Predictors of graft failure after first detection of de novo donor-specific HLA antibodies in kidney transplant recipients.

BACKGROUND: De novo donor-specific antibodies (dnDSAs) may cause antibody-mediated rejection and graft dysfunction. Little is known about the clinical course after first detection of dnDSAs during screening in asymptomatic patients. We aimed to assess the value of estimated glomerular filtration rate (eGFR) and proteinuria to predict graft failure in patients with dnDSAs and their potential utility as surrogate endpoints. METHODS: All 400 kidney transplant recipients with dnDSAs at our centre (1 March 2000-31 May 2021) were included in this retrospective study. The dates of graft loss, rejection, doubling of creatinine, ≥30% eGFR decline, proteinuria ≥500 mg/g and ≥1000 mg/g were registered from the first dnDSA appearance. RESULTS: During 8.3 years of follow-up, graft failure occurred in 33.3% of patients. Baseline eGFR and proteinuria correlated with 5-year graft loss (area under the receiver operating characteristics curve 0.75 and 0.80, P < .001). Creatinine doubled after a median of 2.8 years [interquartile range (IQR) 1.5-5.0] from dnDSA and the time from doubling creatinine to graft failure was 1.0 year (IQR 0.4-2.9). Analysing eGFR reduction ≥30% as a surrogate endpoint (148/400), the time from dnDSA to this event was 2.0 years (IQR 0.6-4.2), with a positive predictive value (PPV) of 45.9% to predict graft loss, which occurred after 2.0 years (IQR 0.8-3.2). The median time from proteinuria ≥500 mg/g and ≥1000 mg/g to graft failure was identical, 1.8 years, with a PPV of 43.8% and 49.0%, respectively. Composite endpoints did not improve PPV. Multivariable analysis showed that rejection was the most important independent risk factor for all renal endpoints and graft loss. CONCLUSIONS: Renal function, proteinuria and rejection are strongly associated with graft failure in patients with dnDSA and may serve as surrogate endpoints.

A single centre in-depth analysis of death with a functioning kidney graft and reasons for overall graft failure.

BACKGROUND: High numbers of unknown classifications and inconsistent methodologies in previous studies make the interpretation of causes leading to graft loss difficult. In addition, data on a holistic view looking at both death with a functioning graft (DWFG) and death-censored graft failure (DCGF) are sparse. METHODS: In this single-centre study we included 1477 adult kidney transplants performed between 1997 and 2017, of which all 286 DWFGs until the end of observation were analysed and causes for death assigned. Additionally, the results were compared with the causes of 303 DCGFs of the same cohort to evaluate the impact of causes for overall graft loss. RESULTS: The most frequent causes for DWFG were cardiovascular disease (CVD) in 30.8%, malignancy in 28.3% and infections in 21%. Only 9.4% of reasons for DWFG were unknown. Sudden death occurred in 40% (35/88) of patients classified as DWFG due to CVD. Overall graft loss was related to the effect of immunosuppression in 36.2% [infection 20.9% (123/589), malignancy 15.3% (90/589)] and CVD in 22.4% (132/589). In 27.4% (161/589), graft failure was associated with underimmunosuppression (rejection). For infections (60 DWFG, 63 DCGF) and CVD (88 DWFG, 44 DCGF), a considerable overlap was observed between DWFG and DCGF. For patients >70 years of age at transplantation, medical events accounted for 78% of overall graft losses and only 6.5% were associated with rejection. CONCLUSIONS: DWFG and DCGF share more causes for graft loss than previously reported and sudden death plays an underestimated role in death with a functioning graft.

Exploring the Complexity of Death-Censored Kidney Allograft Failure.

