Cardiorenal syndrome in renal transplant recipients - It's the fistula at fault: A case series.

Complications arising from a functional arteriovenous fistula (AVF) in successful kidney transplant recipients (KT) have been overlooked despite some reports of its deleterious effect on heart, lungs, and kidney allograft. As such, there is no consensus regarding management of AVF after renal transplantation. We report Cardio-Renal Syndrome Type 5 in kidney transplant recipients who presented with a clinical syndrome of shortness of breath, edematous state, kidney allograft dysfunction, and high pulmonary pressure 3-8 months after successful transplantation. Investigations showed this to be due to high flow functioning AVF (>2 L/min) behaving like a systemic shunt causing high output heart failure, along with pulmonary and venous hypertension. This led to allograft dysfunction of fluid homeostasis. Symptoms resolved with cessation or reduction of AVF flow. Right heart catheterization and echocardiographic features indicating the syndrome are discussed to help clinicians identify the entity and decide management strategy for these AVF.

Renal function following fistulography in patients with advanced chronic kidney disease.

BACKGROUND/AIMS: Contrast-induced acute kidney injury (CIAKI) is associated with an accelerated progression of underlying chronic kidney disease (CKD). We sought to characterize the rate of loss of kidney function following fistulography in patients with advanced CKD. MATERIALS/METHODS: We identified all patients with stage 4 or 5 non-dialysis-dependent CKD who underwent fistulography with iodinated contrast for non-maturing arteriovenous fistulae between 1 January 2010 and 30 November 2011. We recorded all eGFR values measured during the 6 months prior to and 6 months following the procedure, the volume and type of contrast, use of intravenous fluid and N-acetylcysteine (NAC), and timing of dialysis initiation following the procedure. We used mixed linear regression with random effects to compare the composite slope of decline in eGFR prior to and following fistulography. RESULTS: Overall, 27 patients underwent a total of 44 fistulograms. The mean age of the patients was 66 years and mean baseline eGFR was 16.7 ± 5 mL/min/1.73 m(2). Patients received a median volume of contrast of 12 mL [IQR 10-20]. None of the patients initiated acute dialysis within weeks following the procedure. In unadjusted analyses, there was no statistically significant change in the rate of decline in eGFR following fistulography compared to pre-procedure (0.14 mL/min/month versus -0.14 mL/min/month, p = 0.11). In analyses that adjusted for procedural, demographic and clinical variables, the decline in eGFR following fistulography was not statistically different than before the procedure (0.15 mL/min/month versus -0.14 mL/min/month, p = 0.11). CONCLUSIONS: Fistulography with small volumes of iodinated contrast in patients with advanced CKD does not result in more rapid progression of underlying CKD.

Source of Post-Transplant Care and Mortality among Kidney Transplant Recipients Dually Enrolled in VA and Medicare.

BACKGROUND AND OBJECTIVES: Many kidney transplant recipients enrolled in the Veterans Health Administration are also enrolled in Medicare and eligible to receive both Veterans Health Administration and private sector care. Where these patients receive transplant care and its association with mortality are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective cohort study of veterans who underwent kidney transplantation between 2008 and 2016 and were dually enrolled in Veterans Health Administration and Medicare at the time of surgery. We categorized patients on the basis of the source of transplant-related care (i.e., outpatient transplant visits, immunosuppressive medication prescriptions, calcineurin inhibitor measurements) delivered during the first year after transplantation defined as Veterans Health Administration only, Medicare only (i.e., outside Veterans Health Administration using Medicare), or dual care (mixed use of Veterans Health Administration and Medicare). Using multivariable Cox regression, we examined the independent association of post-transplant care source with mortality at 5 years after kidney transplantation. RESULTS: Among 6206 dually enrolled veterans, 975 (16%) underwent transplantation at a Veterans Health Administration hospital and 5231 (84%) at a non-Veterans Health Administration hospital using Medicare. Post-transplant care was received by 752 patients (12%) through Veterans Health Administration only, 2092 (34%) through Medicare only, and 3362 (54%) through dual care. Compared with patients who were Veterans Health Administration only, 5-year mortality was significantly higher among patients who were Medicare only (adjusted hazard ratio, 2.2; 95% confidence interval, 1.5 to 3.1) and patients who were dual care (adjusted hazard ratio, 1.5; 95% confidence interval, 1.1 to 2.1). CONCLUSIONS: Most dually enrolled veterans underwent transplantation at a non-Veterans Health Administration transplant center using Medicare, yet many relied on Veterans Health Administration for some or all of their post-transplant care. Veterans who received Veterans Health Administration-only post-transplant care had the lowest 5-year mortality.

