Brenda Muth

Medical Care of Kidney Transplant Recipients after the First Posttransplant Year

Kidney transplantation is the treatment of choice for patients with ESRD. Despite improvements in short-term patient and graft outcomes, there has been no major improvement in long-term outcomes. The use of kidney allografts from expanded-criteria donors, polyoma virus nephropathy, underimmunosuppression, and incomplete functional recovery after rejection episodes may play a role in the lack of improvement in long-term outcomes. Other factors, including cardiovascular disease, infections, and malignancies, also shorten patient survival and therefore reduce the functional life of an allograft. There is a need for interventions that improve long-term outcomes in kidney transplant recipients. These patients are a unique subset of patients with chronic kidney disease. Therefore, interventions need to address disease progression, comorbid conditions, and patient mortality through a multifaceted approach. The Kidney Disease Outcomes Quality Initiative from the National Kidney Foundation, the European Best Practice Guidelines, and the forthcoming Kidney Disease: Improving Global Outcomes clinical practice guidelines can serve as a cornerstone of this approach. The unique aspects of chronic kidney disease in the transplant recipient require the integration of specific transplant-oriented problems into this care schema and a concrete partnership among transplant centers, community nephrologists, and primary care physicians. This article reviews the contemporary aspects of care for these patients.

C1q Binding Activity of De Novo Donor-specific HLA Antibodies in Renal Transplant Recipients With and Without Antibody-mediated Rejection.

Background Complement fixation by donor-specific HLA antibodies (DSA) is a primary mechanism for antibody-mediated damage of organ allografts. Using a recently developed kit that measures C1q binding to distinguish complement fixing and nonfixing antibodies, studies showed that C1q + DSAs have a higher risk of rejection and graft loss compared to C1q-DSA. The objective of this study was to assess the ability of the C1q-binding assay to identify clinically significant de novo DSA in renal transplant recipients and to define the properties of DSA that confer C1q binding ability. Methods The DSA-positive sera from 34 kidney recipients, 19 with biopsy-proven antibody-mediated rejection (AMR) + and 15 who were AMR−, were assayed in C1q-binding assays (C1q Screen; One Lambda, Inc. Canoga Park, CA). The correlation between C1q-binding activity, presence of AMR, DSA mean fluorescence intensity (MFI) values, and immunoglobulin G isotype was determined. Results Fifty-three percent (10/19) of sera from AMR+ patients had C1q + DSA, whereas only 13% (2/15) of sera from AMR− patients contained C1q + DSA. C1q + DSA exhibited significantly higher MFI values regardless of whether they were from AMR+ or AMR− patients (16,118 ± 6698 vs 6429 ± 4003; P < 0.0001). C1q + DSA converted to C1q − when diluted to a comparable MFI level as the C1q − DSA from AMR− patients, and some C1q − antibodies converted to C1q + when concentrated to MFI levels comparable to those observed for AMR+/C1q + sera. Conclusions The C1q binding activity by de novo DSA in patients with AMR largely reflects differences in antibody strength. The C1q assay does not appear to distinguish functionally distinct DSA with clinical significance.

Antithymocyte Globulin is Associated with a Lower Incidence of De Novo Donor-Specific Antibodies in Moderately Sensitized Renal Transplant Recipients

Background Recent evidence suggests that de novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection (ABMR) and graft failure after kidney transplantation. The effects of induction immunosuppression on dnDSA are unknown. Methods The study population comprised 114 consecutive moderately sensitized (positive DSA and negative flow crossmatch) recipients who received deceased donor renal transplants between December 2009 and November 2011. Patients were divided into two groups based on induction immunosuppression: antithymocyte globulin (ATG) (n=85) or basiliximab (n=29) and were followed up for 36 months. Results Patients in the ATG group received a mean dose of 4.98 mg/kg±7.9 mg/kg, had a significantly higher PRA, and received more plasmapheresis and IVIG at the time of transplant. The incidence of dnDSA (P=0.02, HR=0.33, 95% CI 0.09–1.24) and ABMR (P=0.001, HR=0.9, 95% CI 0.04–0.87) was significantly lower in the ATG group. In multivariate regression analyses, ATG induction was the single most important variable associated with both ABMR and dnDSA. Conclusions In moderately sensitized deceased donor renal transplant recipients, induction with ATG is associated with a reduction in the occurrence of dnDSA and ABMR when compared with basiliximab.

Bisphosphonates and bone fractures in long-term kidney transplant recipients.