BACKGROUND: Few studies have thoroughly investigated the causes of kidney graft loss (GL), despite its importance. METHODS: A novel approach assigns each persistent and relevant decline in renal function over the lifetime of a renal allograft to a standardized category, hypothesizing that singular or multiple events finally lead to GL. An adjudication committee of three physicians retrospectively evaluated indication biopsies, laboratory testing, and medical history of all 303 GLs among all 1642 recipients of transplants between January 1, 1997 and December 31, 2017 at a large university hospital to assign primary and/or secondary causes of GL. RESULTS: In 51.2% of the patients, more than one cause contributed to GL. The most frequent primary or secondary causes leading to graft failure were intercurrent medical events in 36.3% of graft failures followed by T cell-mediated rejection (TCMR) in 34% and antibody-mediated rejection (ABMR) in 30.7%. In 77.9%, a primary cause could be attributed to GL, of which ABMR was most frequent (21.5%). Many causes for GL were identified, and predominant causes for GL varied over time. CONCLUSIONS: GL is often multifactorial and more complex than previously thought.

The relationship between proteinuria and allograft survival in patients with transplant glomerulopathy: a retrospective single-center cohort study.

Proteinuria and transplant glomerulopathy (TG) are common in kidney transplantation. To date, there is limited knowledge regarding proteinuria in different types of TG and its relationship to allograft survival. A retrospective cohort analysis of TG patients from indication biopsies was performed to investigate the relationship of proteinuria, histology, and graft survival. One hundred and seven (57.5%) out of 186 TG patients lost their grafts with a median survival of 14 [95% confidence interval (CI) 10-22] months after diagnosis. Proteinuria ≥1 g/24 h at the time of biopsy was detected in 87 patients (46.8%) and the median of proteinuria was 0.89 (range 0.05-6.90) g/24 h. TG patients with proteinuria ≥1 g/24 h had worse 5-year graft survival (29.9% vs. 53.5%, P = 0.001) compared with proteinuria <1 g/24 h. Proteinuria was associated with graft loss in univariable Cox regression [hazard ratio (HR) 1.25, 95% CI, 1.11-1.41, P < 0.001], and in multivariable analysis (adjusted HR 1.26, 95% CI 1.11-1.42, P < 0.001) independent of other risk factors including creatinine at biopsy, positive C4d, history of rejection, and Banff lesion score mesangial matrix expansion. In this cohort of TG patients, proteinuria at indication biopsy is common and associated with a higher proportion of graft loss.

Predictors of graft survival at diagnosis of antibody-mediated renal allograft rejection: a retrospective single-center cohort study.

Antibody-mediated rejection (ABMR) is a major cause of graft loss in renal transplantation. We assessed the predictive value of clinical, pathological, and immunological parameters at diagnosis for graft survival. We investigated 54 consecutive patients with biopsy-proven ABMR. Patients were treated according to our current standard regimen followed by triple maintenance immunosuppression. Patient characteristics, renal function, and HLA antibody status at diagnosis, baseline biopsy results, and immunosuppressive treatment were recorded. The risk of graft loss at 24 months after diagnosis and the eGFR slope were assessed. Multivariate analysis showed that eGFR at diagnosis and chronic glomerulopathy independently predict graft loss (HR 0.94; P = 0.018 and HR 1.57; P = 0.045) and eGFR slope (beta 0.46; P < 0.001 and beta -5.47; P < 0.001). Cyclophosphamide treatment (6× 15 mg/m2 ) plus high-dose intravenous immunoglobulins (IVIG) (1.5 g/kg) was superior compared with single-dose rituximab (1× 500 mg) plus low-dose IVIG (30 g) (HR 0.10; P = 0.008 and beta 10.70; P = 0.017) and one cycle of bortezomib (4× 1.3 mg/m2 ) plus low-dose IVIG (HR 0.16; P = 0.049 and beta 11.21; P = 0.010) regarding the risk of graft loss and the eGFR slope. In conclusion, renal function at diagnosis and histopathological signs of chronic ABMR seem to predict graft survival independent of the applied treatment regimen. Stepwise modifications of the treatment regimen may help to improve outcome.

Microvascular inflammation is a risk factor in kidney transplant recipients with very late conversion from calcineurin inhibitor-based regimens to belatacept.

