Role of TH1/TH2 Cytokines in Kidney Allograft Rejection

One of the major issues in contemporary kidney transplantation is prevention of acute allograft rejection episodes (AREs). Cytokines are crucial mediators of immune reactions leading to AREs. We correlated serum Th1/Th2 cytokine concentrations with AREs. The project included 44 patients undergoing kidney transplantation. During the 3-month period following the transplantation, ARE was diagnosed in 11 patients. Serum samples collected 1 day before and 2, 7, 14, and 30 days after transplantation were tested for interleukin (IL)-2, IL-4, IL-5, IL-10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α concentrations using flow cytometry. Nonrejection (NONAR) and rejection (ARE) groups of patients did not show significant differences in baseline demographic characteristics. We observed that higher pretransplantation serum levels of IFN-γ (P = .000003) and IL-10 (P = .000001) were associated with AREs. Our analysis also showed slightly higher IL-4 serum levels among NONAR patients up to 7 days posttransplantation, followed by a drop in concentrations in NONAR patients. In contrast, there was a continuous increase among ARE patients. No significant differences were observed in plasma levels of IL-2, IL-5, IL-10, or TNF-α between the two groups. Higher pretransplantation levels of IFN-γ and IL-10 observed in ARE patients indicated ongoing nondetected, probably nonspecific, inflammatory processes able to intensify an immune response directed against the transplanted organ leading to its acute rejection. Higher levels of IL-4 prior to and shortly after transplantation may have protective effects on graft survival. However, a prolonged, increased production of IL-4 after transplantation can also contribute to AREs.     

Malnutrition Risk in Kidney Recipients Treated With Mycophenolate Mofetil Is Associated With IMPDH1 rs2278294 Polymorphism

Background

Malnutrition is known to increase morbidity and mortality in renal transplant recipients, whereas little is known about genetic predisposition to low body mass index (BMI) in the transplant setting. Inosine monophosphate dehydrogenase (IMPDH) regulates intracellular fat accumulation, pre-adipicytes maturation, and is a target of mycophenolic acid (MPA) used as a standard immunosuppressant. We hypothesized that MPA may interfere with fat tissue formation and weight gain in kidney transplant recipients and this process may be modified by IMPDH1 or IMPDH2 (genes encoding constitutive and inducible IMPDH) small nucleotide polymorphism variants.

De Novo Membranous Nephropathy Associated With Antibody-Mediated Rejection in Kidney Transplant Recipients

BackgroundMembranous nephropathy (MN) is a rare autoimmune disease that can develop a persistent nephrotic syndrome and end-stage kidney disease, with a recurrence rate of 30% to 40% after kidney transplant.MethodsRetrospective case series of membranous nephropathy observed in a cohort of kidney transplant recipients with donor-specific anti–human leukocyte antigen antibodies and biopsy-proven antibody-mediated rejection (AMR).ResultsWe report 4 cases of membranous nephropathy associated with AMR. MN was diagnosed 10 to 92 months posttransplant, associated with de novo donor-specific antibodies, specific to class I in 2 cases, and class II in another 2. All cases presented typical morphology of membranous nephropathy, with subepithelial deposits with spikes at electron microscopy. Immunostaining for immunoglobulin G4 was negative in all cases, and podocyte-expressed M-type phospholipase A2 receptor was detected in glomerular basement membrane of 3 cases. Biopsy specimens from patients with longer follow-up showed more intense microvascular inflammation and chronic injury markers, possibly because of subclinical immunologic injury. AMR therapy included immunoglobulin 2g/kg in 3 patients, isolated or associated with plasmapheresis. One patient was not treated because of an active disseminated infection. Two patients remain with functioning grafts and under antiproteinuric therapy. Two grafts were lost, 1 because of chronic failure and the other because of death secondary to infection. Despite treatment, donor-specific antibodies remain detectable in a 6-month follow-up.ConclusionsDe novo MN is a rare manifestation associated with AMR in kidney transplant recipients. The occurrence of podocyte-expressed M-type phospholipase A2 receptor in de novo MN suggests antibody-mediated activation, despite the use of maintenance immunosuppression.     

