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.     

Outcome of Subclinical Antibody-Mediated Rejection in Kidney Transplant Recipients with Preformed Donor-Specific Antibodies

This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3-month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 ± 13.9 vs. 61.9 ± 19.2 mL/min/1.73 m² respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR.     

Regulatory B Cells Profile in Kidney Transplant Recipients With Chronic-Active Antibody-Mediated Rejection

This study aims to reveal the relationship between regulatory B cell (Breg) subsets and chronic-active antibody-mediated rejection (c-aABMR) in renal transplant recipients. Our study involved 3 groups of participants: renal transplant recipients with biopsy-proven c-aABMR as the chronic rejection group (c-aABMR, n = 23), recipients with stable graft functions as the patient control group (PC; n = 11), and healthy volunteers (HV; n = 11). Breg subsets, immature/transitional B cells, plasmablastic cells, B10 cells, and BR1 cells were isolated from venous blood samples by flow cytometry. The median values of Breg frequencies in the total lymphocyte population were analyzed. There were no significant differences between the study groups for immature and/or transitional B cell frequencies. Plasmablastic cell frequencies of the c-aABMR group (7.80 [2.10-27.40]) and the PC group (6.00 [1.80-55.50]) were similar, but both of these values were significantly higher than the HVs’ (3.40 [1.20-8.50]), (respectively, P = .005 and P = .039). B10 cell frequencies were also similar, comparing the c-aABMR (4.20 [0.10-7.40]) and the PC groups (4.10 [0.10-5.90]), whereas the HVs (5.90 [2.90-8.50]) had the highest B10 cell frequency with an only statistical significance against the PC group (respectively, P = .09 and P = .028). The c-aABMR and the PC groups were similar regarding BR1 cell frequencies. However, the HV group significantly had the highest frequency of BR1 cells (5.50 [2.80-10.80]) than the other groups (P < .001 for both). We demonstrated that frequencies of B10 and BR1 cells were higher in HVs than in transplant recipients, regardless of rejection state. However, there was no significant relation between Breg frequencies and the c-aABMR state.     

Preformed Angiotensin II Type-1 Receptor Antibodies Are Associated With Rejection After Kidney Transplantation: A Single-Center,Cohort Study

Antibodies against angiotensin II type-1 receptors (AT1R) have been increasingly recognized in association with rejection and poor allograft outcomes. Our goal was to define the prevalence of preformed antibodies against AT1R and evaluate the association with renal allograft outcomes in a consecutive cohort of 150 transplant recipients. IgG antibodies against AT1R were measured by enzyme-linked immunosorbent assay using cryopreserved serum samples obtained for HLA testing at the time of transplantation. Results were categorized as negative if <10 U/mL (44%), intermediate from 10 to 17 U/mL (38%), or strongly positive if >17 U/mL (18%). The presence of AT1R antibodies was inversely associated with age, dialysis status, and diabetes. We found a strong association between the presence of AT1R antibodies and acute cellular rejection using multivariate analyses, odds ratio 3.86 (95% CI, 1.03–14.47) for intermediate titers and 9.99 (95% CI, 2.6–38.4) for strongly positive titers. There was no association with HLA sensitization or C4d-positive antibody-mediated rejection. We did not observe a significant association with graft failure, allograft function, or proteinuria. Preformed AT1R antibodies are prevalent and highly associated with acute cellular rejection early after transplant, independent of anti-HLA antibodies. The presence of AT1R antibodies correlates with recipient characteristics that may denote stronger immune responses. Future studies are needed to evaluate the mechanism and causative effect of AT1R antibodies.     

Costs of Treatment of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients

BackgroundAntibody-mediated rejection (AMR) remains challenging in kidney transplant recipients. It may negatively impact the graft survival, and its treatment is associated to relatively high expenses. The aim of our study was to assess the costs of treatment of acute AMR in the Polish settings.MethodsA total of 11 kidney transplant recipients with acute AMR diagnosed between September 2016 and August 2019 and treated in our center were included. Direct costs of inpatient and outpatient care in the first year after AMR diagnosis from the perspective of a transplant center were retrospectively calculated.ResultsThe costs of treatment of acute AMR were considerably high, with a mean 1-month cost of treatment 12,718 PLN (～€2925; ～3307 US dollars). That means that costs of management of kidney transplant recipients with acute AMR are almost 2-fold higher than hemodialysis. Intravenous immunoglobulin was responsible for the majority (55%) of costs.ConclusionsTreatment of acute AMR increases the costs of post–kidney transplant care in involved patients. Therefore, efforts should be made to minimize the risk for acute AMR. Despite its potential clinical benefits, management of acute AMR is even more expensive than dialysis. Therefore, further cost-effectiveness analyses are needed to justify the spending and to establish the best treatment regimens.     

Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients

The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2–35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.     

Pregnancy and Maternal Outcomes Among Kidney Transplant Recipients

Fertility rates, pregnancy, and maternal outcomes are not well described among women with a functioning kidney transplant. Using data from the Australian and New Zealand Dialysis and Transplant Registry, we analyzed 40 yr of pregnancy-related outcomes for transplant recipients. This analysis included 444 live births reported from 577 pregnancies; the absolute but not relative fertility rate fell during these four decades. Of pregnancies achieved, 97% were beyond the first year after transplantation. The mean age at the time of pregnancy was 29 ± 5 yr. Compared with previous decades, the mean age during the last decade increased significantly to 32 yr (P < 0.001). The proportion of live births doubled during the last decade, whereas surgical terminations declined (P < 0.001). The fertility rate (or live-birth rate) for this cohort of women was 0.19 (95% confidence interval 0.17 to 0.21) relative to the Australian background population. We also matched 120 parous with 120 nulliparous women by year of transplantation, duration of transplant, age at transplantation ±5 yr, and predelivery creatinine for parous women or serum creatinine for nulliparous women; a first live birth was not associated with a poorer 20-yr graft or patient survival. Maternal complications included preeclampsia in 27% and gestational diabetes in 1%. Taken together, these data confirm that a live birth in women with a functioning graft does not have an adverse impact on graft and patient survival.One of the many perceived benefits of kidney transplantation has been restoration of pituitary-ovarian function and fertility in women of reproductive age. Prenatal advice for women with a functioning kidney transplant has been primarily based on data derived from observational research,^1–13 and the reported live-birth rates achieved in such women range from 43.2¹⁴ to 82%.¹⁵Although an increased pregnancy event number has been reported for women with a functioning kidney transplant,¹⁶ little is actually known about “pregnancy rate changes” during the past 40 yr. More importantly, long-term graft and maternal survival analyses, referred to when advising women who have undergone transplantation and are considering a pregnancy, have been mostly performed without adequate matching,¹² or, alternatively, matching has been used but outcomes followed up for only brief intervals^14,17,18 and in small cohorts.^19–22 Published graft matching studies to date suggest no adverse impact 10 yr after a live birth.¹⁴In most instances, pregnancies in women with a kidney graft have been encouraged. Historically, renal function,^8,15,17,18 baseline proteinuria,²³ intercurrent hypertension,^1,24 and time from transplantation^{1,3,5,8,14,15,18,24,25} have been used to predict adverse event risks to the mother, kidney, and offspring. To this are added the often unquantifiable inherent risks for genetically transmitted diseases or the problems associated with prematurity.^26,27 More recently, epidemiologic evidence suggests low birth weight may be associated with the development of hypertension,²⁸ cardiovascular disease,²⁹ insulin resistance,³⁰ and end-stage renal failure.³¹ Moreover, low birth weight is associated with an increased risk for hypertension, independent of genetic and shared environmental factors.³²Series published to date have not captured all pregnancy events or their outcomes. Limitations of some of the published studies include short duration of follow-up and studies with no adequate or long-term matching for decade and renal function.We examined fertility rates, pregnancy rates, and pregnancy outcomes over 40 yr in an at-risk population, defined as women who were aged between 15 and 49 and had a functioning kidney transplant, using ANZDATA registry data. In addition, maternal and graft outcomes were analyzed, and, uniquely, a matched cohort analysis of 120 nulliparous and 120 parous women who had undergone transplantation enabled analysis of outcomes at 20 yr.     

Clinicopathologic Characteristics and Outcomes of Late Acute Antibody-Mediated Rejection in Thai Kidney Transplant Recipients: A Single-Center Experience

Background

Late antibody-mediated rejection (ABMR) has worse prognosis than early ABMR. The objective of this study was to examine the clinical and pathological features of late acute ABMR in our experience.