BACKGROUND: In de novo kidney transplant recipients (KTR) treatment with belatacept has been established as a comparable option as maintenance immunosuppression, preferably as a strategy to convert from calcineurin inhibitor (CNI)- to belatacept-based immunosuppression. Switch to belatacept demonstrated improved renal function in patients with CNI-induced nephrotoxicity, but risk of transplant rejection and the development of donor-specific antibodies (DSA) are still a matter of debate. Only few data are available in patients at increased immunological risk and late after transplantation. METHODS: We analyzed 30 long-term KTR (including 2 combined pancreas-KTR) converted from CNI to belatacept > 60 months after transplantation with moderate to severe graft dysfunction (GFR ≤ 45 mL/min). Biopsies were classified according to the Banff 2015 criteria. Group differences were assessed in a univariate analysis using Mann Whitney U or Chi square test, respectively. Multivariate analysis of risk factors for treatment failure was performed using a binary logistic regression model including significant predictors from univariate analysis. Fifty-six KTR matched for donor and recipient characteristics were used as a control cohort remaining under CNI-treatment. RESULTS: Patient survival in belatacept cohort at 12/24 months was 96.7%/90%, overall graft survival was 76.7 and 60.0%, while graft survival censored for death was 79.3%/66.7%. In patients with functioning grafts, median GFR improved from 22.5 mL/min to 24.5 mL/min at 24 months. Positivity for DSA at conversion was 46.7%. From univariate analysis of risk factors for graft loss, GFR < 25 mL/min (p = 0.042) and Banff microvascular inflammation (MVI) sum score ≥ 2 (p = 0.023) at conversion were significant at 24 months. In the analysis of risk factors for treatment failure, a MVI sum score ≥ 2 was significant univariately (p = 0.023) and in a bivariate (p = 0.037) logistic regression at 12 months. DSA-positivity was neither associated with graft loss nor treatment failure. The control cohort had comparable graft survival outcomes at 24 months, albeit without increase of mean GFR in patients with functioning grafts (ΔGFR of - 3.6 ± 8.5 mL/min). CONCLUSION: Rescue therapy with conversion to belatacept is feasible in patients with worsening renal function, even many years after transplantation. The benefit in patients with MVI and severe GFR impairment remains to be investigated.

Bioavailability and costs of once-daily and twice-daily tacrolimus formulations in de novo kidney transplantation.

The use of once-daily tacrolimus in de novo kidney transplantation is increasingly common. Therefore, we were interested in bioavailability aspects of novel once-daily tacrolimus (LCPT, Envarsus) and once-daily tacrolimus extended-release formulation (ER-Tac, Advagraf) compared with twice-daily immediate-release tacrolimus (IR-Tac, Prograf). Furthermore, we calculated the costs. Kidney allograft recipients on tacrolimus-based immunosuppression within 2 clinical trials were included in a single-center analysis. The tacrolimus formulations were compared with respect to daily doses, doses per body weight, trough levels, and concentration-dose (C/D) ratio over 12 months. Intrapatient variability in trough levels and C/D ratios after 3 months was calculated. For the calculation of tacrolimus costs, German list prices were used. Eighty patients (21 with LCPT, 23 with IR-Tac, and 36 with ER-Tac) were analyzed. Pharmacokinetic comparisons revealed significantly higher bioavailability of LCPT at all visits. The variability of trough levels and C/D ratios in general was high and highest in LCPT patients. Different dose requirements translated into different costs. Median treatment costs during the first year were 7.825€ (IQR 6.195-8.892€) for LCPT, 9.813€ (IQR 7.630-16.832€) for IR-Tac, and 9.838€ (IQR 7.503- 13.541€) for ER-Tac (Kruskal-Wallis test, P = .003). The 3 tacrolimus formulations exhibit different dose requirements, exposure, and costs in favor of LCPT.

The regulation of interferon type I pathway-related genes RSAD2 and ETV7 specifically indicates antibody-mediated rejection after kidney transplantation.

