Rowena Delos Santos

Obesity and Kidney Transplant Candidates: How Big Is Too Big for Transplantation?

Obesity impacts many inter-related, and sometimes conflicting, considerations for transplant practice. In this article, we describe an approach for applying available data on the importance of body composition to the kidney transplant population that separates implications for candidate selection, risk stratification among selected candidates, and interventions to optimize health of the individual. Transplant recipients with obesity defined by elevated body mass index (BMI) have been shown in many (but not all) studies to experience an array of adverse outcomes more commonly than normal-weight transplant recipients, including wound infections, delayed graft function, graft failure, cardiac disease, and increased costs. However, current studies have not defined limits of body composition that preclude clinical benefit from transplantation compared with long-term dialysis in patients who have passed a transplant evaluation. Formal cost-effectiveness studies are needed to determine if payers and society should be compensating centers for clinical and financial risks of transplanting obese end-stage renal disease patients. Recent studies also demonstrate the limitations of BMI alone as a measure of adiposity, and further research should be pursued to define practical measures of body composition that refine accuracy for outcomes prediction. Regarding individual management, observational registry studies have not found beneficial associations of pretransplant weight loss with patient or graft survival. However, association studies cannot distinguish purposeful from unintentional weight loss as a result of illness and comorbidity. Prospective evaluations of the impact of targeted risk modification efforts in this population including dietary changes, monitored exercise programs, and bariatric surgery are urgently needed.

Cytomegalovirus-induced thrombotic microangiopathy after renal transplant successfully treated with eculizumab: case report and review of the literature

De novo thrombotic microangiopathy (TMA) after renal transplant is rare. Cytomegalovirus (CMV)‐related post‐transplant TMA has only been reported in 6 cases. We report an unusual case of a 75‐year‐old woman who developed de novo TMA in association with CMV viremia. The recurrence of TMA with CMV viremia, the resolution with treatment for CMV, and the lack of correlation with a calcineurin inhibitor (CNI) in our case support CMV as the cause of the TMA. What is unique is that the use of eculizumab without plasmapheresis led to prompt improvement in renal function. After a failure to identify a genetic cause for TMA and the clear association with CMV, eculizumab was discontinued. This case provides insight into the pathogenesis and novel treatment of de novo TMA, highlights the beneficial effects of complement inhibitors in this disease, and shows that they can be safely discontinued once the inciting etiology is addressed.

ABO incompatible renal transplants and decreased likelihood for developing immune responses to HLA and kidney self-antigens.

Immune responses to HLA and tissue-restricted self-antigens (SAgs) have been proposed to play a role in the pathogenesis of renal allograft (KTx) rejection. However, ABO incompatible (ABOi) KTx recipients (KTxR) following depletion of antibodies (Abs) to blood group antigens had fewer rejections. To determine the mechanisms, pre- and post-transplant sera from ABOi (n=18) and ABO-compatible (ABOc) (n=45) KTxR were analyzed for Abs against HLA class I and II by LABScreen single antigen assay. The development of Abs to SAgs was measured by ELISA. Immunity to Collagen IV (Col-IV) and cytokines induced were measured by ELISPOT. While 8/45 (18%) ABOc KTxR developed new donor specific antibodies to HLA (DSA) following transplantation, 0/18 ABOi KTxR developed DSA. ABOi KTxR failed to develop Abs to kidney SAgs (Col-IV and fibronectin (FN)). In contrast, 7 ABOc KTxR developed Abs to both Col-IV and FN. Col-IV stimulation of lymphocytes from ABOc KTxR demonstrated increased IFNγ, IL-17 and decreased IL-10. In contrast ABOi recipients following stimulation with antigens resulted in more IL10 and reduced IFN-γ and IL17 production. At one year, the GFR in ABOi KTxR were significantly better (p<0.04) than ABOc KTxR. De novo DSA and immune responses to SAgs are reduced or absent in ABOi KTxR which we propose leads to less acute rejection and better long term function following ABOi KTx.

Single-dose rituximab for recurrent glomerulonephritis post-renal transplant.

Background/Aims: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. Methods: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. Results: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). Conclusion: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.

