Search

Rationale & Objective: Cardiovascular disease (CVD) is common and overall graft survival is suboptimal among kidney transplant recipients. Although albuminuria is a known risk factor for adverse outcomes among persons with native chronic kidney disease, the relationship of albuminuria with cardiovascular and kidney outcomes in transplant recipients is uncertain., Study Design: Post hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial., Setting & Participants: Stable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil., Predictor: Urine albumin-creatinine ratio (ACR) at randomization., Outcomes: Allograft failure, CVD, and all-cause death., Analytical Approach: Multivariable Cox models adjusted for age; sex; race; randomized treatment allocation; country; systolic and diastolic blood pressure; history of CVD, diabetes, and hypertension; smoking; cholesterol; body mass index; estimated glomerular filtration rate (eGFR); donor type; transplant vintage; medications; and immunosuppression., Results: Among 3,511 participants with complete data, median ACR was 24 (Q1-Q3, 9-98) mg/g, mean eGFR was 49±18 (standard deviation) mL/min/1.73m 2 , mean age was 52±9 years, and median graft vintage was 4.1 (Q1-Q3, 1.7-7.4) years. There were 1,017 (29%) with ACR < 10mg/g, 912 (26%) with ACR of 10 to 29mg/g, 1,134 (32%) with ACR of 30 to 299mg/g, and 448 (13%) with ACR ≥ 300mg/g. During approximately 4 years, 282 allograft failure events, 497 CVD events, and 407 deaths occurred. Event rates were higher at both lower eGFRs and higher ACR. ACR of 30 to 299 and ≥300mg/g relative to ACR < 10mg/g were independently associated with graft failure (HRs of 3.40 [95% CI, 2.19-5.30] and 9.96 [95% CI, 6.35-15.62], respectively), CVD events (HRs of 1.25 [95% CI, 0.96-1.61] and 1.55 [95% CI, 1.13-2.11], respectively), and all-cause death (HRs of 1.65 [95% CI, 1.23-2.21] and 2.07 [95% CI, 1.46-2.94], respectively)., Limitations: No data for rejection; single ACR assessment., Conclusions: In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death. Future studies are needed to evaluate whether reducing albuminuria improves these outcomes., (Copyright © 2018 National Kidney Foundation, Inc. All rights reserved.)

Background: Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality., Study Design: Cohort study., Setting & Participants: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs., Predictor: Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization., Results: During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54)., Limitations: We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites., Conclusions: Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted., (Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.)

The optimal BP level in kidney transplant recipients remains uncertain. This post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort assessed associations of BP with a pooled cardiovascular disease (CVD) outcome and with all-cause mortality. In 3474 prevalent kidney transplant patients, mean age was 52±9 years, 63% were men, 76% were white, 20% had a history of CVD, 40% had a history of diabetes mellitus, and the median time since transplant was 4.1 years (25th to 75th percentiles, 1.7-7.4); mean systolic BP was 136±20 mmHg and mean diastolic BP was 79±12 mmHg. There were 497 CVD events and 406 deaths. After adjustment for demographic and transplant characteristics and CVD risk factors, each 20-mmHg increase in baseline systolic BP associated with a 32% increase in subsequent CVD risk (hazard ratio [HR], 1.32; 95% confidence interval [95% CI], 1.19 to 1.46) and a 13% increase in mortality risk (HR, 1.13; 95% CI, 1.01 to 1.27). Similarly, after adjustment, at diastolic BP levels<70 mmHg, each 10-mmHg decrease in diastolic BP level associated with a 31% increase in CVD risk (HR, 1.31; 95% CI, 1.06 to 1.62) and a 31% increase in mortality risk (HR, 1.31; 95% CI, 1.03 to 1.66). However, at diastolic BP levels>70 mmHg, there was no significant relationship between diastolic BP and outcomes. Higher systolic BP strongly and independently associated with increased risk of CVD and all-cause mortality, without evidence of a J shape, whereas only lower levels of diastolic BP associated with increased risk of CVD and death in this trial., (Copyright © 2014 by the American Society of Nephrology.)

BK polyomavirus (BKV) infection continues to be a significant source of allograft dysfunction in kidney transplant recipients. The optimal screening method to detect BKV remains undetermined. In this retrospective analysis of 347 consecutive kidney transplant recipients, we compare the diagnostic and screening performance of urine electron microscopy (EM) with plasma polymerase chain reaction (PCR) in testing for BKV, using biopsy-proved polyomavirus-associated nephropathy (PVAN) as the gold standard. Sixty-nine of 347 recipients had a positive screening test for BKV infection. Twenty-nine patients underwent biopsy, and 11 were diagnosed with PVAN. Sensitivity rates of urine EM and plasma PCR were 88% and 100%, respectively. Specificity rates of urine EM and plasma PCR were 91% and 78%. There was no statistical difference in the operating characteristics of the two tests. The majority of both plasma PCR and urine EM tests were positive in the six months prior to a diagnostic biopsy confirming PVAN. In those patients who had evidence of BKV infection but did not have PVAN, the percentage of positive screening tests decreased with aggressive lowering of immunosuppression. We conclude that urine EM and plasma PCR both function well in screening for BKV infection and in the diagnosis of PVAN. There is an opportunity to detect viral replication, lower immunosuppression, and to prevent PVAN in this population., (© 2012 John Wiley & Sons A/S.)