Background. There is little information on the role of bisphosphonates and bone mineral density (BMD) measurements for the follow-up and management of bone loss and fractures in long-term kidney transplant recipients. Methods. To address this question, we retrospectively studied 554 patients who had two BMD measurements after the first year posttransplant and compared outcomes in patients treated, or not with bisphosphonates between the two BMD assessments. Kaplan-Meier survival and stepwise Cox regression analyses were performed to examine fracture-free survival rates and the risk-factors associated with fractures. Results. The average time (±SE) between transplant and the first BMD was 1.2±0.05 years. The time interval between the two BMD measurements was 2.5±0.05 years. There were 239 and 315 patients in the no-bisphosphonate and bisphosphonate groups, respectively. Treatment was associated with significant preservation of bone loss at the femoral neck (HR 1.56, 95% CI 1.21–2.06, P=0.0007). However, there was no association between bone loss at the femoral neck and fractures regardless of bisphosphonate therapy. Stepwise Cox regression analyses showed that type-1 diabetes, baseline femoral neck T-score, interleukin-2 receptor blockade, and proteinuria (HR 2.02, 0.69, 0.4, 1.23 respectively, P<0.01), but not bisphosphonates, were associated with the risk of fracture. Conclusions. Bisphosphonates may prevent bone loss in long-term kidney transplant recipients. However, these data suggest a limited role for the initiation of therapy after the first posttransplant year to prevent fractures.

Luminex-based desensitization protocols: The university of wisconsin initial experience

Background. We have demonstrated that immunodominant donor-specific antibody (DSA) more than 100 mean fluorescence intensity (MFI) at the time of transplant is associated with a significantly higher risk of rejection. We now present short-term outcomes of DSA-based desensitization (DSZ) strategies in patients with a negative complement-dependent cytotoxicity crossmatch. Methods. Between January 1, 2009, and January 1, 2010, live-donor kidney transplant recipients were divided into three protocols based on their immunodominant DSA MFI pretransplant (D1: 100–500, D2: 501–1000, and D3: 1001–3000). Deceased donor kidney transplant recipients were stratified into two protocols (D4: 501–1000 and D5: 1001–3000). The intensity of the conditioning treatment increased with DSA levels and included thymoglobulin induction, plasmapheresis, and intravenous immunoglobulin in the highest risk groups. We compared outcomes between desensitized patients (DSZ) and those undergoing no DSZ (or D0) during the same interval. Results. Forty-eight of 249 (23%) kidney transplants underwent DSZ (n=20, 4, 3, 4, and 17 in D1–D5 protocols, respectively). There was more retransplantation (50% vs. 18%, P<0.001) and live donor transplantation (56% vs. 30%, P<0.001) in the DSZ group. In this group, mean peak panel reactive antibody and MFI at transplant were 51%±7% and 960±136, respectively. The incidence of antibody-mediated rejection (25% vs. 12.5%, P=0.008) and acute cellular rejection (23% vs. 14%, P=0.02) was greater in the DSZ group. However, mixed rejection (8%), graft loss (0 vs. 6), patient death (0 vs. 3), cytomegalovirus infection (15% vs. 12%), and 1-year serum creatinine (1.4±0.5 and 1.4±0.4 mg/dL) were similar between DSZ and no-DSZ groups. Conclusion. Long-term follow-up is needed to determine the role of Luminex-based strategies in current preconditioning regimens.

Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients

In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean calculated panel reactive antibody and MFImax ranged from 10.3% to 57.2%, and 262 to 1691, respectively, between low and high-risk protocols. Mean MFImax increased significantly from transplant to one-week and one-year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32% including 14% cellular, 12% antibody-mediated and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71 to 6.45) and increased donor specific antibodies at 1 week post-transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.

Current outcomes of chronic active antibody mediated rejection – A large single center retrospective review using the updated BANFF 2013 criteria

BACKGROUND The updated BANFF 2013 criteria has enabled a more standardized and complete serologic and histopathologic diagnosis of chronic active antibody mediated rejection (cAMR). Little data exists on the outcomes of cAMR since the initiation of this updated criteria. METHODS 123 consecutive patients with biopsy proven cAMR (BANFF 2013) between 2006 and 2012 were identified. RESULTS Patients identified with cAMR were followed for a median of 9.5 (2.7-20.3) years after transplant and 4.3 (0-8.8) years after cAMR. Ninety-four (76%) recipients lost their grafts with a median survival of 1.9 years after diagnosis with cAMR. Mean C4d and allograft glomerulopathy scores were 2.6 ± 0.7 and 2.2 ± 0.8, respectively. 53.2% had class II DSA, 32.2% had both class I and II, and 14.5% had class I DSA only. Chronicity score >8 (HR 2.9, 95% CI 1-8.4, p=0.05), DSA >2500 MFI (HR 2.8, 95% CI 1.1-6.8, p=0.03), Scr >3mg/dL (HR 3.2, 95% CI 1.6-6.3, p=0.001) and UPC >1g/g (HR 2.5, 95% CI 1.4-4.5, p=0.003) were associated with a higher risk of graft loss. CONCLUSIONS cAMR was associated with poor graft survival after diagnosis. Improved therapies and earlier detection strategies are likely needed to improve outcomes of cAMR in kidney transplant recipients.