Method

We retrospectively reviewed all patients who underwent kidney transplantation (KT) between January 2001 and December 2012. Patients who had glomerulitis and/or peritubular capillaritis on kidney biopsy performed 6 months after KT were enrolled.

Results

Of 592 patients, late acute ABMR was diagnosed in 34 cases (5.74%) with a mean onset of 49.2 ± 30.2 months post-KT. Six patients (17.6%) had nonadherence. Allograft histopathology demonstrated concomitant transplant glomerulopathy in 23 patients (67.6%) and positive peritubular C4d staining in 25 patients (73.5%). Donor-specific antibody (DSA) was detected in 25 patients (73.5%). Anti-HLA class II antibody was more prevalent than class I (67.6% vs 20.6%; P = .003) and most of them were anti-HLA DQ. We prescribed intravenous immunoglobulin (IVIG) 1–2 g/kg for 30 patients (88.2%), plasma exchange (PE) for 27 patients (79.4%), and rituximab 375 mg/m² for 18 patients (52.9%). We repeated treatment with PE and IVIG in 12 refractory cases. For clinical outcome, 21 patients (61.7%) had deterioration of graft function; 9 of them (26.5%) eventually lost their graft. Thirteen patients (38.2%) had stable graft function.

Conclusion

Late acute ABMR has unsatisfactory prognosis in spite of aggressive standard antihumoral treatment. Surveillance of late ABMR using DSA monitoring may be helpful in early detection and management.     

Risk Factors and Outcomes Associated With Posttransplant Diabetes Mellitus in Kidney Transplant Recipients

Background

Although our understanding of the risk factors involved in the occurrence of posttransplant diabetes mellitus (PTDM) as well as its outcomes has improved, it still remains incomplete. Our study attempts to analyze the risk factors as well as the outcomes associated with PTDM in the renal transplant patients at the Cleveland Clinic.

Methods

Our study is a retrospective, case-control study. We screened 209 charts of 217 patients who received single-organ kidney transplant at the Cleveland Clinic between January 1996 and December 1998. PTDM was defined by the American Diabetes Association criteria of either a fasting blood glucose ≥126 mg/dL or random blood sugars ≥200 mg/dL confirmed on a second occasion. Kidney transplant recipients who developed PTDM (cases) were compared with kidney transplant recipients who did not develop diabetes but were matched for the time of transplant (controls).

Results

Forty-nine patients (23%) developed PTDM. The data of 47 cases and 47 controls were analyzed. Age ≥40 years, body mass index ≥30, pretransplant triglyceride levels >150 mg/dL, and presence of graft rejection were significant risk factors for developing PTDM. Smoking was associated with increased risk of PTDM but failed to achieve statistical significance. Compared with controls, PTDM patients had higher risk of cardiovascular disease, infections, and graft rejection.

Conclusion

Our results show that PTDM is a significant problem after kidney transplantation, and those who have high risk should be closely monitored after transplant and aggressively treated if they develop diabetes to minimize the risk of complications.     

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.     

Outcomes of Prolonged Treatment With Intravenous Immunoglobulin Infusions for Acute Antibody-mediated Rejection in Kidney Transplant Recipients

Background

Treatment of antibody-mediated rejection (AMR) is one of the main problems after kidney transplantation (KTx). The results of intensive AMR treatment with plasmapheresis (PF) and repeated infusions of intravenous immunoglobulin (IVIg) are presented.

Shared Molecular Eplet Stimulates Acute Antibody-Mediated Rejection in a Kidney Transplant Recipient With Low-Level Donor-Specific Antibodies: A Case Report

HLA antibodies usually recognize epitopes rather than antigens. This case report reveals that acute antibody-mediated rejection (AMR) that occurred in a kidney transplant recipient with low-level donor-specific antibodies (DSAs) could be explained by shared epitope. A 39-year-old woman received a first kidney transplant from a deceased donor (HLA-DRB1*11:06, *12:02, DRB3*02:02, *03:01). She developed acute AMR confirmed by kidney biopsy on day 4 after transplantation. Antibody testing with pretransplant serum showed anti-DR11 DSA below cutoff level (mean fluorescence intensity [MFI], 702; cutoff >1,000). However, high-level DSAs were detected on day 5 after transplantation (anti-DR11 MFI, 8,531; anti-DR12 MFI, 3,146). We hypothesized that the sharp rise in DSA levels was a result of anamnestic response with donor-antigen sensitization that occurred during pregnancy. High-resolution HLA-DR typing of her husband showed HLA-DRB1*03:01, *15:02:01, DRB3*02:02, DRB5*01:02. No sharing between donor HLAs eliciting reactive antibodies and her husband's HLAs was detected. Nevertheless, we speculated that shared epitope, not antigen, was the cause of allosensitization. To identify the shared epitope recognized by patient's antibodies, we used HLAmatchmaker, a computer algorithm that considers small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes for analysis. The results showed that 149H, which was the eplet shared by HLA-DRB1*03:01 (from her husband) and DRB1*11:06, DRB1*12:02, DRB3*03:01 (from donor), was the most prevalent eplet on DRB1 reactive alleles in Luminex assay. In conclusion, pretransplant low-level DSAs can induce AMR early after transplantation as a result of shared epitopes with a previous immunizer.     