Postinfectious glomerulonephritis (PIGN) is a rare etiology of de novo glomerulonephritis following kidney transplantation. To date, there have only been eight cases reported in the literature. We report an additional three patients transplanted at our institution between January 2000 and October 2004 who had clinical and pathologic findings consistent with posttransplant PIGN. All three patients were type 1 diabetics. One had received a cadaveric kidney transplant, one a simultaneous kidney-pancreas transplant, and the third a living related kidney transplant followed by a pancreas transplant. All patients were on triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and prednisone. In each case, an acute decline in allograft function developed in association with a known or suspected infectious process, and renal biopsies revealed an immune complex glomerulonephritis with features of PIGN. All regained renal function with treatment of their known or suspected infections and without specific therapies for their glomerulonephritis, including corticosteroids.

Background: Although innate immunity is crucial to host defense against pathogens, the extent to which innate immune mechanisms participate in the rejection of allogenic tissues in humans is unknown. We hypothesize that activation of innate immunity through Toll-like receptors (TLRs) critically regulates the development of renal allograft rejection. We have recently demonstrated decreased acute rejection in lung transplant recipients heterozygous for either of two functional polymorphisms in TLR4 associated with endotoxin hyporesponsiveness. In the present investigation, we sought to evaluate the role of innate immune activation through TLR4, in either donor or recipient, upon the development of renal allograft rejection., Methods: Patients and donors were screened for the TLR4 functional polymorphisms (Asp299Gly and Thr399Ile) by polymerase chain reaction (PCR) using sequence-specific primers., Results: The incidence of biopsy-proven acute renal allograft rejection was significantly reduced in patients receiving donor grafts heterozygous for the Asp299Gly or Thr399Ile alleles, when compared with wild type (22% vs. 0%, respectively, p = 0.02). There was no association with recipient TLR4 allele and rejection., Conclusions: The results suggest activation of innate immunity through TLR4 in the donor kidney contributes to the development of acute rejection after renal transplantation.

Acute humoral rejection (AHR) in kidney transplantation is associated with higher rates of allograft loss when compared with acute cellular rejection (ACR). Treatment with intravenous immunoglobulin (IVIG) combined with plasmapheresis (PP) has been used recently in many centers. We report the incidence, clinical characteristics, and outcome of patients with AHR treated with IVIG and PP. All patients (n=519) at our institution who underwent kidney transplantation between January 1999 and August 2003 were retrospectively analyzed and classified according to biopsy results into three groups: AHR, ACR, and no rejection. AHR was diagnosed in 23 patients (4.5%) and ACR in 75 patients (15%). Mean follow-up was 844+/-23 days. Female sex, black race, and high panel-reactive antibody were risk factors for AHR. Most AHR patients (22 of 23) were treated with IVIG and PP. Two-year graft survival was numerically worse in patients with AHR versus ACR (78% vs. 85%, p=0.5) but the difference was not statistically significant. Graft survival after AHR treated with IVIG and PP is much better than it has been historically. IVIG in combination with PP is an effective treatment for AHR. Graft survival in this setting is similar to graft survival in patients with ACR.

Recurrent episodes of acute rejection (AR) and/or the intense immunosuppression used for their treatment have been proposed as risk factors for BK nephritis (BKN; BK refers to the initials of the first patient from whom this polyomavirus was isolated). To further examine the relationship between AR and BKN, we analyzed all kidney transplants performed at our center between January 1999 and August 2001 (n = 286). After a mean follow-up of 737 +/- 22 d, we identified nine cases of BKN (3.1%). The mean time to diagnosis of BKN was 326 +/- 56 d. No patient with BKN had a prior history of AR. During the same period, 62 patients were diagnosed with AR (22%). The mean time to diagnosis of AR was 197 +/- 40 d (p = 0.01 vs. time to diagnosis of BKN). Despite aggressive therapy with methylprednisolone and, in some cases, anti-lymphocyte antibody, none of these patients with AR developed BKN. We compared the baseline characteristics of patients in both groups and found that BKN patients were more likely to be white people (78 vs. 44%, p = 0.05) and male (89 vs. 53%, p = 0.04). Moreover, the mean tacrolimus (TAC) levels before diagnosis were higher in BKN than in AR patients (11.7 +/- 0.5 vs. 6.5 +/- 0.6 ng/mL, p < 0.001). In summary, our study shows that BKN often occurs in the absence of prior episodes of AR. In addition, our findings suggest that white males exposed to higher TAC levels are at greater risk of developing BKN.

Enteric drainage of secretions by anastomosing the donor duodenum to the recipient's small bowel has become common in pancreatic transplantation. While it eliminates many problems, endoscopic access to the transplanted duodenum and pancreas is made difficult. After a pancreas kidney transplant, the patient presented with massive hematochezia. Upper and lower endoscopy revealed large amounts of red blood in the colon but no specific bleeding site. Mesenteric angiography was normal but pelvic angiography showed rapid extravasation of contrast from a pseudoaneurysm of the pancreatic transplant artery. This was successfully embolized with coils. To the best of our knowledge, this is the first case of massive gastrointestinal hemorrhage because of rupture of a pseudoaneurysm of the donor pancreatic artery in a pancreas transplant patient. We report this case and review our institution's experience with all forms of gastrointestinal bleeding in pancreas transplant patients.

In vitro data suggest that calcium plays an important role in normal and disordered erythropoiesis. The purpose of this study is to determine whether there is an association between serum calcium, various hormone levels, and the development of post transplant erythrocytosis (PTE). Data were collected on 283 patients who underwent renal transplantation between 1994 and 1998. The relationship between serum calcium and PTE development was tested using the chi-square test. Univariate and multivariable adjusted models were employed to determine predictors of maximum hematocrit. Selected patients underwent measurement of intact parathyroid hormone (PTH), 1,25-dihydroxy vitamin D, and erythropoietin (EPO). Seventy-three patients (26%) developed PTE. Post transplant erythrocytosis was more common in patients with hypercalcemia compared with patients with normal serum calcium (34% vs. 18%, p = 0.002). In multivariable analyses, serum calcium was a strong independent predictor of maximum hematocrit post transplant, even after adjustment for renal function. A serum calcium of >or=10.2 mg/dL was associated with greater than two-fold increased odds of PTE. There were no differences in hormone levels between subjects with hypercalcemia and PTE, subjects with PTE alone, and subjects with hypercalcemia alone. Hypercalcemia is associated with the development of PTE in renal transplant recipients.

Background: Acute humoral rejection (AHR) has been associated with enhanced graft loss. Our study compared the renal allograft survival of patients with AHR treated with plasmapheresis (PP) and intravenous immunoglobulin (IVIG) with allograft survival in patients with acute cellular rejection (ACR)., Methods: We retrospectively analyzed all kidney transplants performed at our institution between January 1999 and August 2001 (n=286). Recipients were classified into three groups according to biopsy reports: AHR, ACR, or no rejection. The ACR group was further divided into early and late rejection (<90 and >90 days posttransplant, respectively)., Results: After a mean follow-up of 569+/-19 days, the incidence of AHR was 5.6% (n=16). Recipient presensitization, delayed graft function, early rejection, and higher creatinine at diagnosis were characteristic of AHR. Most AHR patients (14/16) were treated with PP and IVIG. One patient received only IVIG, whereas another received only PP. All AHR patients were given steroid pulses, but only four received antilymphocyte therapy because of concomitant severe ACR. The ACR group comprised 43 patients (15%). One patient with mild rejection received no therapy, 20 improved with steroids alone, and 22 required additional antilymphocyte therapy. One-year graft survival by Kaplan Meier analysis was 81% and 84% in the AHR and ACR groups, respectively (P=NS). Outcomes remained similar when AHR patients were compared with those with early ACR., Conclusions: We conclude that AHR, when diagnosed early and treated aggressively with PP and IVIG, carries a short-term prognosis that is similar to ACR.

A racial disparity in graft survival for renal transplant recipients has been documented for both cadaveric and living-donor transplants. In the present single-center study we analyzed graft survival by race for recipients of living-donor kidney transplants in three eras: 1985-89, 1990-94, and 1995-2000. There was an intensification of the immunosuppressant regimen beginning in 1996, such that all patients received cyclosporine or tacrolimus with mycophenolate and prednisone. Graft survival was analyzed using the Cox proportional hazards model. There were 79 black recipients and 210 white recipients with no difference in mean age, degree of HLA matching, or proportion of recipients with diabetes as the cause of end-stage renal disease. Using all data from 1985 to 2000, graft survival was significantly better for whites vs. blacks adjusted for age, gender, diabetes, era of the transplant, and haplotype match (p = 0.05). However, when analyzed by era, there was a temporal trend for a progressive decrease in the racial disparity in graft survival. In confirmation of this effect, there was a significant race-era interaction (p = 0.01) on multivariable Cox proportional hazards analysis. The most recent data from the United States Renal Data System (USRDS) show a similar decrease in the racial difference in 1-year graft survival. We conclude that the influence of race on living-donor graft survival is diminishing over time.