Development of immune response to tissue‐restricted self‐antigens in simultaneous kidney‐pancreas transplant recipients with acute rejection

Simultaneous kidney‐pancreas transplantation (SKP Tx) is a treatment for end‐stage kidney disease secondary to diabetes mellitus. We investigated the role of immune responses to donor human leukocyte antigens (HLA) and tissue‐restricted kidney and pancreas self‐antigens (KSAgs and PSAgs, respectively) in SKP Tx recipients (SKP TxRs). Sera collected from 39 SKP TxRs were used to determine de novo Abs specific for KSAgs (collagen‐IV, Col‐IV; fibronectin, FN) and PSAgs (insulin, islet cells, glutamic acid decarboxylase, and pancreas‐associated protein‐1) by ELISA. KSAg‐specific IFN‐γ, IL‐17, and IL‐10 cytokines were enumerated by ELISpot. Abs to donor HLA classes I and II were determined by Luminex assay. Abs to KSAgs and PSAgs were detectable in recipients with rejection compared with stable recipients (P<.05). Kidney‐only rejection recipients had increased Abs against KSAgs compared with stable (P<.05), with no increase in Abs against PSAgs. Pancreas‐only rejection recipients showed increased Abs against PSAgs compared to stable (P<.05), with no Abs against KSAgs. SKP TxRs with rejection showed increased frequencies of KSAg‐specific IFN‐γ and IL‐17 with reduction in IL‐10‐secreting cells. SKP TxRs with rejection developed Abs to KSAgs and PSAgs demonstrated increased frequencies of kidney or pancreas SAg‐specific IFN‐γ and IL‐17‐secreting cells with reduced IL‐10, suggesting loss of peripheral tolerance to SAgs.

Immunological Assessment of the Transplant Patient

The main objective of this chapter is to provide an overview of the immunological evaluation of all potential kidney transplant recipients. The discussion begins with the various immunologic barriers to transplantation, including ABO blood group differences, circulating anti-donor human leukocyte antigen (HLA) antibodies from previous antigen exposure, and minor histocompatibility antigens, which is why even HLA-identical siblings require at least some immunosuppression. Another important concept for readers to grasp is that allograft survival is related to the number of HLA matches. A greater degree of HLA mismatches is also related to higher rates of rejection, which underscores the importance of testing recipients for the presence of preformed antibodies against potential donor HLA antigens.

The privilege of induction avoidance and calcineurin inhibitors withdrawal in 2 haplotype HLA matched white kidney transplantation

Background White recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients. Methods We reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2-haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013. Results There were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89). Conclusions This study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients.

Immunoglobulin isotype switching of antibodies to vimentin is associated with development of transplant glomerulopathy following human renal transplantation

BACKGROUND Immune responses to tissue-restricted self-antigens are thought to play a role in chronic rejection after solid organ transplantation. De novo development of antibodies (Abs) to vimentin have been reported to be associated with interstitial fibrosis/tubular atrophy after kidney transplant, and it has been suggested that immunoglobulin isotype switching of Abs to vimentin may occur during this process. We aimed to determine the correlation between immunoglobulin isotype switching of Abs to vimentin and development of transplant glomerulopathy (TG) after kidney transplant, and to determine whether citrullinated modification of vimentin is required for de novo anti-vimentin development. METHODS Sera were collected from 24 patients with TG (diagnosed on biopsy), 24 matched stable kidney transplant recipients (KTxRs) and 22 normal healthy subjects who did not undergo transplant. Serum vimentin Abs concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Immunoglobulin isotypes of anti-vimentin were determined using isotype-specific Abs conjugated with horseradish peroxidase. Samples were considered positive to vimentin Abs if the values were above mean+2× standard deviations of the levels in the healthy control subjects. Specificities of anti-vimentin for mutated citrullinated vimentin and anti-mutated citrullinated vimentin were measured by ELISA. RESULTS In this retrospective analysis of 24 KTxRs with TG, 16/24 (67%) patients with biopsy-proven TG developed Abs to vimentin (645±427ng/ml). In contrast, only 4/24 (17%) stable KTxRs had detectable Abs to vimentin (275±293ng/ml; p=0.001). Of the patients with TG, 15/24 (63%) developed Abs to vimentin of IgG isotype (572±276ng/ml), whereas only 6/24 (25%) stable KTxRs (310±288ng/ml) had anti-vimentin of IgG isotype (p=0.002). However, no significant difference was noted in the concentration of IgM isotype anti-vimentin between KTxRs with TG (9/24 [38%], 407±401ng/ml) and stable KTxRs (5/24 [21%], 348±439ng/ml; p=0.631). The serum concentration of Abs specific for the mutated form of citrullinated vimentin was not significantly different between KTxRs with TG and stable KTxRs. CONCLUSIONS Patients with biopsy-proven TG demonstrated significantly increased levels of anti-vimentin Abs of the IgG isotype compared with stable KTxRs. Anti-vimentin in stable KTxRs was primarily of IgM isotype. Therefore, the observed isotype switching of anti-vimentin from IgM to IgG isotype strongly suggests ongoing immune responses to vimentin in KTxRs diagnosed with TG. Furthermore, as opposed to patients with rheumatoid arthritis (who develop immune responses primarily to citrullinated vimentin), KTxRs diagnosed with TG developed immune responses to non-citrullinated vimentin, suggesting that modification of vimentin protein via citrullination is not required for the de novo anti-vimentin response seen in patients with TG.