CONTEXT: Antibody-mediated rejection (ABMR) after kidney transplantation (KTx) remains the crucial obstacle to successful long-term graft function. The identification of gene signatures involved in ABMR could grant the basis for better prevention and treatment strategies. OBJECTIVE: The identification of gene signatures in whole blood cells specific for ABMR after KTx. MATERIALS AND METHODS: Total RNA from blood cells of 16 kidney-transplanted patients with ABMR, stable graft function (SGF), and with T-cell-mediated rejection (TCMR) was isolated. Gene expression was determined by high-throughput sequencing followed by validation and analyses of differentially expressed candidates on mRNA level and on protein level in a large patient cohort (n = 185) in patients with SGF, urinary tract infection (UTI), borderline rejection (BL), TCMR, ABMR, and interstitial fibrosis and tubular atrophy. RESULTS: From the 570 genes detected, 111 discriminated ABMR from SGF and TCMR. A distinct enrichment of interferon (IFN) type I and type II signature gene set was observed. The expression of candidate genes IFIT1, ETV7, and RSAD2 distinguished ABMR patients from patients with SGF and also TCMR, whereas ETV7 and RSAD2 differentiated ABMR also from BL. CONCLUSION: The IFN-inducible genes ETV7 and RSAD2 represent specific biomarkers for ABMR episodes after KTx.

Outcome of membranoproliferative glomerulonephritis and C3-glomerulopathy in children and adolescents.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is a rare cause of glomerulopathy in children. Recently, a new classification based on immunohistological features has been established. Infections and anomalies in complement-regulating genes, leading to alternative complement pathway activation, are suspected to trigger the disease. Nevertheless, little is known about optimal treatment and outcome in children with immune-complex-MPGN (IC-MPGN) and C3-glomerulopathy (C3G). METHODS: The method used is retrospective analysis of clinical, histological, and genetic characteristics of 14 pediatric patients with MPGN in two medical centers. RESULTS: Mean age of the patients was 10.6 ± 4.5 years. Patients were grouped into C3G (n = 6) and IC-MPGN (n = 8). One patient showed a likely pathogenic variant in the CFHR5 gene. All 10 patients had risk polymorphisms in complement-regulating genes. Most patients were treated with ACE inhibition, steroids, and mycophenolate mofetil. Three patients with C3G received eculizumab. Median follow-up was 2.3 years. After 1 year of disease, three patients (two C3G, one IC-MPGN) reached complete, five patients partial (three IC-MPGN, two C3G), and five patients no remission (four IC-MPGN, one C3G). One patient progressed to end-stage renal disease (ESRD) 6 years after disease onset. CONCLUSIONS: IC-MPGN and C3G are rare disorders in children. Most patients have signs of complement activation associated with risk polymorphisms or likely pathogenic variants in complement-regulating genes. Steroids and mycophenolate mofetil seem to be effective and for some patients, eculizumab might be a treatment option. Outcome is heterogeneous and precise differentiation between IC-MPGN and C3G is still pending.

The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts that develop de novo thrombotic microangiopathy.

BACKGROUND: Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. METHODS: Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. RESULTS: The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. CONCLUSION: The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses.

Neuroprotection against permanent focal cerebral ischemia by ginkgolides A and B is associated with obstruction of the mitochondrial apoptotic pathway via inhibition of c-Jun N-terminal kinase in rats.

We have previously reported that ginkgolides containing ginkgolides A and B (GKAB) reduce infarct size in a rat model of focal ischemia. c-Jun N-terminal kinase (JNK), also known as stress-activated kinase (SAPK), is a critical stress-responsive kinase activated by various brain insults. Previous studies have demonstrated a brief increase in p-SAPK/JNK levels after focal ischemic brain injuries. In this study, we sought to investigate whether the neuroprotective effects of GKAB in rat models of permanent focal cerebral ischemia are associated with the JNK signaling pathway. Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion by intraluminal suture blockade. GKAB was injected intravenously immediately after ischemia onset. Here we demonstrate in rats that GKAB reduces neuronal apoptosis and blocks the increase of p-SAPK/JNK levels and nuclear translocation after cerebral ischemia in a dose-dependent manner. Furthermore, we report that cerebral ischemia increases ischemia-induced induction of reactive oxygen species, and this effect was blocked by GKAB. In addition, we show that BimL is induced and attenuated by GKAB. GKAB also repressed the ischemia-induced increase in the expression of Bax and reversed the decline in expression of Bcl-2. Likewise, there was a reduction in the release or activation of several mitochondrial proapoptotic molecules, including cytochrome c, caspases 3 and 9, and PARP. Taken together, our findings strongly suggest that GKAB-mediated neuroprotective effects against focal ischemia act through the inhibition of p-SAPK/JNK activation, in which the obstruction of the mitochondrial apoptotic pathway via the JNK signaling pathway is a key downstream mechanism of GKAB.