Serum β2-microglobulin at discharge predicts mortality and graft loss following kidney transplantation

Serum β(2)-microglobulin (β(2)M), a novel marker of kidney function, predicts mortality and kidney failure in the general population, and its elevation following transplantation is a marker of acute rejection. The association between post-transplant serum β(2)M and outcomes following kidney transplantation, however, is unknown. To help determine this, we conducted a retrospective cohort study of 2190 individuals receiving a primary kidney transplant with serum β(2)M measured at discharge. A total of 452 deaths and 347 graft failures before death (669 total graft losses) occurred over a median of 4.1 years of follow-up. After adjustment, the highest quintile of β(2)M (5.0 mg/l and above), compared with the lowest quintile (<2.3 mg/l), was associated with a hazard ratio of 4.6 (95% confidence interval 2.8, 7.5) for death, 4.1 (2.4, 7.0) for death-censored graft loss, and 3.8 (2.5, 5.6) for total graft loss. Serum β(2)M was more strongly associated with each outcome than was serum creatinine. Higher serum β(2)M at discharge was independently associated with each outcome in models stratified by the presence of delayed graft function, donor type, or estimated glomerular filtration rate at discharge. Thus, serum β(2)M at discharge is a potent predictor of long-term mortality and graft loss in kidney transplant recipients, providing information on allograft function beyond that of serum creatinine.

Initial Vascular Access Type in Patients with a Failed Renal Transplant

BACKGROUND AND OBJECTIVES Permanent hemodialysis vascular access is crucial for RRT in ESRD patients and patients with failed renal transplants, because central venous catheters are associated with greater risk of infection and mortality than arteriovenous fistulae or arteriovenous grafts. The objective of this study was to determine the types of vascular access used by patients initiating hemodialysis after a failed renal transplant. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data from the US Renal Data System database on 16,728 patients with a failed renal transplant and 509,643 patients with native kidney failure who initiated dialysis between January 1, 2006, and September 30, 2011 were examined. RESULTS At initiation of dialysis, of patients with a failed transplant, 27.7% (n=4636) used an arteriovenous fistula, 6.9% (n=1146) used an arteriovenous graft, and 65.4% (n=10,946) used a central venous catheter. Conversely, 80.8% (n=411,997) of patients with native kidney failure initiated dialysis with a central venous catheter (P<0.001). Among patients with a failed transplant, predictors of central venous catheter use included women (adjusted odds ratio, 1.75; 95% confidence interval, 1.63 to 1.87), lack of referral to a nephrologist (odds ratio, 2.00; 95% confidence interval, 1.72 to 2.33), diabetes (odds ratio, 1.14; 95% confidence interval, 1.06 to 1.22), peripheral vascular disease (odds ratio, 1.31; 95% confidence interval, 1.16 to 1.48), and being institutionalized (odds ratio, 1.53; 95% confidence interval, 1.23 to 1.89). Factors associated with lower odds of central venous catheter use included older age (odds ratio, 0.85 per 10 years; 95% confidence interval, 0.83 to 0.87), public insurance (odds ratio, 0.74; 95% confidence interval, 0.68 to 0.80), and current employment (odds ratio, 0.87; 95% confidence interval, 0.80 to 0.95). CONCLUSIONS Central venous catheters are used in nearly two thirds of failed renal transplant patients. These patients are usually followed closely by transplant physicians before developing ESRD after a failed transplant, but the relatively low prevalence of arteriovenous fistulae/arteriovenous grafts in this group at initiation of dialysis needs to be investigated more thoroughly.

Tacrolimus trough level at discharge predicts acute rejection in moderately sensitized renal transplant recipients.

Background Goal tacrolimus concentrations for the prevention of rejection in sensitized renal transplant recipients are not well established. Methods We evaluated the association between discharge tacrolimus trough concentration and the incidence of biopsy-proven acute rejection (BPAR) in 216 moderately sensitized renal transplant recipients (negative flow crossmatch and positive donor-specific antibodies) treated with tacrolimus. Results At transplant, the mean±standard deviation (SD) peak panel-reactive antibody was 60±33 and median donor-specific antibody level was a mean fluorescence intensity of 710 (interquartile range, 328–1202). The mean±SD tacrolimus trough concentration at discharge (median postoperative day, 5; interquartile range, 4–7) was 7.6±3.7 ng/dL. Patients were divided into two groups based on a discharge tacrolimus trough concentration of 8 ng/mL. Baseline characteristics were similar between groups. Thirty-four (28.6%) of the 119 patients with a tacrolimus trough concentration less than 8 ng/mL and 19 (19.6%) of 97 patients with concentrations of 8 ng/mL or greater experienced BPAR during a median follow-up of 14±4.7 months (P=0.04). Adjusting for age, race, donor status, and peak panel-reactive antibody, a discharge tacrolimus trough concentration less than 8 ng/mL was significantly associated with a higher risk of BPAR (hazard ratio, 1.84; 95% confidence interval, 1.04–3.25; P=0.04). Serum creatinine, cytomegalovirus, BK viremia, or BK nephropathy at 1 year did not differ between groups. Conclusions In a patient population predisposed to BPAR, discharge tacrolimus trough concentration less than 8 ng/mL was associated with a nearly two times greater risk of BPAR.