Effect of Frequent Dialysis on Renal Recovery: Results From the Acute Renal Failure Trial Network Study

Introduction The optimal frequency of intermittent hemodialysis (IHD) in the treatment of acute kidney injury (AKI) remains unclear. Increasing the frequency of IHD, while offering the possible advantage of reduced ultrafiltration requirement and less hemodynamic instability per session, amplifies patient contact with an extracorporeal circuit with possible deleterious cardiovascular and immunological consequences. A recent study suggested that intensive renal replacement therapy (RRT) is associated with a decrease in urine output during AKI. We hypothesized that increased frequency of IHD may be associated with delayed renal recovery. Methods This is a post hoc analysis of the Acute Renal Failure Trial Network (ATN) study. The ATN study was a large randomized multicenter trial of intensive versus less-intensive RRT in critically ill patients with AKI. This study used either continuous RRT or IHD, depending on the hemodynamic status of the patient. Of 1124 patients, 246 were treated solely with IHD during the study period and were included in this analysis. The participants were randomized to receive IHD 3 days per week (L-IntRRT) or 6 days per week (IntRRT). The primary outcome of interest was renal recovery at day 28. Results L-IntRRT was associated with higher number of RRT-free days through day 28 than IntRRT (mean difference 2.5 days; 95% confidence interval [CI]: −4.79 to −0.27 days; P = 0.028). The likelihood for renal recovery at day 28 was lower in the IntRRT group (OR: 0.49; 95% CI: 0.28–0.87; P = 0.016). Conclusion In hemodynamically stable patients with AKI, intensifying the frequency of IHD from 3 to 6 days per week may be associated with impaired renal recovery.

Accelerated humoral renal allograft rejection due to HLA-C14 mediated allosensitization to HLA-Bw6

OBJECTIVES To investigate immunological mechanisms underlying accelerated antibody-mediated rejection (AMR) of a living-related renal allograft in a patient with no detectable antibodies to donor human leukocyte antigens (HLA) in pre-transplant sera. METHODS Pre- and post-transplant HLA antibody specificities were determined by single-antigen bead assay, and crossmatching was performed by flow cytometry- and complement-dependent cytotoxicity-based methods. Intermediate- and high-resolution HLA typing were performed by molecular methods. RESULTS Pre-transplant patient serum reacted weakly against Bw6-positive beads; cytotoxicity and flow crossmatches were negative. The patient was mismatched for the donor antigens B62 and C10 (Bw6-positive). Following transplantation, strong antibody responses against B62, C10, and all Bw6-positive beads were detected. This reactivity was initially masked by complement interference, but became apparent at 1:20 dilution. High-resolution typing suggested that the anti-C16 antibody reactivity detected was an allele-specific response to donor C∗16:01 (Bw6-positive) but not recipient C∗16:02 (Bw6-negative). Alloimmunization likely occurred during pregnancy, during which HLA-C14 (Bw6-positive) was the only mismatched paternal HLA Class I allele. CONCLUSIONS Sensitization to HLA-Bw6 via exposure to paternal HLA-C14 during pregnancy likely predisposed this patient to AMR. The case demonstrates the immunogenicity of HLA-C14-associated Bw6 epitopes in vivo and the clinical significance of low-level antibodies to HLA-Bw6.