Diagnosis and Treatment of Acute Humoral Kidney Allograft Rejection

Acute humoral rejection (AHR) is a severe form of rejection associated with poor graft survival. Prompt diagnosis and rapid institution of therapy are crucial to improve the prognosis. A therapeutic approach based on plasmapheresis, intravenous imunoglobulin, and rituximab seems to be effective in refractory cases. Herein we have described our experience with 11 patients with biopsy-proven AHR who were treated between January 2005 and June 2008. Seven of these patients had panel reactive antibodies titers more than 50%. The diagnosis was based on Banff 2001 criteria; treatment consisted of a combination of plasmapheresis and intravenous immunoglobulin. Four refractory cases were also treated with a single dose of rituximab. One graft was lost due to thrombosis. All other patients recovered graft function with an average creatinine level of 1.6 mg/dL at 8.6 ± 2.7 months of follow-up.     

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.     

Pancreatic Panniculitis Associated with Allograft Pancreatitis and Rejection in a Simultaneous Pancreas–Kidney Transplant Recipient

Pancreatic panniculitis is an uncommon condition that can occur in association with pancreatic disease. We present a case of pancreatic panniculitis in a female pancreas-kidney transplant recipient 5 months post-transplant. The patient was on standard immunosuppressive medications and had acute rejection of her renal allograft. The diagnosis of allograft pancreatitis and rejection presenting with pancreatic panniculitis was supported clinically, histopathologically and by laboratory and imaging data. This is the fourth case of pancreatic panniculitis occurring in a transplant recipient and the first in a simultaneous pancreas-kidney transplant recipient. It is also the first case associated with allograft rejection. Clinicians should be aware that pancreatic panniculitis may be a manifestation of underlying allograft pancreatic disease.     

Monocyte Infiltration and Kidney Allograft Dysfunction During Acute Rejection

Multiple cell types infiltrate acutely rejecting renal allografts. Typically, monocytes and T cells predominate. Although T cells are known to be required for acute rejection, the degree to which monocytes influence this process remains incompletely defined. Specifically, it has not been established to what degree monocytes impact the clinical phenotype of rejection or how their influence compares to that of T cells. We therefore investigated the relative impact of T cells and monocytes by correlating their presence as measured by immunohistochemical staining with the magnitude of the acute change in renal function at the time of biopsy in 78 consecutive patients with histological acute rejection. We found that functional impairment was strongly associated with the degree of overall cellular infiltration as scored using Banff criteria. However, when cell types were considered, monocyte infiltration was quantitatively associated with renal dysfunction while T-cell infiltration was not. Similarly, renal tubular stress, as indicated by HLA-DR expression, increased with monocyte but not T-cell infiltration. These data suggest that acute allograft dysfunction is most closely related to monocyte infiltration and that isolated T-cell infiltration has less acute functional impact. This relationship may be useful in assigning acute clinical relevance to biopsy findings.     

Uric Acid Is Highly Associated With Kidney Allograft Survival in a Time-Varying Analysis

Background

Hyperuricemia may be associated with the development of new cardiovascular events and graft loss in renal transplant recipients. This study was conducted to clarify whether hyperuricemia is a persistently independent predictor of long-term graft survival and patient outcome.

Methods

Renal allograft recipients (n = 880) who underwent transplantation from December 1999 to March 2013 were included. Participants were divided into 2 groups: a hyperuricemic group (n = 389) and a normouricemic group (n = 491). The mean serum uric acid (UA) level was obtained by averaging all measurements, once per month for 3 months, before the study began. Clinical and laboratory data were collected. We investigated the role of hyperuricemia in the primary endpoint of graft failure by using time-varying analysis and Kaplan-Meier plots. All-cause mortality in renal transplant recipients was also surveyed.