Pregnancy after Kidney Transplantation-Impact of Functional Renal Reserve, Slope of eGFR before Pregnancy, and Intensity of Immunosuppression on Kidney Function and Maternal Health.

Women of childbearing age show increased fertility after kidney transplantation. Of concern, preeclampsia, preterm delivery, and allograft dysfunction contribute to maternal and perinatal morbidity and mortality. We performed a retrospective single-center study, including 40 women with post-transplant pregnancies after single or combined pancreas-kidney transplantation between 2003 and 2019. Outcomes of kidney function up to 24 months after the end of pregnancy were compared with a matched-pair cohort of 40 transplanted patients without pregnancies. With a maternal survival rate of 100%, 39 out of 46 pregnancies ended up with a live-born baby. The eGFR slopes to the end of 24 months follow-up showed mean eGFR declines in both groups (-5.4 ± 14.3 mL/min in pregnant versus -7.6 ± 14.1 mL/min in controls). We identified 18 women with adverse pregnancy events, defined as preeclampsia with severe end-organ dysfunction. An impaired hyperfiltration during pregnancy was a significant risk contributor for both adverse pregnancy events (p < 0.05) and deterioration of kidney function (p < 0.01). In addition, a declining renal allograft function in the year before pregnancy was a negative predictor of worsening allograft function after 24 months of follow-up. No increased frequency of de novo donor-specific antibodies after delivery could be detected. Overall, pregnancies in women after kidney transplantation showed good allograft and maternal outcomes.

Poor Outcomes in Patients With Transplant Glomerulopathy Independent of Banff Categorization or Therapeutic Interventions.

Background: Transplant glomerulopathy (TG) may indicate different disease entities including chronic AMR (antibody-mediated rejection). However, AMR criteria have been frequently changed, and long-term outcomes of allografts with AMR and TG according to Banff 2017 have rarely been investigated. Methods: 282 kidney allograft recipients with biopsy-proven TG were retrospectively investigated and diagnosed according to Banff'17 criteria: chronic AMR (cAMR, n = 72), chronic active AMR (cAAMR, n = 76) and isolated TG (iTG, n = 134). Of which 25/72 (34.7%) patients of cAMR group and 46/76 (60.5%) of cAAMR group were treated with antihumoral therapy (AHT). Results: Up to 5 years after indication biopsy, no statistically significant differences were detected among iTG, cAMR and cAAMR groups in annual eGFR decline (-3.0 vs. -2.0 vs. -2.8 ml/min/1.73 m2 per year), 5-year median eGFR (21.5 vs. 16.0 vs. 20.0 ml/min/1.73 m2), 5-year graft survival rates (34.1 vs. 40.6 vs. 31.8%) as well as urinary protein excretion during follow-up. In addition, cAMR and cAAMR patients treated with AHT had similar graft and patient survival rates in comparison with those free of AHT, and similar comparing with iTG group. The TG scores were not associated with 5-year postbiopsy graft failure; whereas the patients with higher scores of chronic allograft scarring (by mm-, ci- and ct-lesions) had significantly lower graft survival rates than those with mild scores. The logistic-regression analysis demonstrated that Banff mm-, ah-, t-, ci-, ct-lesions and the eGFR level at biopsy were associated with 5-year graft failure. Conclusions: The occurrence of TG is closely associated with graft failure independent of disease categories and TG score, and the long-term clinical outcomes were not influenced by AHT. The Banff lesions indicating progressive scarring might be better suited to predict an unfavorable outcome.

Role of TRPC6 in kidney damage after acute ischemic kidney injury.