Positive Crossmatch Kidney Transplant Recipients Treated With Eculizumab: Outcomes Beyond 1 Year

This study examined outcomes beyond 1 year in eculizumab‐treated (EC) positive crossmatch kidney transplants (+XMKTx) compared to a historical control group. +XMKTx received desensitization with either plasma exchange (PE) alone (N = 48) or PE and EC (N = 30). EC, given for at least 1 month, was continued in the setting of persistently high DSA (B flow cytometric crossmatch [BFXM] >200) including: 4 weeks (n = 14); 9 weeks (n = 6), 6 months (n = 2), and 12 months (n = 8). All patients had at least 2 years follow‐up. The incidence of acute clinical ABMR was lower in the EC group than controls (6.7% vs. 43.8% p < 0.01). Death‐censored allograft survival was similar between groups. Chronic ABMR was the main cause of graft loss. On 1‐year protocol biopsies, no differences were noted between EC and controls including: cg score >0, 26.7% versus 31.9% (p = 0.62), ptc score ≥ 2, 60.0% versus 60.0% (p = 1.00), or C4d + , 33.8% versus 13.5% (p = 0.08). A persistently high BFXM in EC‐treated patients was associated with cg score >0 at 1 year, while EC appeared to protect against cg if the BFXM remained low. We conclude that despite decreasing acute clinical ABMR rates, EC treatment does not prevent chronic ABMR in recipients with persistently high BFXM after +XMKTx.     

Factors Associated With the Development of Sarcopenia in Kidney Transplant Recipients

Introduction

Sarcopenia is characterized by an involuntary loss of skeletal muscle mass, strength, and function. Previous studies suggest that it is generally associated with aging and chronic kidney diseases. The focus of this study was on the association between sarcopenia and pre-sarcopenia in kidney transplant recipients.

Clinicopathologic Features and Treatment Response of Early Acute Antibody-Mediated Rejection in Thai Kidney Transplant Recipients: A Single-Center Experience

Background

Acute antibody-mediated rejection (AMR) is a major cause of early kidney allograft dysfunction. This study was conducted to examine the clinicopathologic features and long-term outcomes of early AMR in our center.

Methods

We retrospectively reviewed all patients who underwent kidney transplantation between January 2005 and December 2012. Patients who had histopathologic features of AMR within 3 months after transplantation were enrolled.

Results

Of 444 patients, early acute AMR was diagnosed in 25 patients (5.36%). Seventeen patients (68%) were highly sensitized. Histological analysis revealed acute vascular rejection and thrombotic microangiopathy in 21 (84%) and 6 (24%) patients, respectively. Staining of C4d in peritubular capillaries was detected in 6/20 patients (12%). All patients received plasma exchange (PE) 1.5 blood volume for 1–5 sessions followed by intravenous immunoglobulin (IVIG) 2 g/kg. Sixteen patients (64%) received 1–2 doses of rituximab 375 mg/m². We repeated treatment with PE and IVIG in refractory cases. Allografts could be rescued in 20 patients (80%) whereas 5 patients (20%) lost their grafts. Kaplan-Meier survival analysis revealed lower cumulative graft survival in the early AMR group compared with patients without early AMR (1 year survival rate of 80% vs 96% and 3 survival of 64% vs 80%; P < .001). After median follow-up time of 25 months, 7/20 patients (33%) developed late AMR.

Conclusion

ABMR is a serious early complication after KT. Early detection and intensive treatment is mandatory for salvaging the graft. After surpassing from early AMR, long-term close monitoring is also necessary.