Results

During a mean follow-up of 43.3 ± 26.3 months, the major predisposing factors in the 389 patients with hyperuricemia were male predominance (62.98%), high entry serum UA (7.70; range 6.70–8.80 mg/dL), more hypertension (92.29%), previous hemodialysis mode (29.56%), hepatitis C infection (24.42%), more frequent use of UA-lowering agents (43.44%), and use of more drugs for inducing high serum UA (17.74%). After 12 months, the hyperuricemic group had persistently high serum UA (7.66 ± 2.00 vs 6.17 ± 1.60 mg/dL, P < .001) and poor renal function (serum creatinine 2.96 ± 3.20 vs 1.61 ± 1.96 mg/dL, P < .001) compared with the normouricemic group. Survival analysis showed the hyperuricemic group had poorer graft survival (60.47%) than the normouricemic group (75.82%, P = .0069) after 13-year follow-up. However, there was no difference in all-cause mortality between the 2 groups.

Conclusion

Persistently high serum UA seems to be implicated in elevation of serum creatinine, which could increase the risk for allograft dysfunction.     

Acute Pancreas Allograft Rejection Is Associated With Increased Risk of Graft Failure in Pancreas Transplantation

The effect of acute allograft rejection (AR) on long‐term pancreas allograft function is unclear. We retrospectively studied 227 consecutive pancreas transplants performed at our institution between January 1, 998 and December 31, 2009 including: 56 simultaneous pancreas and kidney (SPK), 69 pancreas transplantation alone (PTA); and 102 pancreas after kidney (PAK) transplants. With a median follow‐up of 6.1 (IQR 3–9) years, 57 patients developed 79 episodes of AR, and 19 experienced more than one episode. The cumulative incidence for AR was 14.7%, 19.7%, 26.6% and 29.1% at 1, 2, 5 and 10 years. PTA transplant (hazards ratio [HR] = 2.28, p = 0.001) and donor age (per 10 years) (HR = 1.34, p = 0.006) were associated with higher risk for AR. The first AR episode after 3 months post PT was associated with increased risk for complete loss (CL) (HR 3.79, p < 0.001), and the first AR episode occurring during 3‐ to 12‐month and 12‐ to 24‐month periods after PT were associated with significantly increased risk for at least partial loss (PL) (HR 2.84, p = 0.014; and HR 6.25, p < 0.001, respectively). We conclude that AR is associated with increased risk for CL and at least PL. The time that the first AR is observed may influence subsequent graft failure.     

CD152 and PD-1 Down-Regulation on CD8 T Cells Is Associated With Human Acute Liver Allograft Rejection

PurposeTo investigate CD152 and PD-1 expression on T lymphocytes and the function of CD152- and PD-1–positive CD8 T cells in human acute liver allograft rejection.Materials and methodsSixty-three patients undergoing liver transplantation were enrolled in this study, including 26 cases with acute allograft rejection (Gr-AR) and 37 cases with stable allograft liver function (Gr-SF). The expression of CD152 and PD-1 on T lymphocytes and the expression of granzyme and perforin on CD152- and PD-1–positive CD8 T cells in peripheral blood were analyzed using flow cytometry.ResultsThe peripheral CD4/CD8 ratio in Gr-AR was significantly lower than that in Gr-SF (P < .01). The expression of CD152 and PD-1 on CD8 and CD4 T cells was significantly lower in Gr-AR than in Gr-SF (all P < .01). The expression of granzyme B and perforin was significantly higher in Gr-AR than in Gr-SF (P < .01).ConclusionsDown-regulation of the expression of negative costimulatory molecules such as CD152 and PD-1 on CD8 T cells may be associated with human acute liver allograft rejection.     

The APOL1 Gene and Allograft Survival after Kidney Transplantation

Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with nephropathy in African Americans (AAs). The effect of transplanting kidneys from AA donors with two APOL1 nephropathy risk variants is unknown. APOL1 risk variants were genotyped in 106 AA deceased organ donors and graft survival assessed in 136 resultant kidney transplants. Cox‐proportional hazard models tested for association between time to graft failure and donor APOL1 genotypes. The mean follow‐up was 26.4 ± 21.8 months. Twenty‐two of 136 transplanted kidneys (16%) were from donors with two APOL1 nephropathy risk variants. Twenty‐five grafts failed; eight (32%) had two APOL1 risk variants. A multivariate model accounting for donor APOL1 genotype, overall African ancestry, expanded criteria donation, recipient age and gender, HLA mismatch, CIT and PRA revealed that graft survival was significantly shorter in donor kidneys with two APOL1 risk variants (hazard ratio [HR] 3.84; p = 0.008) and higher HLA mismatch (HR 1.52; p = 0.03), but not for overall African ancestry excluding APOL1. Kidneys from AA deceased donors harboring two APOL1 risk variants failed more rapidly after renal transplantation than those with zero or one risk variants. If replicated, APOL1 genotyping could improve the donor selection process and maximize long‐term renal allograft survival.     

Matrix Metalloproteases 1 and 3 Promoter Gene Polymorphism Is Associated With Rotator Cuff Tear

Clinical Orthopaedics and Related Research® - Studies suggest that the collagen degeneration and disordered arrangement of collagen fibers in rotator cuff tears are associated with an increase...     

Presentation and Outcomes of Antibody-Mediated Rejection Associated With Angiotensin II Receptor 1 Antibodies Among Kidney Transplant Recipients

BackgroundIt remains challenging to manage antibody-mediated rejection (ABMR) associated with angiotensin II type 1 receptor antibodies (AT1R-Abs) in kidney transplant recipients and the outcomes are not well defined. We describe the presentation, clinical course, and outcomes of this condition.MethodsThis retrospective study included kidney transplant recipients with AT1R-Ab levels ≥10 units/mL and biopsy-proven ABMR in the absence of significant HLA-donor-specific antibodies at the time of rejection.ResultsWe identified 13 recipients. Median creatinine (Cr) at rejection was significantly higher (2.05 mg/dL) compared with baseline (1.2 mg/dL), P = .006. After ABMR management, the difference in median Cr was not significant (1.5 mg/dL), P = .152. Median AT1R-Ab level was higher in the pretransplant sample (34.5 units/mL) compared with the level at rejection (19 units/mL) and after rejection treatment (13 units/mL); however, these differences were not significant, P = .129. Eight of the 13 recipients received antibody reduction therapy with plasmapheresis and intravenous immunoglobulin, and 5 of the 13 recipients had other therapies. After rejection management, 6 of the 13 recipients had improvement in Cr to baseline and 7 of the 13 recipients had > 50% reduction in proteinuria.ConclusionsAT1R-Ab–associated ABMR management and outcomes depend on the clinical presentation and may include antibody-reducing therapies among other therapies. Further prospective cohorts will improve recognizing and managing this condition.     

Posttransplant-Alloantibodies Against MICA Antigens Associated With Decreased Long-Term Allograft Survival of Kidney Transplant Recipients

BackgroundPrevious evidence showed that antibodies against major histocompatibility complex class I-related chain A (MICA) could lead to antibody-mediated rejection in kidney transplantation in case where the patients had no alloantibodies against HLA. However, the effects of posttransplant anti-MICA antibodies on long-term renal allograft survival and function remained unsettled. We tested the posttransplant anti-MICA antibodies in 150 kidney transplant patients. The aim of this study was to compare the long-term graft survival and function between patients who were MICA positive and those who were negative.MethodsThe posttransplant serum samples from 150 patients receiving kidney transplantation in our center from 2012 to 2013 were tested for MICA antibodies and HLA antibodies by Luminex single antigen array technology. Graft survival and function were followed up for a mean time of 74.2 months. The research was conducted in accordance with the Helsinki Congress and the Declaration of Istanbul.ResultsOf the 150 patients, 38 (25.3%) were sensitized against MICA after transplantation. The anti-MICA antibodies-positive (anti-MICA+) group had a worse long-term renal allograft survival than that of anti-MICA-negative (anti-MICA–) group (P = .029), even when stratified by posttransplant HLA sensitization status or donor source. Anti-MICA antibodies also had a detrimental impact on renal allograft function, but only at 1 year posttransplantation (estimated glomerular filtration rates at 1 year: anti-MICA+ 66.6 mL/min/1.73 m² vs anti-MICA– 78.7 mL/min/1.73 m²; P = .023).ConclusionPosttransplant anti-MICA antibodies were associated with decreased long-term renal allograft survival and short-term renal allograft function.     

De novo Membranous Nephropathy in Renal Allograft Associated With Antibody-Mediated Rejection and Review of the Literature

A 71-year-old woman with unknown renal failure etiology received living donor transplantation had normal graft function for many years. At 11 years from transplantation, she developed nephrotic syndrome. Allograft biopsy showed membranous nephropathy (MN) and C4d positivity in the peritubular capillaries, suggestive of antibody-mediated rejection. At the time of nephrosis onset, she had new donor-specific antibody positivity. The case is unusual in that the diagnosis of de novo MN is based on evidence that she had antibody-mediated rejection. De novo MN remains relatively uncommon; we have reviewed the literature on this diagnosis.     

Increased Asymmetric Dimethylarginine Serum Levels are Associated With Acute Rejection in Kidney Transplant Recipients

Asymmetric dimethylarginine (ADMA) has been identified as a marker of endothelial dysfunction and an independent risk factor for cardiovascular events in uremic subjects. This study evaluated ADMA plasma levels in kidney transplant recipients. ADMA levels were serially measured during the first year posttransplantation in 41 recipients treated with cyclosporine regimen (CY), sirolimus (SIR), or low-dose cyclosporine plus everolimus (E). Homocysteine, C reactive protein (CRP), nitric oxide (NO), and standard routine laboratory analyses were determined serially. ADMA significantly increased at 6 months posttransplantation, but was significantly lower among patients on SIR or E. NO was only slightly reduced in patients with increased ADMA levels. Interestingly, ADMA was significantly increased during the first 4 days posttransplantation in patients who experienced acute rejection during the first 6 months after transplantation. The same group of patients demonstrated higher levels of CRP and systolic blood pressure before transplantation. Our results demonstrated that ADMA was increased in patients on CY at 6 months. When increased soon after transplantation ADMA may be associated with episodes of acute rejection in kidney transplant recipients. The presence of elevated systolic blood pressure, as well as CRP and ADMA levels, suggested a role for endothelial dysfunction in the development of acute rejection episodes among deceased donor kidney transplant recipients.     

Glutathione S-Transferase M1 Gene Polymorphism Is Associated with Susceptibility to Impaired Long-term Allograft Outcomes in Renal Transplant Recipients

Background

Despite improved post-transplantation care, progress in long-term kidney allograft survival of diabetic renal transplant recipients (pre-DM RTR) is worse than that of non-diabetic recipients (non-DM). We hypothesized that there are other potential risk factors, that predispose RTR to adverse renal allograft outcomes.

Methods

A total of 323 transplant recipients who underwent renal transplantation between March 2000 and January 2008 were recruited. The composite end-point consisted of serum creatinine (SCr) doubling, graft failure, and death. Baseline clinical data were recorded, and polymerase chain reaction-restriction fragment length polymorphism measurements of interleukin (IL)-4, IL-10, IL-23, glutathione S-transferase (GST)A1, GSTM1, and GSTP1 polymorphisms were determined. The risk factors for developing the primary outcome were analyzed among these clinical and genetic factors.

Results

Within a mean follow-up of 71.1 ± 24 months, there were 43 (13.3 %) patients with the primary outcome. Stepwise multivariate Cox regression analysis was used to determine the risk factors for the primary outcome of RTR. Renal transplant recipients who possessed the GSTM1 null genotype had a 2.2-fold risk (95 % CI: 1.10–4.40; P = 0.026) of developing the primary outcome. Additionally, RTR that had DM before transplantation (aHR: 3.31; 95 % CI: 1.77–6.20; P = 0.0002) or changes in SCr 6 to 12 months after transplantation (aHR: 2.83; 95 % CI: 1.29–6.19; P = 0.0095) had an increased risk of developing the primary outcome.

Conclusions

In addition to the adverse role played by DM, the GSTM1 null genotype also has an unfavorable influence on the long-term allograft outcome of RTR.