Transient receptor potential channel subfamily C, member 6 (TRPC6), a non-selective cation channel that controls influx of Ca2+ and other monovalent cations into cells, is widely expressed in the kidney. TRPC6 gene variations have been linked to chronic kidney disease but its role in acute kidney injury (AKI) is unknown. Here we aimed to investigate the putative role of TRPC6 channels in AKI. We used Trpc6-/- mice and pharmacological blockade (SH045 and BI-749327), to evaluate short-term AKI outcomes. Here, we demonstrate that neither Trpc6 deficiency nor pharmacological inhibition of TRPC6 influences the short-term outcomes of AKI. Serum markers, renal expression of epithelial damage markers, tubular injury, and renal inflammatory response assessed by the histological analysis were similar in wild-type mice compared to Trpc6-/- mice as well as in vehicle-treated versus SH045- or BI-749327-treated mice. In addition, we also found no effect of TRPC6 modulation on renal arterial myogenic tone by using blockers to perfuse isolated kidneys. Therefore, we conclude that TRPC6 does not play a role in the acute phase of AKI. Our results may have clinical implications for safety and health of humans with TRPC6 gene variations, with respect to mutated TRPC6 channels in the response of the kidney to acute ischemic stimuli.

The natural history of de novo donor-specific HLA antibodies after kidney transplantation.

Background: De novo donor-specific HLA antibodies (dnDSA) are key factors in the diagnosis of antibody-mediated rejection (ABMR) and related to graft loss. Methods: This retrospective study was designed to evaluate the natural course of dnDSA in graft function and kidney allograft survival and to assess the impact of mean fluorescence intensity (MFI) evolution as detected by annual Luminex® screening. All 400 kidney transplant recipients with 731 dnDSA against the last graft (01/03/2000-31/05/2021) were included. Results: During 8.3 years of follow-up, ABMR occurred in 24.8% and graft loss in 33.3% of the cases, especially in patients with class I and II dnDSA, and those with multiple dnDSA. We observed frequent changes in MFI with 5-year allograft survivals post-dnDSA of 74.0% in patients with MFI reduction ≥ 50%, 62.4% with fluctuating MFI (MFI reduction ≥ 50% and doubling), and 52.7% with doubling MFI (log-rank p < 0.001). Interestingly, dnDSA in 168 (24.3%) cases became negative at some point during follow-up, and 38/400 (9.5%) patients became stable negative, which was associated with better graft survival. Multivariable analysis revealed the importance of MFI evolution and rejection, while class and number of dnDSA were not contributors in this model. Conclusion: In summary, we provide an in-depth analysis of the natural course of dnDSA after kidney transplantation, first evidence for the impact of MFI evolution on graft outcomes, and describe a relevant number of patients with a stable disappearance of dnDSA, related to better allograft survival.

Clinicopathologic Features and Risk Factors of Proteinuria in Transplant Glomerulopathy.

Background: Transplant glomerulopathy (TG) is one of the main causes of post-transplant proteinuria (PU). The features and possible risk factors for proteinuria in TG patients are uncertain. Methods: We investigated all patients who had biopsy-proven TG from 2000 to 2018 in our center. The clinical and histological data were compared between two groups with or without PU (cut-off = 0.3 g/day). Spearman correlation analysis was used to evaluate the relationship between PU and pathological changes. The risk factors for PU in TG patients were determined by multivariable logistic regression analysis. Results: One hundred and twenty-five (75.76%) of all enrolled 165 TG patients had proteinuria ≥0.3 g/day at the time of biopsy. TG patients' PU level was significantly correlated with Banff lesion score cg (ρ = 0.247, P = 0.003), and mm (ρ = 0.257, P = 0.012). Systolic blood pressure ≥140 mmHg (OR 2.72, 95% CI 1.04-7.10, P = 0.041), diastolic blood pressure ≥90 mmHg (OR 4.84, 95% CI 1.39-16.82, P = 0.013), peak PRA ≥5% (OR 6.47, 95% CI 1.67-25.01, P = 0.007), positive C4d staining (OR 4.55, 95% CI 1.29-16.11, 0.019), tacrolimus-based regimen (OR 3.5, 95% CI 1.28-9.54, P = 0.014), and calcium channel blocker usage (OR 4.38, 95% CI 1.59-12.09, P = 0.004) were independent risk factors for PU. Conclusions: Proteinuria is common in TG patients. systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, peak PRA ≥5%, positive C4d staining, tacrolimus-based regimen, and calcium channel blocker usage are associated with proteinuria in TG patients.

