtained from office blood pressure (OBP). Here, we review evidence supporting the clinical utility of HBP and automatic remote monitoring of blood pressure (ARM-BP) in kidney transplant recipients (KTR). RECENT FINDINGS: BP from 24-h ambulatory blood pressure monitoring (24-h ABPM) is higher than but better associated with kidney and cardiovascular outcomes compared to OBP and HBP. While there is discordance of BP readings across different BP measurement methods causing BP misclassification, HBP provides BP readings closer to the readings from the 24-h ABPM than those from OBP. Systolic and diastolic BP is better controlled within 30 days after utilizing ARM-BP. SUMMARY: Compared to OBP, HBP minimizes the attended effect of OBP, and its readings are closer to the gold standard 24-h ABPM. ARM-BP improves BP control in the short term and trials of longer follow-up duration are required to evaluate sustained clinical benefits in KTR. The paradigm of BP monitoring may shift toward HBP, while OBP may be utilized primarily for KTR who cannot perform HBP for hypertension diagnosis and management.

Chronic kidney disease promotes cerebral microhemorrhage formation.

BACKGROUND: Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. METHODS: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. RESULTS: CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood-brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001). CONCLUSIONS: CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

A randomized study to compare oral potassium binders in the treatment of acute hyperkalemia.

BACKGROUND: The KBindER (K+ Binders in Emergency Room and hospitalized patients) clinical trial is the first head-to-head evaluation of oral potassium binders (cation-exchange resins) for acute hyperkalemia therapy. METHODS: Emergency room and hospitalized patients with a blood potassium level ≥ 5.5 mEq/L are randomized to one of four study groups: potassium binder drug (sodium polystyrene sulfonate, patiromer, or sodium zirconium cyclosilicate) or nonspecific laxative (polyethylene glycol). Exclusion criteria include recent bowel surgery, ileus, diabetic ketoacidosis, or anticipated dialysis treatment within 4 h of treatment drug. Primary endpoints include change in potassium level at 2 and 4 h after treatment drug. Length of hospital stay, next-morning potassium level, gastrointestinal side effects and palatability will also be analyzed. We are aiming for a final cohort of 80 patients with complete data endpoints (20 per group) for comparative statistics including multivariate adjustment for kidney function, diabetes mellitus, congestive heart failure, metabolic acidosis, renin-angiotensin-aldosterone system inhibitor prescription, and treatment with other agents to lower potassium (insulin, albuterol, loop diuretics). DISCUSSION: The findings from our study will inform decision-making guidelines on the role of oral potassium binders in the treatment of acute hyperkalemia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04585542 . Registered 14 October 2020.

Novel intestinal dialysis interventions and microbiome modulation to control uremia.

PURPOSE OF REVIEW: In patients with chronic kidney disease (CKD), the gut plays a key role in the homeostasis of fluid and electrolyte balance and the production and disposal of uremic toxins. This review summarizes the current evidence on the gut-targeted interventions to control uremia, fluid overload, hyperkalemia and hyperphosphatemia in CKD. RECENT FINDINGS: Studies have emerged that support the concept of intestinal dialysis, such as colonic perfusion with a Malone antegrade continence enema stoma or colonic irrigation with a rectal catheter, as a promising adjuvant approach to control uremia in CKD, although most findings are preliminary. The use of AST-120, an oral adsorbent, has been shown to reduce circulating levels of indoxyl sulfate and p-cresol sulfate and have potential renoprotective benefits in patients with advanced CKD. Diarrhea or inducing watery stools may modulate fluid retention and potassium and phosphorus load. Accumulating evidence indicates that plant-based diets, low-protein diets, and pre-, pro-, and synbiotic supplementation may lead to favorable alterations of the gut microbiota, contributing to reduce uremic toxin generation. The effects of these gut-targeted interventions on kidney and cardiovascular outcomes are still limited and need to be tested in future studies including clinical trials. SUMMARY: Interventions aimed at enhancing bowel elimination of uremic toxins, fluid and electrolytes and at modulating gut microbiota may represent novel therapeutic strategies for the management of uremia in patients with CKD.

Comparative Effectiveness of Dialysis Modality on Laboratory Parameters of Mineral Metabolism.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are prevalent in patients undergoing maintenance dialysis. Yet, there are limited and mixed evidence on the effects of different dialysis modalities involving longer treatment times or higher frequencies on CKD-MBD markers. METHODS: This cohort study used data from 132,523 incident dialysis patients treated with any of the following modalities: conventional thrice-weekly in-center hemodialysis, nocturnal in-center hemodialysis (NICHD), home hemodialysis (HHD), or peritoneal dialysis (PD) from 2007 to 2011. We used marginal structural models fitted with inverse probability weights to adjust for fixed and time-varying confounding and informative censoring. We estimated the average effects of treatments with different dialysis modalities on time-varying serum concentrations of CKD-MBD markers: albumin-corrected calcium, phosphate, parathyroid hormone (PTH), and alkaline phosphatase (ALP) using pooled linear regression. RESULTS: Most of the cohort were exclusively treated with conventional in-center hemodialysis, while few were ever treated with NICHD or HHD. At the baseline, PD patients had the lowest mean and median values of PTH, while NICHD patients had the highest median values. During follow-up, compared to hemodialysis patients, patients treated with NICHD had lower mean serum PTH (19.8 pg/mL [95% confidence interval: 2.8, 36.8] lower), whereas PD and HHD patients had higher mean PTH (39.7 pg/mL [31.6, 47.8] and 51.2 pg/mL [33.0, 69.3] higher, respectively). Compared to hemodialysis patients, phosphate levels were lower for patients treated with NICHD (0.44 mg/dL [0.37, 0.52] lower), PD (0.15 mg/dL [0.12, 0.19] lower), or HHD (0.33 mg/dL [0.27, 0.40] lower). There were no clinically meaningful associations between dialysis modalities and concentrations of calcium or ALP. CONCLUSION: In incident dialysis patients, compared to treatment with conventional in-center hemodialysis, treatments with other dialysis modalities with longer treatment times or higher frequency were associated with different patterns of serum phosphate and PTH. Given the recent growth in the use of dialysis modalities other than hemodialysis, the associations between the treatment and the CKD-MBD markers warrant additional study.

Association of serum potassium with decline in residual kidney function in incident hemodialysis patients.

BACKGROUND: Hyperkalemia is associated with kidney function decline in patients with non-dialysis dependent chronic kidney disease, but this relationship is unclear for residual kidney function (RKF) among hemodialysis (HD) patients. METHODS: We conducted a retrospective cohort study of 6655 patients, who started HD January 2007 and December 2011 and who had data on renal urea clearance (KRU). Serum potassium levels were stratified into four groups (i.e. ≤4.0, >4.0 to ≤4.5, >4.5 to ≤5.0 and >5.0 mEq/L) and 1-year KRU slope for each group was estimated by a linear mixed-effects model. RESULTS: Higher serum potassium was associated with a greater decline in KRU, and the greatest decrease in KRU (-0.20, 95% confidence interval -0.50 to -0.06) was observed for baseline potassium >5.0 mEq/L in the fully adjusted model. Mediation analysis showed that KRU slope mediated 1.78% of the association between serum potassium and mortality. CONCLUSIONS: Hyperkalemia is associated with a decline in RKF amongst incident HD patients. These findings may have important clinical implications in the management of hyperkalemia in advanced CKD if confirmed in additional clinical trials.

Microbiome modulation as a novel therapeutic approach in chronic kidney disease.

PURPOSE OF REVIEW: Gut dysbiosis has been implicated in the pathogenesis of chronic kidney disease (CKD). Interventions aimed at restoring gut microbiota have emerged as a potential therapeutic option in CKD. This review summarizes the current evidence on gut microbiota-targeted strategies in patients with CKD. RECENT FINDINGS: A growing number of studies have shown that plant-based diets, low-protein diets, prebiotic, probiotic, and synbiotic supplementation, and constipation treatment may lead to favorable alterations in the gut microbiota. Current evidence suggests that the implementation of both plant-based and low-protein diets has potential benefits for the primary prevention of CKD, and for slowing CKD progression, with minimal risk of hyperkalemia and/or cachexia. The use of prebiotics, probiotics, and synbiotics and laxatives may have beneficial effects on uremic toxin generation, but their evidence is limited for the prevention and treatment of CKD. Recent advances in diagnostic technologies (e.g., high-throughput sequencing and nanotechnology) could enhance rapid diagnosis, monitoring, and design of effective therapeutic strategies for mitigating gut dysbiosis in CKD. SUMMARY: Plant-based and low-protein diets, prebiotic, probiotic, and synbiotic supplementation, and constipation treatment represent novel gut microbiota-targeted strategies in the conservative management of CKD, which could improve clinical outcomes in CKD.

Cardiovascular and Bleeding Outcomes with Anticoagulants across Kidney Disease Stages: Analysis of a National US Cohort.

BACKGROUND: While direct oral anticoagulants (DOACs) are considered safe among patients without chronic kidney disease (CKD), the evidence is conflicting as to whether they are also safe in the CKD and end-stage kidney disease (ESKD) population. In this observational cohort study, we examined whether DOACs are a safe alternative to warfarin across CKD stages for a variety of anticoagulation indications. METHODS: Individuals on DOACs or warfarin were identified from OptumLabs® Data Warehouse (OLDW), a longitudinal dataset with de-identified administrative claims, from 2010 to 2017. Cox models with sensitivity analyses were used to assess the risk of cardiovascular disease and bleeding outcomes stratified by CKD stage. RESULTS: Among 351,407 patients on anticoagulation, 45% were on DOACs. CKD stages 3-5 and ESKD patients comprised approximately 12% of the cohort. The most common indications for anticoagulation were atrial fibrillation (AF, 44%) and venous thromboembolism (VTE, 23%). DOACs were associated with a 22% decrease in the risk of cardiovascular outcomes (HR 0.78, 95% CI: 0.77-0.80, p < 0.001) and a 10% decrease in the risk of bleeding outcomes (HR 0.90, 95% CI: 0.88-0.92, p < 0.001) compared to warfarin after adjustment. On stratified analyses, DOACs maintained a superior safety profile across CKD stages. Patients with AF on DOACs had a consistently lower risk of cardiovascular and bleeding events than warfarin-treated patients, while among other indications (VTE, peripheral vascular disease, and arterial embolism), the risk of cardiovascular and bleeding events was the same among DOAC and warfarin users. CONCLUSION: DOACs may be a safer alternative to warfarin even among CKD and ESKD patients.

The consequences of altered microbiota in immune-related chronic kidney disease.

The normal gut microbiome modulates host enterocyte metabolism and shapes local and systemic immunity. Accumulation of urea and other waste products in chronic kidney disease induces gut dysbiosis and intestinal wall inflammation (leaky gut). There are decreased numbers of bacteria that generate short-chain fatty acids, which are an important nutrient source for host enterocytes and also contribute to regulation of the host immune system. Anaerobic proteolytic bacteria that express urease, uricase and indole and p-cresol enzymes, such as Enterobacteria and Enterococci, are increased. Microbial-derived uremic toxins such as indoxyl sulfate and trimethylamine N-oxide contribute to the pathophysiology of immune-related kidney diseases such as diabetic nephropathy, lupus nephritis and immunoglobulin A (IgA) nephropathy. Animal and clinical studies suggest potential benefits of dietary and probiotic interventions in slowing the progression of immune-related kidney diseases.

Controversies: Stroke Prevention in Chronic Kidney Disease.

Risk of both ischemic and hemorrhagic stroke is increased in the chronic kidney disease (CKD) population, particularly in end-stage kidney disease patients. Uremic factors that contribute to stroke risk include blood pressure variability, vascular calcification, build-up of vascular toxins, chronic inflammation, platelet dysfunction and increased brain microbleeds. This paper discusses the controversial evidence for stroke prevention strategies including blood pressure control, statins, antiplatelet agents, and anticoagulation in the CKD population. Only a few randomized clinical trials included patients with advanced CKD, thus evidence is derived mostly from observational cohorts and real-world data. Overall, targeting a lower systolic blood pressure below 120 mmHg and statin prescription do not appear to decrease stroke risk in CKD. Antiplatelet agents have not shown a clear benefit for secondary stroke prevention, but aspirin may reduce incident stroke in hypertensive CKD stage 3B-5 patients. Observational data suggests that the factor Xa inhibitor apixaban has a favorable profile over warfarin in dialysis patients with atrial fibrillation; apixaban being associated with lower stroke risk and fewer major bleeding events.

Cerebral Blood Flow in Chronic Kidney Disease.

The prevalence of mild cognitive impairment increases with age and is further exacerbated by chronic kidney disease (CKD). CKD is associated with (1) mild cognitive impairment, (2) impaired endothelial function, (3) impaired blood-brain barrier, (4) increased cerebral microhemorrhage burden, (5) increased cerebral blood flow (CBF), (6) impaired cerebral autoregulation, (7) impaired cerebrovascular reactivity, and (8) increased arterial stiffness. We report preliminary findings from our group that demonstrate altered cerebrovascular reactivity in a mouse model of CKD-associated vascular calcification. The CBF of CKD mice increased more quickly in response to hypercapnia (p < 0.05) but then decreased prematurely during hypercapnia challenge (p < 0.05). Together, these results indicate that altered kidney function can lead to alterations in the cerebral microvasculature, and hence brain health.

A Case of Novel Coronavirus Disease 19 in a Chronic Hemodialysis Patient Presenting with Gastroenteritis and Developing Severe Pulmonary Disease.

Novel coronavirus disease 2019 (COVID-19) is a highly infectious, rapidly spreading viral disease with an alarming case fatality rate up to 5%. The risk factors for severe presentations are concentrated in patients with chronic kidney disease, particularly patients with end-stage renal disease (ESRD) who are dialysis dependent. We report the first US case of a 56-year-old nondiabetic male with ESRD secondary to IgA nephropathy undergoing thrice-weekly maintenance hemodialysis for 3 years, who developed COVID-19 infection. He has hypertension controlled with angiotensin receptor blocker losartan 100 mg/day and coronary artery disease status-post stent placement. During the first 5 days of his febrile disease, he presented to an urgent care, 3 emergency rooms, 1 cardiology clinic, and 2 dialysis centers in California and Utah. During this interval, he reported nausea, vomiting, diarrhea, and low-grade fevers but was not suspected of COVID-19 infection until he developed respiratory symptoms and was admitted to the hospital. Imaging studies upon admission were consistent with bilateral interstitial pneumonia. He was placed in droplet-eye precautions while awaiting COVID-19 test results. Within the first 24 h, he deteriorated quickly and developed acute respiratory distress syndrome (ARDS), requiring intubation and increasing respiratory support. Losartan was withheld due to hypotension and septic shock. COVID-19 was reported positive on hospital day 3. He remained in critical condition being treated with hydroxychloroquine and tocilizumab in addition to the standard medical management for septic shock and ARDS. Our case is unique in its atypical initial presentation and highlights the importance of early testing.

Route of intestinal absorption and tissue distribution of iron contained in the novel phosphate binder ferric citrate.

BACKGROUND: Anemia of chronic kidney disease (CKD) is, in part, caused by hepcidin-mediated impaired iron absorption. However, phosphate binder, ferric citrate (FC) overcomes the CKD-induced impairment of iron absorption and increases serum iron, transferrin saturation, and iron stores and reduces erythropoietin requirements in CKD/ESRD patients. The mechanism and sites of intestinal absorption of iron contained in FC were explored here. METHODS: Eight-week old rats were randomized to sham-operated or 5/6 nephrectomized (CKD) groups and fed either regular rat chow or rat chow containing 4% FC for 6 weeks. They were then euthanized, and tissues were processed for histological and biochemical analysis using Prussian blue staining, Western blot analysis to quantify intestinal epithelial tight junction proteins and real-time PCR to measure Fatty Acid receptors 2 (FFA2) and 3 (FFA3) expressions. RESULTS: CKD rats exhibited hypertension, anemia, azotemia, and hyperphosphatemia. FC-treated CKD rats showed significant reductions in blood pressure, serum urea, phosphate and creatinine levels and higher serum iron and blood hemoglobin levels. This was associated with marked increase in iron content of the epithelial and subepithelial wall of the descending colon and modest iron deposits in the proximal tubular epithelial cells of their remnant kidneys. No significant difference was found in hepatic tissue iron content between untreated and FC-treated CKD or control groups. Distal colon's epithelial tight Junction proteins, Occludin, JAM-1 and ZO-1 were markedly reduced in the CKD groups. The FFA2 expression in the jejunum and FFA3 expression in the distal colon were significantly reduced in the CKD rats and markedly increased with FC administration. CONCLUSION: Iron contained in the phosphate binder, FC, is absorbed by the distal colon of the CKD animals via disrupted colonic epithelial barrier and upregulation of short chain fatty acid transporters.

Phosphate Binder, Ferric Citrate, Attenuates Anemia, Renal Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in 5/6 Nephrectomized CKD Rats.

Chronic kidney disease (CKD) causes anemia and impairs intestinal iron absorption. However, use of the phosphate binder ferric citrate (FC) increases body iron stores and hemoglobin levels in CKD patients. By intensifying oxidative stress and inflammation iron overload resulting from excessive use of intravenous iron can accelerate CKD progression. The present study explored the route of absorption and tissue distribution of iron with FC administration and its effect on renal function, histology, and inflammatory, oxidative, and fibrosis pathways in CKD rats. Male Sprague Dawley rats were randomized to sham-operated control (CTL) group and 5/6 nephrectomized (CKD) groups fed either regular or 4% FC-supplemented diets for 6 weeks. Animals were then sacrificed, and blood and target tissues were harvested and processed. The untreated CKD rats exhibited anemia, hypertension, upregulation of renal tissue inflammatory, oxidative, and fibrotic pathways, impaired nuclear translocation, and downregulation of Nrf2's target gene products and depletion of colonic epithelial tight junction proteins. FC administration raised serum iron, improved anemia, attenuated hyperphosphatemia, partially improved renal function, reduced oxidative stress, inflammation, and fibrosis, and restored colonic epithelial zonula occludens-1 protein abundance. Tissue iron staining detected presence of iron in epithelial cells and subepithelium of colon and in renal proximal tubules. In conclusion ferric citrate administration resulted in modest amelioration of renal function and histology and partial improvements of fibrosis, inflammation, and oxidative stress in the kidney tissues of CKD rats.

The Phosphate Binder Ferric Citrate Alters the Gut Microbiome in Rats with Chronic Kidney Disease.

In chronic kidney disease (CKD), the gut microbiome is altered and bacterial-derived uremic toxins promote systemic inflammation and cardiovascular disease. Ferric citrate complex is a dietary phosphate binder prescribed for patients with end-stage kidney disease to treat hyperphosphatemia and secondary hyperparathyroidism. Iron is an essential nutrient in both microbes and mammals. This study was undertaken to test the hypothesis that the large iron load administered with ferric citrate in CKD may significantly change the gut microbiome. Male Sprague-Dawley rats underwent 5/6 nephrectomy to induce CKD. Normal control and CKD rats were randomized to regular chow or a 4% ferric citrate diet for 6 weeks. Fecal and cecal microbial DNA was analyzed via 16S ribosomal RNA gene sequencing on the Illumina MiSeq system. CKD rats had lower abundances of Firmicutes and Lactobacillus compared with normal rats and had lower overall gut microbial diversity. CKD rats treated with ferric citrate had improved hemoglobin and creatinine clearance and amelioration of hyperphosphatemia and hypertension. Ferric citrate treatment increased bacterial diversity in CKD rats almost to levels observed in control rats. The tryptophanase-possessing families Verrucomicrobia, Clostridiaceae, and Enterobacteriaceae were increased by ferric citrate treatment. The uremic toxins indoxyl sulfate and p-cresyl sulfate were not increased with ferric citrate treatment. Verrucomicrobia was largely represented by Akkermansia muciniphila, which has important roles in mucin degradation and gut barrier integrity. In summary, ferric citrate therapy in CKD rats was associated with significant changes in the gut microbiome and beneficial kidney and blood pressure parameters.

Impact of Obesity on Modality Longevity, Residual Kidney Function, Peritonitis, and Survival Among Incident Peritoneal Dialysis Patients.

BACKGROUND: The prevalence of severe obesity, often considered a contraindication to peritoneal dialysis (PD), has increased over time. However, mortality has decreased more rapidly in the PD population than the hemodialysis (HD) population in the United States. The association between obesity and clinical outcomes among patients with end-stage kidney disease remains unclear in the current era. STUDY DESIGN: Historical cohort study. SETTING & PARTICIPANTS: 15,573 incident PD patients from a large US dialysis organization (2007-2011). PREDICTOR: Body mass index (BMI). OUTCOMES: Modality longevity, residual renal creatinine clearance, peritonitis, and survival. RESULTS: Higher BMI was significantly associated with shorter time to transfer to HD therapy (P for trend < 0.001), longer time to kidney transplantation (P for trend < 0.001), and, with borderline significance, more frequent peritonitis-related hospitalization (P for trend = 0.05). Compared with lean patients, obese patients had faster declines in residual kidney function (P for trend < 0.001) and consistently achieved lower total Kt/V over time (P for trend < 0.001) despite greater increases in dialysis Kt/V (P for trend < 0.001). There was a U-shaped association between BMI and mortality, with the greatest survival associated with the BMI range of 30 to < 35kg/m2 in the case-mix adjusted model. Compared with matched HD patients, PD patients had lower mortality in the BMI categories of < 25 and 25 to < 35kg/m2 and had equivalent survival in the BMI category ≥ 35kg/m2 (P for interaction = 0.001 [vs < 25 kg/m2]). This attenuation in survival difference among patients with severe obesity was observed only in patients with diabetes, but not those without diabetes. LIMITATIONS: Inability to evaluate causal associations. Potential indication bias. CONCLUSIONS: Whereas obese PD patients had higher risk for complications than nonobese PD patients, their survival was no worse than matched HD patients.

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins.

In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

There's no place like home: 35-year patient survival on home hemodialysis.

The vast majority of maintenance dialysis patients suffer from poor long-term survival rates and lower levels of health-related quality of life. However, home hemodialysis is a historically significant dialysis modality that has been associated with favorable outcomes as well as greater patient autonomy and control, yet only represents a small minority of the total dialysis performed in the United States. Some potential disadvantages of home hemodialysis include vascular access complications, infection-related hospitalizations, patient fatigue, and attrition. In addition, current barriers and challenges in expanding the utilization of this modality include limited patient and provider education and technical expertise. Here we report a 65-year old male with end-stage renal disease due to Alport's syndrome who has undergone 35 years of uninterrupted thrice-weekly home hemodialysis (ie, every Sunday, Tuesday, and Thursday evening, each session lasting 3 to 3» hours in length) using a conventional hemodialysis machine who has maintained a high functional status allowing him to work 6-8 hours per day. The patient has been able to liberalize his dietary and fluid intake while only requiring 3-4 liters of ultrafiltration per treatment, despite having absence of residual kidney function. Through this case of extraordinary longevity and outcomes after 35 years of dialysis and a review of the literature, we illustrate the history of home hemodialysis, its significant clinical and psychosocial advantages, as well as the barriers that hinder its widespread adaptation.

Pharmacologic Blockade of αvß1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo.

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor ß (PDGFRß) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFRß promoter-driven Cre system to delete αv integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFRß-Cre line to isolate and study renal fibroblasts ex vivo We found that renal fibroblasts express three αv integrins, namely αvß1, αvß3, and αvß5. Blockade of αvß1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-ß1 and prevented activation of the latent TGF-ß complex. Continuous administration of a recently described potent small molecule inhibitor of αvß1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of αvß1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

Warfarin Use and Increased Mortality in End-Stage Renal Disease.

BACKGROUND: Controversy exists regarding the benefits and risks of warfarin therapy in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. In this study, we assessed mortality and cardiovascular outcomes associated with warfarin treatment in patients with stages 3-5 CKD and ESRD admitted to the University of California-Irvine Medical Center. METHODS: In a retrospective matched cohort study, we identified 59 adult patients with stages 3-6 CKD initiated on warfarin during the period 2011-2013, and 144 patients with stages 3-6 CKD who had indications for anticoagulation therapy but were not initiated on warfarin. All-cause mortality risk associated with warfarin treatment was estimated using Cox proportional hazard regression analysis, and the risk of significant bleeding and major adverse cardiovascular events were analyzed with Poisson regression analysis. Adjustment models were used to account for age, gender, diabetes mellitus, use of antiplatelet agents, and preexisting cardiovascular disease, and stratified by pre-dialysis CKD stages 3-5 vs. ESRD. FINDINGS: During 5.8 years of follow-up, unadjusted mortality risk was higher in CKD patients on warfarin therapy (hazard ratio [HR] 2.34 with 95% CI 1.25-4.39; p < 0.01). After multivariate adjustment and stratification by CKD stage, the mortality risk remained significant in ESRD patients receiving warfarin (HR 6.62 with 95% CI 2.56-17.16; p < 0.001). Furthermore, adjusted rates of significant bleeding (incident rate ratio, IRR 3.57 with 95% CI 1.51-8.45; p < 0.01) and myocardial infarction (IRR 4.20 with 95% CI 1.78-9.91; p < 0.01) were higher among warfarin users. No differences in rates of ischemic or hemorrhagic strokes were found between the 2 groups. CONCLUSIONS: Warfarin use was associated with several-fold higher risk of death, bleeding, and myocardial infarction in dialysis patients. If additional studies suggest similar associations, the use of warfarin in dialysis patients warrants immediate reconsideration.