A rare case of MGRS with immunotactoid glomerulopathy responding to bortezomib, dexamethasone, and rituximab.

Patients with monoclonal gammopathy of renal significance should be treated with clone-directed therapy against sources of monoclonal proteins in order to prevent progression to more advanced monoclonal gammopathies and renal failure.

Unexpected Race and Ethnicity Differences in the US National Veterans Affairs Kidney Transplant Program.

BACKGROUND: Racial/ethnic minorities have lower rates of deceased kidney transplantation (DDKT) and living donor kidney transplantation (LDKT) in the United States. We examined whether social determinants of health (eg, demographics, cultural, psychosocial, knowledge factors) could account for differences in the Veterans Affairs (VA) Kidney Transplantation (KT) Program. METHODS: We conducted a multicenter longitudinal cohort study of 611 Veterans undergoing evaluation for KT at all National VA KT Centers (2010-2012) using an interview after KT evaluation and tracking participants via medical records through 2017. RESULTS: Hispanics were more likely to get any KT (subdistribution hazard ratios [SHR] [95% confidence interval (CI)]: 1.8 [1.2-2.8]) or DDKT (SHR [95% CI]: 2.0 [1.3-3.2]) than non-Hispanic white in univariable analysis. Social determinants of health, including marital status (SHR [95% CI]: 0.6 [0.4-0.9]), religious objection to LDKT (SHR [95% CI]: 0.6 [0.4-1.0]), and donor preference (SHR [95% CI]: 2.5 [1.2-5.1]), accounted for some racial differences, and changes to Kidney Allocation System policy (SHR [95% CI]: 0.3 [0.2-0.5]) mitigated race differences in DDKT in multivariable analysis. For LDKT, non-Hispanic African American Veterans were less likely to receive an LDKT than non-Hispanic white (SHR [95% CI]: 0.2 [0.0-0.7]), but accounting for age (SHR [95% CI]: 1.0 [0.9-1.0]), insurance (SHR [95% CI]: 5.9 [1.1-33.7]), presenting with a living donor (SHR [95% CI]: 4.1 [1.4-12.3]), dialysis duration (SHR [95% CI]: 0.3 [0.2-0.6]), network of potential donors (SHR [95% CI]: 1.0 [1.0-1.1]), self-esteem (SHR [95% CI]: 0.4 [0.2-0.8]), transplant knowledge (SHR [95% CI]: 1.3 [1.0-1.7]), and changes to Kidney Allocation System policy (SHR [95% CI]: 10.3 [2.5-42.1]) in multivariable analysis eliminated those disparities. CONCLUSIONS: The VA KT Program does not exhibit the same pattern of disparities in KT receipt as non-VA centers. Transplant centers can use identified risk factors to target patients who may need more support to ensure they receive a transplant.

Has the Department of Veterans Affairs Found a Way to Avoid Racial Disparities in the Evaluation Process for Kidney Transplantation?

BACKGROUND: Minority groups are affected by significant disparities in kidney transplantation (KT) in Veterans Affairs (VA) and non-VA transplant centers. However, prior VA studies have been limited to retrospective, secondary database analyses that focused on multiple stages of the KT process simultaneously. Our goal was to determine whether disparities during the evaluation period for KT exist in the VA as has been found in non-VA settings. METHODS: We conducted a multicenter longitudinal cohort study of 602 patients undergoing initial evaluation for KT at 4 National VA KT Centers. Participants completed a telephone interview to determine whether, after controlling for medical factors, differences in time to acceptance for transplant were explained by patients' demographic, cultural, psychosocial, or transplant knowledge factors. RESULTS: There were no significant racial disparities in the time to acceptance for KT [Log-Rank χ = 1.04; P = 0.594]. Younger age (hazards ratio [HR], 0.98; 95% confidence interval [CI], 0.97-0.99), fewer comorbidities (HR, 0.89; 95% CI, 0.84-0.95), being married (HR, 0.81; 95% CI, 0.66-0.99), having private and public insurance (HR, 1.29; 95% CI, 1.03-1.51), and moderate or greater levels of depression (HR, 1.87; 95% CI, 1.03-3.29) predicted a shorter time to acceptance. The influence of preference for type of KT (deceased or living donor) and transplant center location on days to acceptance varied over time. CONCLUSIONS: Our results indicate that the VA National Transplant System did not exhibit the racial disparities in evaluation for KT as have been found in non-VA transplant centers.

Perceived discrimination predicts longer time to be accepted for kidney transplant.

BACKGROUND: Although end-stage kidney disease in African Americans (AAs) is four times greater than in whites, AAs are less than one half as likely to undergo kidney transplantation (KT). This racial disparity has been found even after controlling for clinical factors such as comorbid conditions, dialysis vintage and type, and availability of potential living donors. Therefore, studying nonmedical factors is critical to understanding disparities in KT. METHODS: We conducted a longitudinal cohort study with 127 AA and white patients with end-stage kidney disease undergoing evaluation for KT (December 2006 to July 2007) to determine whether, after controlling for medical factors, differences in time to acceptance for transplant is explained by patients' cultural factors (e.g., perceived racism and discrimination, medical mistrust, religious objections to living donor KT), psychosocial characteristics (e.g., social support, anxiety, depression), or transplant knowledge. Participants completed two telephone interviews (shortly after initiation of transplant evaluation and after being accepted or found ineligible for transplant). RESULTS: Results indicated that AA patients reported higher levels of the cultural factors than did whites. We found no differences in comorbidity or availability of potential living donors. AAs took significantly longer to get accepted for transplant than did whites (hazard ratio=1.49, P=0.005). After adjustment for demographic, psychosocial, and cultural factors, the association of race with longer time for listing was no longer significant. CONCLUSIONS: We suggest that interventions to address racial disparities in KT incorporate key nonmedical risk factors in patients.

Urinary biomarkers and renal recovery in critically ill patients with renal support.

BACKGROUND AND OBJECTIVES: Despite significant advances in the epidemiology of acute kidney injury (AKI), prognostication remains a major clinical challenge. Unfortunately, no reliable method to predict renal recovery exists. The discovery of biomarkers to aid in clinical risk prediction for recovery after AKI would represent a significant advance over current practice. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted the Biological Markers of Recovery for the Kidney study as an ancillary to the Acute Renal Failure Trial Network study. Urine samples were collected on days 1, 7, and 14 from 76 patients who developed AKI and received renal replacement therapy (RRT) in the intensive care unit. We explored whether levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary hepatocyte growth factor (uHGF), urinary cystatin C (uCystatin C), IL-18, neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9, and urine creatinine could predict subsequent renal recovery. RESULTS: We defined renal recovery as alive and free of dialysis at 60 days from the start of RRT. Patients who recovered had higher uCystatin C on day 1 (7.27 versus 6.60 ng/mg·creatinine) and lower uHGF on days 7 and 14 (2.97 versus 3.48 ng/mg·creatinine; 2.24 versus 3.40 ng/mg·creatinine). For predicting recovery, decreasing uNGAL and uHGF in the first 14 days was associated with greater odds of renal recovery. The most predictive model combined relative changes in biomarkers with clinical variables and resulted in an area under the receiver-operator characteristic curve of 0.94. CONCLUSIONS: We showed that a panel of urine biomarkers can augment clinical risk prediction for recovery after AKI.

Cystic fibrosis transmembrane conductance regulator differentially regulates human and mouse epithelial sodium channels in Xenopus oocytes.

The cystic fibrosis transmembrane conductance regulator (CFTR), in addition to its well defined Cl- channel properties, regulates other ion channels. CFTR inhibits murine or rat epithelial Na+ channel (mENaC or rENaC) currents in many epithelial and non-epithelial cells, whereas murine or rat ENaC increases CFTR functional expression. These regulatory interactions are reproduced in Xenopus oocytes where both the open probability and surface expression of wild type CFTR Cl- channels are increased when CFTR is co-expressed with alphabetagamma mENaC, and conversely the activity of mENaC is inhibited after wild type CFTR activation. Using the Xenopus oocyte expression system, differences in functional regulatory interactions were observed when CFTR was co-expressed with either alphabetagamma mENaC or alphabetagamma human ENaC (hENaC). Co-expression of CFTR and alphabetagamma mENaC or hENaC resulted in an approximately 3-fold increase in CFTR Cl- current compared with oocytes expressing CFTR alone. Oocytes co-injected with both CFTR and mENaC or hENaC expressed an amiloride-sensitive whole cell current that was decreased compared with that observed with the injection of mENaC or hENaC alone before CFTR activation with forskolin/3-isobutyl-1-methylxanthine. CFTR activation resulted in a further 50% decrease in mENaC-mediated currents, an approximately 20% decrease in alpha-T663-hENaC-mediated currents, and essentially no change in alpha-A663-hENaC-mediated currents. Changes in ENaC functional expression correlated with ENaC surface expression by oocyte surface biotinylation experiments. Assessment of regulatory interactions between CFTR and chimeric mouse/human ENaCs suggest that the 20 C-terminal amino acid residues of alpha ENaC confer species specificity regarding ENaC inhibition by activated CFTR.

Characterization of an amiloride binding region in the alpha-subunit of ENaC.

One of the defining characteristics of the epithelial sodium channel (ENaC) is its block by the diuretic amiloride. This study investigates the role of the extracellular loop of the alpha-subunit of ENaC in amiloride binding and stabilization. Mutations were generated in a region of the extracellular loop, residues 278-283. Deletion of this region, WYRFHY, resulted in a loss of amiloride binding to the channel. Channels formed from wild-type alpha-subunits or alpha-subunits containing point mutations in this region were examined and compared at the single-channel level. The open probabilities (Po) of wild-type channels were distributed into two populations: one with a high Po and one with a low Po. The mean open times of all the mutant channels were shorter than the mean open time of the wild-type (high-Po) channel. Besides mutations Y279A and H282D, which had amiloride binding affinities similar to that of wild-type alpha-ENaC, all other mutations in this region caused changes in the amiloride binding affinity of the channels compared with the wild-type channel. These data provide new insight into the relative position of the extracellular loop with respect to the pore of ENaC and its role in amiloride binding and channel gating.

Ontogeny of flow-stimulated potassium secretion in rabbit cortical collecting duct: functional and molecular aspects.

High urinary flow rates stimulate K secretion in the fully differentiated but not neonatal or weanling rabbit cortical collecting duct (CCD). Both small-conductance secretory K and high-conductance Ca2+/stretch-activated maxi-K channels have been identified in the apical membrane of the mature CCD by patch-clamp analysis. We reported that flow-stimulated net K secretion in the adult rabbit CCD is 1) blocked by TEA and charybdotoxin, inhibitors of intermediate- and high-conductance (maxi-K) Ca2+-activated K channels, and 2) associated with increases in net Na absorption and intracellular Ca2+ concentration ([Ca2+]i). The present study examined whether the absence of flow-stimulated K secretion early in life is due to a 1) limited flow-induced rise in net Na absorption and/or [Ca2+]i and/or 2) paucity of apical maxi-K channels. An approximately sixfold increase in tubular fluid flow rate in CCDs isolated from 4-wk-old rabbits and microperfused in vitro led to an increase in net Na absorption and [Ca2+]i, similar in magnitude to the response observed in 6-wk-old tubules, but it failed to generate an increase in net K secretion. By 5 wk of age, there was a small, but significant, flow-stimulated rise in net K secretion that increased further by 6 wk of life. Luminal perfusion with iberiotoxin blocked the flow stimulation of net K secretion in the adult CCD, confirming the identity of the maxi-K channel in this response. Maxi-K channel alpha-subunit message was consistently detected in single CCDs from animals >/=4 wk of age by RT-PCR. Indirect immunofluorescence microscopy using antibodies directed against the alpha-subunit revealed apical labeling of intercalated cells in cryosections from animals >/=5 wk of age; principal cell labeling was generally intracellular and punctate. We speculate that the postnatal appearance of flow-dependent K secretion is determined by the transcriptional/translational regulation of expression of maxi-K channels. Furthermore, our studies suggest a novel function for intercalated cells in mediating flow-stimulated K secretion.

Functional polymorphism in the carboxyl terminus of the alpha-subunit of the human epithelial sodium channel.

A common human epithelial sodium channel (ENaC) polymorphism, alphaT663A, is present in the cytoplasmic C terminus of the alpha-subunit, although it is unclear whether this polymorphism segregates with blood pressure. We examined whether this polymorphism was associated with differences in functional Na(+) channel expression. Whole cell amiloride-sensitive currents in Xenopus oocytes expressing wild type channels (alphaT663betagamma) were significantly approximately 1.3-2.0-fold higher than currents measured in oocytes expressing channels with an Ala, Gly or Leu, or Lys at position alpha663. In contrast, differences in functional human ENaC expression were not observed with oocytes expressing channels having Thr (wild type), Ser, or Asp at this position. The surface expression of channels, measured using an epitope-tagged beta-subunit, was significantly reduced in oocytes expressing alphaT663Abetagamma when compared with oocytes expressing alphaT663betagamma. The corresponding polymorphism was generated in the mouse alpha-subunit (malphaA692T) and was not associated with differences in functional alphabetagamma-mouse ENaC expression. The polymorphism is present in a region that is not well conserved between human and mouse. We generated a mouse/human chimera by replacement of the distal C terminus of the mouse alpha-subunit with the distal C terminus of the human alpha-subunit. Co-expression of this m(1-678)/h(650-669)T663A chimera with mouse betagamma led to a significant reduction in whole cell Na(+) currents and surface expression when compared with m(1-678)/h(650-669)T663-mbetagamma. Our results suggest that halphaT663A is a functional polymorphism that affects human ENaC surface expression.