Belatacept Combined With Transient Calcineurin Inhibitor Therapy Prevents Rejection and Promotes Improved Long-Term Renal Allograft Function.

Belatacept, a T cell costimulation blocker, demonstrated superior renal function, lower cardiovascular risk, and improved graft and patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011, we have utilized belatacept-based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n = 535) with a historical cohort receiving a tacrolimus-based protocol (n = 205). Patient and graft survival were equivalent for all groups. An increased rate of acute rejection was observed in an initial cohort treated with a protocol similar to the low-intensity regimen from the BENEFIT trial versus the historical tacrolimus group (50.5% vs. 20.5%). The addition of a transient course of tacrolimus reduced rejection rates to acceptable levels (16%). Treatment with belatacept was associated with superior estimated GFR (belatacept 63.8 mL/min vs. tacrolimus 46.2 mL/min at 4 years, p < 0.0001). There were no differences in serious infections including rates of cytomegalovirus or BK viremia. We describe the development of a costimulatory blockade-based strategy that ultimately allows renal transplant recipients to achieve calcineurin inhibitor-free immunosuppression.

Effect of Replacing Race With Apolipoprotein L1 Genotype in Calculation of Kidney Donor Risk Index.

Renal allografts from deceased African American donors with two apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need.

Decreasing Estimated Glomerular Filtration Rate Is Associated With Increased Risk of Hospitalization After Kidney Transplantation.

INTRODUCTION: Following renal transplantation, decreased renal function is associated with increased risk of cardiovascular disease, graft loss and mortality. We investigated whether declining renal function was associated with hospitalization post-transplant. METHODS: Adult, first-time, kidney transplant recipients between 2004 and 2006 from the United Network for Organ Sharing database and hospitalizations one year after the 6-month post-transplant follow-up visit were examined. Generalized linear models explored the relationship between estimated glomerular filtration rate (eGFR) measured at 6 months and the number of hospitalizations in the following year. RESULTS: Of 15,778 kidney transplant recipients, 19.1% were admitted in the year after the 6-month follow-up visit. Among those hospitalized, the mean number of hospitalizations was 1.71 and increased with decreasing eGFR. In multivariable models, a decrease in eGFR was significantly associated with increased hospitalizations: for every 10 ml/min/1.73m2 decrease in eGFR, there was an 11% increase in hospitalization rate (p <0.001). Lower eGFR after the first 6 months following transplantation was associated with an increase in late hospitalizations among adult kidney transplant recipients. DISCUSSION: Identifying patients with declining eGFR and other risk factors may help prevent morbidity and mortality associated with hospitalization post-transplantation.

Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.

Kidney transplant access in the Southeast: view from the bottom.

The Southeastern region of the United States has the highest burden of end-stage renal disease (ESRD) but the lowest rates of kidney transplantation in the nation. There are many patient-, dialysis facility-, ESRD Network- and health system-level barriers that contribute to this regional disparity. Compared to the rest of the nation, the Southeast has a larger population of African-Americans and higher poverty, as well as more prevalent ESRD risk factors including hypertension, obesity and diabetes. Dialysis facilities--where ESRD patients receive the majority of their healthcare--play an important role in transplant access. Identifying characteristics of individual dialysis units with low rates of kidney transplantation, such as understaffing or for-profit status, can help identify targets for quality improvement initiatives. Geographic differences across the country can identify opportunities to increase funding for healthcare resources in proportion to patient and disease burden. Focusing interventions among dialysis facilities with the lowest transplant rates within the Southeast, such as provider and patient education, has the potential to increase referrals for kidney transplantation, leading to higher rates of kidney transplants in this region. Referral for transplantation should be measured on a national level to monitor disparities in early access to transplantation. Transplant centers have an obligation to assist underserved populations in ensuring equity in access to services. Policies that improve access to care for patients, such as the Affordable Care Act and Medicaid expansion, are particularly important for Southern states and may alleviate geographic disparities.

Dialysis facility and network factors associated with low kidney transplantation rates among United States dialysis facilities.

Variability in transplant rates between different dialysis units has been noted, yet little is known about facility-level factors associated with low standardized transplant ratios (STRs) across the United States End-stage Renal Disease (ESRD) Network regions. We analyzed Centers for Medicare & Medicaid Services Dialysis Facility Report data from 2007 to 2010 to examine facility-level factors associated with low STRs using multivariable mixed models. Among 4098 dialysis facilities treating 305 698 patients, there was wide variability in facility-level STRs across the 18 ESRD Networks. Four-year average STRs ranged from 0.69 (95% confidence interval [CI]: 0.64-0.73) in Network 6 (Southeastern Kidney Council) to 1.61 (95% CI: 1.47-1.76) in Network 1 (New England). Factors significantly associated with a lower STR (p < 0.0001) included for-profit status, facilities with higher percentage black patients, patients with no health insurance and patients with diabetes. A greater number of facility staff, more transplant centers per 10 000 ESRD patients and a higher percentage of patients who were employed or utilized peritoneal dialysis were associated with higher STRs. The lowest performing dialysis facilities were in the Southeastern United States. Understanding the modifiable facility-level factors associated with low transplant rates may inform interventions to improve access to transplantation.

The role of race and poverty on steps to kidney transplantation in the Southeastern United States.

Racial disparities in access to renal transplantation exist, but the effects of race and socioeconomic status (SES) on early steps of renal transplantation have not been well explored. Adult patients referred for renal transplant evaluation at a single transplant center in the Southeastern United States from 2005 to 2007, followed through May 2010, were examined. Demographic and clinical data were obtained from patient's medical records and then linked with United States Renal Data System and American Community Survey Census data. Cox models examined the effect of race on referral, evaluation, waitlisting and organ receipt. Of 2291 patients, 64.9% were black, the mean age was 49.4 years and 33.6% lived in poor neighborhoods. Racial disparities were observed in access to referral, transplant evaluation, waitlisting and organ receipt. SES explained almost one-third of the lower rate of transplant among black versus white patients, but even after adjustment for demographic, clinical and SES factors, blacks had a 59% lower rate of transplant than whites (hazard ratio = 0.41; 95% confidence interval: 0.28-0.58). Results suggest that improving access to healthcare may reduce some, but not all, of the racial disparities in access to kidney transplantation.

Promoting quality of care for ESRD patients: the role of the ESRD Networks.

The 18 End Stage Renal Disease (ESRD) Networks were established by Congress to oversee the care of Medicare beneficiaries with ESRD, serving as HCFA's primary quality improvement (QI) agents. The Networks play a critical role in the ESRD surveillance system by collecting, analyzing and disseminating data from dialysis clinics regarding the occurrence of ESRD, and the processes of care and outcomes of ESRD patients. In addition, under the direction of volunteer Medical Review Boards, the Networks propose, design and implement regional QI activities targeting specific areas in the delivery of ESRD care, and provide technical assistance to foster QI at the facility level. In this article, we discuss the ESRD Network system and review the scope of QI activities through which the Networks accomplish their mission.

Peritoneal dialysis adequacy and risk of death.

BACKGROUND: The purpose of this study was to evaluate the relationship between dialysis dose, patient characteristics, and medical comorbidities on mortality in chronic peritoneal dialysis patients. METHODS: This work comprised a study cohort of 1446 patients obtained from a random sample of chronic peritoneal dialysis patients from each dialysis center in three southeastern states. Data collected on a standardized form were used to calculate weekly Kt/V urea and creatinine clearance. Data were linked to Network files containing data on patient demographic and medical comorbidities. RESULTS: Both weekly Kt/V urea and creatinine clearance were measured at least once in only 60.5% of continuous ambulatory peritoneal dialysis (CAPD) patients and 63.7% of cycler patients. Among the 873 patients who had at least one calculable adequacy measure, the mean (+/-SD) weekly Kt/V urea was 2.13 +/- 0.55, and the normalized mean weekly creatinine clearance was 62.9 +/- 20.4 L/week/m2. During the seven month period of follow-up, there were 140 deaths. In separate logistic regression models that included all of the studied risk factors, using separate variables for the urinary and peritoneal components of dialysis adequacy, each 10 L/week/1.73 m2 increase in the urinary component of weekly creatinine clearance was associated with a 40% decreased risk of death, and each 0.1 unit increase in the urinary component of weekly Kt/V urea was associated with a 12% decreased risk of death. In contrast, the dialysate components of neither weekly creatinine clearance nor weekly Kt/V urea were predictive of death. Other factors that were associated with an increased risk of death included increasing age, diabetes mellitus as the cause of end-stage renal disease (ESRD), and a history of myocardial infarction. CONCLUSIONS: Residual renal function, as expressed by weekly creatinine clearance or Kt/V urea, is an important predictor of death in chronic peritoneal dialysis patients. The nonsignificant findings regarding peritoneal clearances and mortality may possibly be secondary to the narrow range of peritoneal clearances in this study cohort.

Cardiac disease in patients with end-stage renal disease.

Cardiovascular diseases remain the leading cause of death in ESRF patients. Coronary risk factors such as hypertension and lipid abnormalities are prevalent in the dialysis population and may be difficult to control. Special factors contributing to the imbalance between myocardial oxygen supply and demand include anemia, arteriovenous fistula, and the hemodialysis procedure itself. LVH and left ventricular dilation frequently result in symptomatic CHF. Atrial and ventricular arrhythmias are common; pericarditis may also occur. Control of the extracellular fluid volume through ultrafiltration with dialysis and the dietary avoidance of salt and water is critical to controlling hypertension in the dialysis population. The potential for drug side effects and the altered pharmacokinetics of medications in renal failure patients should be considered when prescribing cardiovascular drugs.

Total body water measured by bioelectrical impedance in patients after hemodialysis. Comparison with urea kinetics.

Bioelectrical impedance (BEI) measurements have been used to measure total body water volume (VBEI). The VBEI were measured after hemodialysis in 14 patients, as was dialyzer blood water urea clearance (KBW) and dialysate urea clearance (KD). Urea clearance based on the mass transfer coefficient, KoA, was determined (KKoA). Residual renal function was measured, and three point variable volume single pool urea kinetic modeling (UKM) was done. Urea distribution volumes were calculated using the measured urea clearance values from blood water (VBW), dialysate (VD), and KoA (VKoA) as inputs. Direct dialysate quantitation was calculated based on total dialysate collections to measure urea clearance (KDDQ) and urea distribution volume (VDDQ). Total body water estimates were made using the Hume and Watson anthropometric formulas (VHUME and VWATSON). It was found that average VBEI (34.76 L) was larger than VBW (27.50 L) and VD (26.69 L), but it was not different from VKoA (32.15 L), VHUME (35.15 L), or VWATSON (34.53 L). Linear regression revealed a good correlation between VBEI and both VBW and VD (R = 0.873 and 0.882, respectively). The BEI measurements provide a simple method for measuring total body water in dialysis patients that correlated well with UKM volumes.

Urea kinetics during continuous hemofiltration.

Urea kinetic analysis allows for the calculation of the urea distribution volume and urea generation rate. This method was employed in patients with acute renal failure managed by continuous venovenous hemofiltration (CVVH). Based on serial serum urea nitrogen concentration measurements, each patient's treatment course consisted of both steady state and non-steady state periods. Thirteen data sets were obtained from 11 critically ill patients treated with CVVH. The duration of therapy was 9.5 +/- 7.5 days (mean +/- SD). Serum urea nitrogen concentration fell from 114 +/- 32 mg/dl to a steady state value of 79 +/- 17 mg/dl (p < 0.0005). The urea distribution volume was 0.55 +/- 0.11 L/kg (range 0.29-0.73), and the urea generation rate 11.7 +/- 3.1 mg urea N/min (range 7.1-17.3). The steady state serum urea nitrogen concentration had a linear relationship to the rate of urea generation (r = 0.92). Urea kinetic analysis permitted the simultaneous determination of the urea generation rate and distribution volume, on an individualized basis, in patients with acute renal failure treated with CVVH.

Prospective comparison of peritoneoscopic and surgical implantation of CAPD catheters.

Prospectively collected data were analyzed comparing surgically and peritoneoscopically placed peritoneal dialysis catheters in 88 patients. Peritoneoscopically placed catheters were found to survive longer than surgically placed ones. Rates of exit site infection and pericatheter leaks were found to be similar with both techniques.

Transcellular urea gradients cause minimal depletion of extracellular volume during hemodialysis.

Concern exists that increasingly high-efficiency dialysis will result in large urea gradients between intracellular and extracellular compartments (VI, VE) leading to large amounts of extracellular volume depletion (delta VE) and hemodynamic instability induced by rapid water flow from VE to VI. The authors investigated this question with a two-compartment model that provided estimates of VI, VE, and osmotically active intracellular and extracellular urea and nonurea concentrations during hemodialysis. The authors found that the urea gradient-induced transcellular water shift is only a very small fraction of VE, even with high urea clearance and short hemodialysis time. The net water shift was small because the urea and nonurea transcellular osmolar gradients were of similar magnitudes but in offsetting directions.