Poor Long-Term Renal Allograft Survival in Patients with Chronic Antibody-Mediated Rejection, Irrespective of Treatment-A Single Center Retrospective Study.

The Banff 2017 report permits the diagnosis of pure chronic antibody-mediated rejection (cAMR) in absence of microcirculation inflammation. We retrospectively investigated renal allograft function and long-term outcomes of 67 patients with cAMR, and compared patients who received antihumoral therapy (cAMR-AHT, n = 21) with patients without treatment (cAMRwo, n = 46). At baseline, the cAMR-AHT group had more concomitant T-cell-mediated rejection (9/46 (19.2%) vs. 10/21 (47.6%); p = 0.04), a higher g-lesion score (0.4 ± 0.5 versus 0.1 ± 0.3; p = 0.01) and a higher median eGFR decline in the six months prior to biopsy (6.6 vs. 3.0 mL/min; p = 0.04). The median eGFR decline six months after biopsy was comparable (2.6 vs. 4.9 mL/min, p = 0.61) between both groups, and three-year graft survival after biopsy was statistically lower in the cAMR-AHT group (35.0% vs. 61.0%, p = 0.03). Patients who received AHT had more infections (0.38 vs. 0.20 infections/patient; p = 0.04). Currently, antihumoral therapy is more often administered to patients with cAMR and rapidly deteriorating renal function or concomitant TCMR. However, long-term graft outcomes remain poor, despite treatment.

Inosine 5'-Monophosphate Dehydrogenase Activity for the Longitudinal Monitoring of Mycophenolic Acid Treatment in Kidney Allograft Recipients.

BACKGROUND: Mycophenolic acid (MPA) is a standard immunosuppressant in organ transplantation. A simple monitoring biomarker for MPA treatment has not been established so far. Here, we describe inosine 5'-monophosphate dehydrogenase (IMPDH) monitoring in erythrocytes and its application to kidney allograft recipients. METHODS: IMPDH activity measurements were performed using a high-performance liquid chromatography assay. Based on 4203 IMPDH measurements from 1021 patients, we retrospectively explored the dynamics early after treatment start. In addition, we analyzed the influence of clinically relevant variables on IMPDH activity in a multivariate model using data from 711 stable patients. Associations between IMPDH activity and clinical events were evaluated in hospitalized patients. RESULTS: We found that IMPDH activity reflects MPA exposure after 8 weeks of constant dosing. In addition to dosage, body mass index, renal function, and coimmunosuppression affected IMPDH activity. Significantly lower IMPDH activities were found in patients with biopsy-proven acute rejection as compared to patients without rejection (median [interquartile range]: 696 [358-1484] versus 1265 [867-1618] pmol xanthosine-5'-monophosphate/h/mg hemoglobin, P < 0.001). The highest IMPDH activities were observed in hospitalized patients with clinically evident MPA toxicity as compared to patients with hospitalization not related to MPA treatment (1548 [1021-2270] versus 1072 [707-1439] pmol xanthosine-5'-monophosphate/h/mg hemoglobin; P < 0.001). Receiver operating characteristic curve analyses underlined the usefulness of IMPDH to predict rejection episodes (area, 0.662; confidence interval, 0.584-0.740; P < 0.001) and MPA-associated adverse events (area, 0.632; confidence interval, 0.581-0.683; P < 0.001), respectively. CONCLUSIONS: IMPDH measurement in erythrocytes is a novel and useful strategy for the longitudinal monitoring of MPA treatment.

IL-2 Therapy Diminishes Renal Inflammation and the Activity of Kidney-Infiltrating CD4+ T Cells in Murine Lupus Nephritis.

An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN.