Calcineurin Inhibitor Toxicity Research Articles

Switching renal transplant recipients to belatacept therapy: results of a real-life gradual conversion protocol

Conversion to belatacept immunosuppression is a therapeutic option for renal-transplant recipients with calcineurin inhibitors (CNI) toxicity, but it associates with high risk of acute rejection. Gradual conversion and serial immune monitoring with urinary chemokine CXCL9 may allow increasing safety of this maneuver.We converted kidney transplant recipients with signs of toxicity to CNI or other immunosuppressive drugs to belatacept over a 2-month period. We monitored renal function, metabolic profile, and circulating lymphocyte subsets. We also quantified urinary CXCL9 over a 12-month follow-up period.Between September 2016 and March 2017, 35 patients were successfully switched to belatacept immunosuppression at 3.3 (1.3–7.2) years after transplant. Two patients had a reversible rise in serum creatinine, associated with acute rejection in one case. Urinary CXCL9 increased before serum creatinine. After conversion, blood pressure and HbA1c significantly declined while eGFR and proteinuria remained stable. The percentage of circulating effector T cells and memory B cells significantly declined.Conversion from CNI to belatacept, in this setting, was feasible and safe, provided it was performed over a 2-month time-period. Monitoring urinary CXCL9 may further increase safety through earlier identification of patients at risk for acute rejection. The procedure associates with improved blood pressure, metabolic profile, and reduced circulating effector T and B cells.

Clinical Significance of Renal Allograft Protocol Biopsies: A Single Tertiary Center Experience in Malaysia.

Background The role of protocol renal allograft biopsy in kidney transplantation is controversial due to the concern with procedural-related complications; however, its role is slowly evolving. Recent evidence suggests that protocol biopsy is useful in detecting subclinical renal pathology. Early recognition and treatment of renal pathologies can improve long-term outcomes of renal allografts. Methodology A total of 362 renal allograft protocol biopsies were performed in adult recipients of kidney transplantation between 2012 and 2017. After excluding those with poor quality or those performed with a baseline serum creatinine level >200 umol/L, we analyzed 334 (92.3%) biopsies. Histology reports were reviewed and categorized into histoimmunological and nonimmunological changes. The immunological changes were subcategorized into the following: (1) no acute rejection (NR), (2) borderline changes (BC), and (3) subclinical rejection (SCR). Nonimmunological changes were subcategorized into the following: (1) chronicity including interstitial fibrosis/tubular atrophy (IFTA), chronic T-cell-mediated rejection (TCMR), unspecified chronic lesions, and arterionephrosclerosis, (2) de novo glomerulopathy/recurrence of primary disease (RP), and (3) other clinically unsuspected lesions (acute pyelonephritis, calcineurin inhibitors toxicity, postinfective glomerulonephritis, and BK virus nephropathy). Risk factors associated with SCR were assessed. Results For the histoimmunological changes, 161 (48.2%) showed NR, 145 (43.4%) were BC, and 28 (8.4%) were SCR. These clinical events were more pronounced for the first 5 years; our data showed BC accounted for 59 (36.4%), 64 (54.2%), and 22 (40.7%) biopsies within <1 year, 1-5 years, and > 5 years, respectively (p = 0.011). Meanwhile, the incidence for SCR was 6 (3.7%) biopsies in <1 year, 18 (15.3%) in 1-5 years, and 4 (7.4%) in >5 years after transplantation (p=0.003). For the nonimmunological changes, chronicity, de novo glomerulopathy/RP, and other clinically unsuspected lesions were seen in 40 (12%), 10 (3%), and 12 (3.6%) biopsies, respectively. Living-related donor recipients were associated with decreased SCR (p=0.007). Conclusions Despite having a stable renal function, our transplant recipients had a significant number of subclinical rejection on renal allograft biopsies.

Impact of calcineurin inhibitors on rat glioma cells viability

BackgroundAlthough kidney transplantation outcomes have improved dramatically after using calcineurin inhibitors (CNIs), CNI toxicity continues to be reported and the mechanism remains uncertain. Here, we investigated the neurotoxicity of CNIs by focusing on the viability of glioma cells.MethodsGlioma cells were treated with several concentrations of CNIs for 24 hours at 37℃ and their cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ResultsExposure to 0, 0.25, 0.5, 2.5, 5.0, and 10.0 mM concentrations respectively showed 100%, 64.3%, 61.3%, 68.1%, 62.4%, and 68.6% cell viability for cyclosporine and 100%, 38.6%, 40.8%, 43.7%, 37.8%, and 43.0% for tacrolimus. The direct toxic effect of tacrolimus on glioma cell viability was stronger than that of cyclosporine at the same concentration.ConclusionCNIs can cause neurological side effects by directly exerting cytotoxic effects on brain cells. Therefore, we should carefully monitor the neurologic symptoms and level of CNIs in kidney transplant patients.

Using functional magnetic resonance imaging to evaluate an acute allograft rejection model in rats

PurposeTo assess the longitudinal changes of allograft pathophysiology by intravoxel incoherent motion (IVIM) and blood oxygen level-dependent (BOLD) MRI in a rat model of acute renal allograft rejection. Materials and methodsAcute rejection (AR) was induced by transplantation of Dark Agouti donor kidneys into Lewis recipients (n = 18). A Lewis-Lewis rat syngeneically transplanted (sTX) model served as the control (n = 6). Acute tubular necrosis (n = 6) and acute calcineurin inhibitor toxicity (n = 6) groups were established using Lewis rats. MRI was performed on postoperative day (POD) 1, 4 and 7 in the allogeneically transplanted (aTX) group and on POD4 in the other groups. Histological evaluation and PCR were performed. ResultsAfter the allogenic transplantation, all MRI parameters of allograft further decreased until POD7, and the D and ADC values in the cortex were significantly lower than that in the sTX group (1.03 ± 0.09 vs 1.52 ± 0.09 × 10−3 mm2/s, Padj < 0.05; 1.21 ± 0.03 vs 1.78 ± 0.07 × 10−3 mm2/s, Padj < 0.05). The D*, f and R2* values of the aTX group in the cortex and medulla were significantly lower than those in the sTX group on POD7 (cortex, D*: 25.60 ± 4.78 vs 69.32 ± 9.79 × 10−3 mm2/s, Padj < 0.05; f: 7.84 ± 1.83 vs 20.34 ± 3.08%, Padj < 0.05; R2*: 16.61 ± 4.18 vs 31.48 ± 6.43 1/s, Padj < 0.05; medulla, D*: 13.59 ± 6.08 vs 62.75 ± 9.20 × 10−3 mm2/s, Padj < 0.05; f: 7.46 ± 1.62 vs 14.68 ± 2.05%, Padj < 0.05; R2*: 21.59 ± 3.45 vs 39.53 ± 4.34 1/s, Padj < 0.05). AR grafts presented serve interstitial inflammation, tubulitis and infiltration of T-lymphocytes and macrophages. The MRI parameters, including D, ADC, D*, f and R2*, were significantly correlated with the histological changes, cell infiltration and inflammatory cytokine mRNA levels. ConclusionsIVIM coupled with BOLD MRI allows longitudinal assessment of allograft diffusion, perfusion and oxygen consumption impairment caused by acute renal allograft rejection in rat model.

Serum uromodulin as a marker of kidney graft function*

Serum uromodulin (sURO) was recently found as a sensitive tubular marker in early chronic kidney disease stages. Thus far, mainly early uromodulin urinary excretion was tested in kidney recipients. The aim of our study was to conduct a long-lastinlong-term assessment of sURO in kidney graft function monitoring. Forty-one stable kidney recipients (aged 47 (13.7)) were studied around the 3&lt;sup&gt;rd&lt;/sup&gt; month (3m) and the 2&lt;sup&gt;nd&lt;/sup&gt; year (2y) after kidney transplantation. Sera were tested for sURO, creatinine and tacrolimus levels. Kidney biopsy was scored according to revised Banff 97 classification. sURO level (mean 66.06ng/ml at 3m; 77.81 at 2y) increased borderline significantly (P = 0.051) in time and significantly correlated with eGFR (3m RS = 0.46; 2y RS = 0.58), creatinine levels (RS respectively –0.55 and –0.56) and donor age (3m Rs = –0.33; 2y RS = –0.41). We observed borderline correlations between sURO and Banff biopsy scoring: 3m-sURO with arteriolar hyalinosis-ah (RS = –0.3, P = 0.06) and 2y-sURO with peritubular capillaritis-ptc (RS = 0.45, P = 0.07). Correlations of sURO with 3m tacrolimus levels (Rs = 0.3, P = 0.08) were borderline, however patients with CNI toxicity lesions in biopsy had sURO significantly lower (mean 3m-sURO 52.7 vs 83.1 ng/ml; 2y-sURO 61.9 vs 98.1 ng/ml). sURO can reflect kidney graft quality and function. sURO correlated with ptc, which is considered to be an early marker of a chronic antibody-mediated graft injury. Tacrolimus doesn’t influence sURO levels directly, but sURO is lower in patients with toxic kidney injury in biopsy.

Comparison of Transplant Outcomes for Low-level and Standard-level Tacrolimus at Different Time Points after Kidney Transplantation.

BackgroundOptimal tacrolimus (TAC) trough levels for different periods after kidney transplantation (KT) has not been definitely established. This study aimed to investigate transplant outcomes of low-level (LL) and standard-level (SL) TAC according to post-transplant period.MethodsA total of 278 consecutive kidney transplant recipients (KTRs) receiving TAC-based immunosuppression were divided into LL and SL-TAC groups (4–7 and 7–12 ng/mL for 0–2 months, 3–6 and 6–10 ng/mL for 3–6 months, 2–5 and 5–8 ng/mL for 7–12 months, respectively) according to TAC trough level at each period. We compared estimated glomerular filtration rate (eGFR), biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA), calcineurin inhibitor (CNI) toxicity, opportunistic infection, and allograft survival.ResultsSL-TAC group showed significantly higher mean eGFR at 0–2 months than LL-TAC group (72.1 ± 20.3 vs. 64.2 ± 22.7 mL/min/1.73m2; P = 0.003). Incidence of BPAR at 7–12 months was significantly lower in SL-TAC group than in LL-TAC group (0.0% vs. 3.9%; P = 0.039). Patients with persistent SL-TAC lasting 12 months showed higher eGFR at 7–12 months than those with persistent LL-TAC (65.5 ± 13.0 vs. 57.9 ± 13.9 mL/min/1.73m2; P = 0.007). No significant differences in dnDSA, CNI toxicity, serious infections, or allograft survival were observed.ConclusionsMaintenance of proper TAC trough level after 6 months could reduce BPAR without adverse drug toxicities in KTRs. Moreover, persistent SL-TAC during the first year after KT might have a beneficial effect on a trend for a lower incidence of dnDSA and better renal allograft function.

MTOR inhibitors in pediatric liver transplant recipients

During the past decade, mTOR inhibitors (mTORi), everolimus and sirolimus, have been increasingly used after adult liver transplantation (LT). The aim of the present study was to describe the use of mTORi in pediatric LT recipients. All pediatric LT recipients who received mTORi before December 2017 from 4 European pediatric LT centers were included and analyzed. The present retrospective study included 30 patients; 21 were male (70%), median age was 9.3 years (range: 1.2-17.1 years) at mTORi introduction. Main indications for mTORi introduction were pre-existing liver malignancy (43.3%), calcineurin inhibitor (CNI) nephrotoxicity (26.7%), or rejection (23.4%). At last follow-up, mTORi CNIs were withdrawn in 10 patients (10/29, 34.5%). The median dose of mTORi was 1.8 mg/day (range: 0.3-5.0) or 0.058 mg/kg/day (range: 0.01-0.26), and the median trough level was 5.1 μg/L (range: 1.0-15.5). After a median follow-up of 2.8 years (range: 0.2-10.0), 50.0% of the patients presented with at least one adverse event. The main adverse events included hyperlipidemia, proteinuria, dermatitis, and mucitis. Overall mTORi discontinuation rate was 23.3% (10.0% because of adverse event). Introduction of mTORi had no significant impact on renal function. Our results suggest that mTORi can be used in pediatric LT recipients in different clinical situations, both to reinforce immunosuppressive therapy, and to reduce CNI and related toxicity.

Early onset of graft glomerulopathy in a patient with post-transplant diabetes mellitus after renal transplantation: a case report

BackgroundPost-transplant diabetes mellitus (PTDM) is an emerging problem in kidney transplantation, representing an important risk factor for kidney function loss. Diabetic nephropathy (DN) occurrence in transplanted kidneys is poorly investigated. Current knowledge describes DN recurrence in graft 5.9 years from kidney transplantation however there is little data about PTDM and DN.Here, we report a clinical case peculiar for an early appearance of advanced glomerular diabetic lesions, after kidney transplantation.Case presentationA 45-year-old Caucasian male affected by autosomal polycystic kidney disease was transplanted with a cadaveric-kidney-donor from 58-year-old male. Induction immunosuppressive therapy included basiliximab and steroids while the maintenance treatment included, tacrolimus, mofetil micophenolate and methylprednisolone.One month after transplantation the patient developed diabetes requiring treatment with repaglinide quickly replaced with insulin to obtain an acceptable glycemic control (HbA1c 52 mmol/mol). Glycosuria was detected persistently during the first six months after transplantation. To achieve further improvement in glycemic control, a shift from tacrolimus to cyclosporine (CyA) was made and steroids were rapidly tapered and stopped. To minimize calcineurin inhibitors toxicity, which was revealed in the 1-year-protocol-biopsy, everolimus was introduced thereby lowering CyA through levels. Moderate hypertension was well controlled with doxazosin. Thirty months after transplantation a second graft biopsy was performed owing to renal function decline and microalbuminuria appearance. Histological analysis surprisingly showed mesangiolysis and microaneurysms; glomerular sclero-hyalinosis and basal membrane thickness and typical nodular glomerulosclerosis. C4d staining was negative and no evidence of immune deposits were detected. Donor Specific Antibodies, serum C3 and C4 levels and autoimmunity tests were negative. Retrospective analysis on donor history didn’t show diabetes or insulin resistance and no diabetic lesions were found in kidney pre-implant biopsy.ConclusionsIn our knowledge, this is the first report describing a very early onset of advanced diabetic glomerular lesions in a graft biopsy after PTDM. We hypothesize that additional factors such as everolimus and hypertension, may have contribute to kidney damage.

P026Timing is everything – Even for DP antibodies

Introduction Donor Specific Antibodies (DSA) can be a contraindication for kidney transplants. The clinical relevance of DSA to DP antigens and correlation with crossmatch (XM) remain unclear. We report the conversion of a negative XM to positive due to development of DSA to DP6, most likely caused by an unreported sensitizing event. Methods A 38 yo female received a deceased donor (DD) kidney transplant (Tx) after negative T/B cell flow XMs using sera drawn 35 and 44 days pre Tx (day −35 and −44). Delta channel shifts (DCS) in these XMs were: T = 0 for both sera; B = 37 and 31 for days −35 and −44. These sera were negative for DSA. We received a serum drawn at admission for Tx (day −1). The patient received blood transfusions within the previous week (day −6). The day-1 serum had high level DSA to DP6 (MFI = 13,723), compared to day −44 (1,321) and day-35 (1,653). By flow XM, the day −1 serum was T negative, B positive (DCS = 228), likely due to the increase in DSA to DP6. In addition to standard immunosuppression, this recipient also received thymoglobulin and basiliximab once the program was notified of high level DSA and positive flow XM. Post Tx monitoring showed an immediate decline in DSA to DP6: post Tx day 6 (MFI = 7,380), day 12 (5,669), day 21 (4,042), day 63 (485). The DSA to DP6 remained low (MFI 400) for five years. However, the recipient had BK viremia and a kidney biopsy five years post Tx showed “arteriolar hyalinosis and arteriosclerosis related to possible CNI toxicity”. The recipient is re-listed in UNET for another kidney Tx, the primary reason for graft failure deemed transplant glomerulopathy. Discussion This case emphasizes the importance of timely antibody testing in relation to XM testing, awareness of sensitizing events, and updated HLA typing. Our lab now employs stricter guidelines to ensure more frequent receipt of patient sera, especially following potential sensitizing events. At the time of this patient’s Tx, DP typing was not performed on DD. After discovering the increase in antibodies at pre Tx day −1, but absence of DSA, we performed DP typing. Finding DP6 as a DD antigen helped explain the change to positive XM, as the level of DSA to DP6 significantly increased following the sensitizing event pre-Tx. This early peri and post Tx antibody response may have contributed to reduced graft survival and transplant glomerulopathy.

Urinary miRNA as a Potential Biomarker in Kidney Transplantation

Introduction and Aims Kidney transplantation is the best available treatment for patients with end stage chronic kidney disease. The diagnosis of the pathology of the kidney graft relies on the determination of the creatinine, estimated glomerular filtration rate and proteinuria. These parameters are altered after the onset of renal injury and they are not able to discern between various pathologies. The kidney biopsy, an invasive and not extent of complications procedure, remains essential for the diagnosis of the renal pathology. Hence the importance of finding parameters that allow an early diagnosis of the pathology involved in graft dysfunction. Urine is ideal for the study of possible biomarkers, its collection is easy, non-invasive and repeatable. Our aim was to analyse the miRNA content of urinary extracellular vesicles of the transplanted patients and define differential patterns of expression of miRNA specific to the different pathologies of the transplanted kidney. Methods Kidney transplanted patients with a kidney biopsy performed for clinical indication were selected. The biopsies were assessed according to Banff classification. From all biopsies those exhibiting acute cellular rejection (ACR), interstitial fibrosis and tubular atrophy (IFTA) and calcineurin inhibitors toxicity (CIT) were selected. Kidney transplanted patients with normal function (defined as eGFR CKD-EPI >90ml/min/1,72m2) and without proteinuria were defined as control group. First morning void urine was collected from patients. After low speed centrifugation to eliminate cell debris, Urine EVs were obtained by Size exclusion chromatography after urine concentration. EV-contained fractions selected as CD63 and CD9 positive fractions were pooled. Then, total RNA was extracted using mirCURY kit and high-throughput sequencing was done. Taqman qPCR were performed using the Taqman Advance miRNA assays for the following miRNAs (hsa-miR-1; has-miR-2, hsa-miR-3; hsa-miR-4, hsa-miR-5, hsa-miR-6; hsa-miR-7; hsa-miR-8; hsa-miR-9, has-miR-10). hsa-miR-10a-5p was used as internal control and Total RNA kidney (Thermosfisher) was used as positive control. Ct values of triplicates were averaged and used for ΔCt calculations. Principal component analysis (PCA), Receiver Operating Characteristic (ROC) analysis and Mann-Whitney test were done using GraphPrims v5 and SPSS v15. P<0.05 were set as significant. Results A total of 8 control samples and 14 pathological samples (3 IFTA, 6 ACR and 5 CIT) were processed by next generation sequencing. A total of 1500 miRNAs were identified, then after normalization and principal component analysis 12 miRNAs were selected to be tested in a new cohort. A new control group(N=8) and patients (IFTA: n=9; ACR: n=9; CIT: n=6) were selected as mentioned before. Then, uEVs and total RNA were isolated as described above. We found that eight miRNAs had different expression patterns in the urine of patients with any kind of graft pathology compared to controls. Conclusion miRNA profiling in urine has potential as a novel method for detecting pathology in kidney transplant.

Validation of an Integrative and Dynamic Prognostic Score for Response to Therapy in Solid Organ Transplants

Introduction Drug development in transplantation has diminished due to the lack of suitable endpoints and the long time span between transplantation and graft failure. We sought to validate the performance of an integrative scoring system for predicting long-term kidney allograft loss in the setting of therapeutic interventions after transplantation. Materials and methods We used an integrative risk-scoring system that predicts the long-term allograft failure, previously derived and validated in an international cohort comprising 5,125 kidney transplant recipients (http//http://www.paristransplantgroup.org). The risk score is based on readily-accessible clinical, biochemical, immunological and histological parameters measured after transplant. We included patients from the Paris Transplant Group reference cohort who underwent therapeutic interventions following standardized protocols for antibody-mediated rejection (ABMR), T-cell mediated rejection (TCMR) and CNI toxicity and tested the performance of the risk score for predicting response to therapy in the 3 clinical scenarios. ABMR patients received standard of care treatment, plasma exchange, and anti-CD-20 rituximab. Patients with TCMR received 3 IV methylprednisolone pulses together with oral steroid tapering. The last group consisted of patients diagnosed with CNI toxicity by biopsy and converted to Belatacept (CTLA4-Ig). All patients underwent risk score measurement at treatment and 3 months after treatment. The outcome measure was the performance of the score to predict long-term allograft failure as compared with the actual events observed (kidney allograft loss). Results 484 patients were included: 224 receiving SOC ABMR treatment; 143 receiving SOC treatment for TCMR and 117 receiving Belatacept for CNI toxicity. The mean time follow-up post transplantation was 4.048 ± 3.07 years. The mean time between transplant and diagnosis was 385 ± 808 days. The prognostic risk score was significantly modified by the therapeutic interventions (mean risk score of 3.01 ± 0.79 at the time of treatment vs 2.71±0.82 after treatment, p<0.001; Figure 1A). 2 prototypes of patients were identified by the risk score: i) Group 1 showing decreasing predicted probability of graft loss after treatment (blue lines, responders, 68%); ii) Group 2 showing stable or increased predicted probability of graft loss after treatment (red lines, non-responders, 32%). The risk score prediction capability of individual patient long-term allograft loss was highly accurate (C-index 0·84; 95% bootstrap percentile CIs=0·80-0·89). The calibration plot showed an optimal agreement between the risk score prediction model after therapeutic intervention and the actual observation of kidney allograft loss at 3, 5 and 7 years after treatment (Figure 1B).Conclusion This integrative risk scoring system for long-term allograft loss showed high performance in the setting of therapeutic interventions after kidney transplant, correlated well with the true clinical outcome and captured the net effect of treatment on the clinical outcome. Our result suggests that this scoring system could be used as a valid surrogate endpoint for next-generation multicenter trials and in the approval of drugs in solid organ transplantation.

Early Outcomes of Living-Donor Kidney Transplantation With Immunosuppression Therapy Induction With Tacrolimus Extended-Release: A Comparison With Cyclosporine

BackgroundExtended-release tacrolimus (TacER), administered once daily, offers improved adherence with reduced side effects while still maintaining an immunosuppressive potency equivalent to that of conventional tacrolimus preparations. MethodsThe study included 83 patients who received consecutive living-donor kidney transplants at our facility from June 2013 to December 2016. Comparisons were made between 48 cases of induction with TacER and 35 cases of induction with cyclosporine (CyA). The observation period was 3 months after transplantation. Transplanted kidney function, rejection, infectious disease, lipid abnormalities, and glucose tolerance were compared. ResultsThe 2 groups showed no significant difference in donor background or transplanted kidney function. Within the 3-month observation period, an acute rejection response was observed in 2 cases in the TacER group and in 8 cases in the CyA group. After transplantation, hyperlipidemia requiring medication was observed more frequently in the CyA group. The 2 groups did not show a marked difference in systemic infection or renal calcineurin inhibitor toxicity in histopathologic examination of the transplanted kidneys 3 months after surgery. DiscussionProactive use of TacER leads to improved adherence while yielding immunosuppressive potency equivalent to that of conventional tacrolimus preparations; however, tacrolimus has a potent blood sugar-elevating effect; thus, direct comparison with the CyA group is important for assessing the side effects. ConclusionTacER has the potential to also reduce side effects in the early stages after surgery, suggesting its potential as a drug of first choice.

Etiological analysis of graft dysfunction following living kidney transplantation: a report of 366 biopsies

Aim: The aim of this study is to investigate the clinical features of graft dysfunction following living kidney transplantation and to assess its causes.Methods: We retrospectively analyzed a series of 366 living kidney transplantation indication biopsies with a clear etiology and diagnosis from July 2003 to June 2016 at our center. The classifications and diagnoses were performed based on clinical and pathological characteristics. All biopsies were evaluated according to the Banff 2007 schema.Results: Acute rejection (AR) occurred in 85 cases (22.0%), chronic rejection (CR) in 62 cases (16.1%), borderline rejection (BR) in 12 cases (3.1%), calcineurin inhibitor (CNI) toxicity damage in 41 cases (10.6%), BK virus-associated nephropathy (BKVAN) in 43 cases (11.1%), de novo or recurrent renal diseases in 134 cases (34.7%), and other causes in nine cases (2.3%); additionally, 20 cases had two simultaneous causes. The 80 cases with IgA nephropathy (IgAN) had the highest incidence (59.7%) of de novo or recurrent renal diseases. After a mean ± SD follow up of 3.7 ± 2.3 years, the 5-year graft cumulative survival rates of AR, CR, CNI toxicity, BKVAN, and de novo or recurrent renal diseases were 60.1%, 31.2%, 66.6%, 66.9%, and 67.1%, respectively.Conclusions: A biopsy is helpful for the diagnosis of graft dysfunction. De novo or recurrent renal disease, represented by IgAN, is a major cause of graft dysfunction following living kidney transplantation.

The Spectrum of Histopathological Changes in the Renal Allograft - a 12 Months Protocol Biopsy Study.

INTRODUCTION:Renal transplantation became a routine and successful medical treatment for Chronic Kidney Disease in the last 30 years all over the world. Introduction of Luminex based Single Antigen Beads (SAB) and recent BANFF consensus of histopathological phenotypes of different forms of rejection enables more precise diagnosis and changes the therapeutic approach. The graft biopsies, protocol or cause, indicated, remain a golden diagnostic tool for clinical follow up of kidney transplant recipients (KTR).AIM:The study aimed to analyse the histopathological changes in renal grafts 12 months after the surgery in KTR with satisfactory kidney function.MATERIAL AND METHODS:A 12-month protocol biopsy study was performed in a cohort of 50 Kidney transplant recipients (42 from living and 8 from deceased donors). Usual work-up for suitable donors and recipients, standard surgical procedure, basic principles of peri and postoperative care and follow up were done in all KTR. Sequential quadruple immunosuppression including induction with Anti-thymocyte globulin (ATG) or Interleukin-2R antagonist (IL-2R), and triple drug maintenance therapy with Calcineurin Inhibitors (CNI), Mycophenolate Mofetil (MMF) and Steroids were prescribed to all pts. Different forms of Glomerulonephritis (16), Hypertension (10), End Stage Renal Disease (13), Hereditary Nephropathies (6), Diabetes (3) and Vesicoureteral Reflux (2) were the underlying diseases. All biopsies were performed under ultrasound guidance. The 16 gauge needles with automated “gun” were used to take 2 cores of tissue. The samples were stained with HE, PAS, Trichrome Masson and Silver and reviewed by the same pathologist. A revised and uploaded BANFF 2013 classification in 6 categories (Cat) was used.RESULTS:Out of 48 biopsies, 15 (31%) were considered as normal, 4 (8%), Borderline (BL-Cat 3), 5 (10%) as Interstitial Fibrosis/Tubular Atrophy (IF/TA-Cat 5), 5 (10%) were classified as non-immunological (Cat 6), 2 as a pure antibody-mediated rejection (ABMR-Cat 2) and T-cell Mediated Rejection (TCMR-Cat 4). The remaining 17 samples were classified as a “mixed” rejection: 7 (41%) ABMR + IF/TA, 5 (29%) ABMR + BL + IF/TA, 2 (11%) BL + IF/TA, 1 (5%) ABMR + BL, 1 (5%) ABMR + TCMR and 1 (5%) TCMR + IF/TA. The mean serum creatinine at the time of the biopsy was 126.7 ± 23.4 µmol/L, while GFR-MDRD 63.4 ± 20.7 ml/min, which means that the majority of the findings were subclinical. Among the non-immunological histological findings (Cat 6), 3 cases belonged to CNI toxicity, 1 to BK nephropathy and 1 to recurrence of the primary disease.CONCLUSION:Our 12-month protocol biopsy study revealed the presence of different forms of mixed subclinical rejection. Use of recent BANFF classification and scoring system enables more precise diagnosis and subsequently different approach to the further treatment of the KTR. More correlative long-term studies including Anti HLA antibodies and Endothelial Cell Activation- Associated Transcripts (ENDAT) are needed.

Successful treatment of recurrent immunoglobulin a nephropathy using steroid pulse therapy plus tonsillectomy 10\xa0years after kidney transplantation: a case presentation

BackgroundBoth prevention and treatment of recurrent immunoglobulin A nephropathy (IgAN) in kidney transplant recipients are important since recurrent IgAN seems to affect long-term graft survival. We present here a case of recurrent IgAN that was successfully treated using steroid pulse therapy plus tonsillectomy 10 years after kidney transplantation.Case presentationA 46-year-old male was admitted for an episode biopsy with a serum creatinine level of 1.8 mg/dl and proteinuria (0.7 g/day). Histological features showed recurrent IgAN (only focal segmental mesangial proliferation) and severe arteriolar hyalinosis partly associated with calcineurin inhibitor toxicity, with limited interstitial fibrosis and tubular atrophy (5%) (IF/TA) 8 years after transplantation. Sodium restriction and conversion from cyclosporine to tacrolimus successfully reduced his proteinuria to the level of 0.15 g/day. However, 2 years later, his proteinuria increased again (1.0 g/day) and a second episode biopsy showed global mesangial proliferation with glomerular endocapillary and extracapillary proliferation accompanied by progressive IF/TA (20%). The steroid pulse therapy plus tonsillectomy successfully decreased his proteinuria and he achieved clinical remission 3 years after this treatment.ConclusionThis case, presented with a review of relevant literature, demonstrates the difficulty and importance of the treatment of recurrent IgAN and calcineurin inhibitor arteriolopathy, especially in long-term kidney allograft management.

De Novo Thrombotic Microangiopathy in Renal Transplant Patients.

Thrombotic microangiopathy is a form of renal capillary injury possibly associated with calcineurin inhibitor toxicity, acute humoral rejection, infections, and recurrent diseases. Here, we examined its incidence in patients diagnosed with acute and chronic active humoral rejection, polyomavirus nephropathy, acute cellular rejection, and immunoglobulin A recurrence. In total, 272 renal allograft recipients who met the inclusion criteria were reevaluated for presence of renal thrombotic microangiopathy. Thrombotic microangiopathy diagnosis was established by clinical, laboratory, and histologic features. C4d expression in peritubular capillaries was determined. Clinical data were collected from medical records. Of 272 patients (mean age of 42.8 ± 12.7 years), only 74 patients (27.2%) had de novo thrombotic microangiopathy, which was found in 30/90 patients (33.3%) with acute humoral rejection, 9/51 (17.6%) with acute cellular rejection, 22/53 (41.5%) with chronic active humoral rejection, 10/55 (18.2%) with polyomavirus nephropathy, and 3/23 (13%) with immunoglobulin A nephropathy. Significant differences were shown between therapy type and thrombotic microangiopathy development (P = .02). Patients who received cyclosporine (38.5%) tended to show higher incidence of thrombotic microangiopathy than patients who received tacrolimus (20.7%) or sirolimus (7.7%). Patients with C4d-positive acute humoral (97.6% vs 2.4%) and chronic active humoral rejection (68.2% vs 31.8%) had greater incidence of thrombotic microangiopathy versus those who were C4d-negative. Graft loss was significantly higher in C4d-positive than in C4d-negative thrombotic microangiopathy groups (P < .001). Overall 1-, 3-, and 5-year graft survival was 94%, 85%, and 85% versus 83%, 51%, and 51% in thrombotic microangiopathy-negative versus thrombotic microangiopathy-positive patients (P < .001). Acute humoral rejection and chronic active humoral rejection were the most common and therefore most important causes of de novo thrombotic microangiopathy in renal transplant patients. Its presence in the renal allograft biopsy should arouse suspicion for underlying acute or chronic active humoral rejection.

Non-immunologic allograft loss in pediatric kidney transplant recipients.

Non-immunologic risk factors are a major obstacle to realizing long-term improvements in kidney allograft survival. A standardized approach to assess donor quality has recently been introduced with the new kidney allocation system in the USA. Delayed graft function and surgical complications are important risk factors for both short- and long-term graft loss. Disease recurrence in the allograft remains a major cause of graft loss in those who fail to respond to therapy. Complications of over immunosuppression including opportunistic infections and malignancy continue to limit graft survival. Alternative immunosuppression strategies are under investigation to limit calcineurin inhibitor toxicity. Finally, recent studies have confirmed long-standing observations of the significant negative impact of a high-risk age window in late adolescence and young adulthood on long-term allograft survival.

The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys.

Calcineurin inhibitor toxicity (CNT) is a frequent occurrence in transplanted renal grafts and autochthone kidneys from patients undergoing long-term treatment with calcineurin inhibitors, notably cyclosporin A (CsA) and tacrolimus. Here, we show an indispensable role of the tumor necrosis factor superfamily (TNFS) molecule TNF-related weak inducer of apoptosis (TWEAK) (TNFSF12) in the pathogenesis of acute CNT lesions in mice. A deficiency in TWEAK resulted in limited tubulotoxicity after CsA exposure, which correlated with diminished expression of inflammatory cytokines and reduced intraparenchymal infiltration with immune cells. We further identified tubular epithelial cells of the kidney as major targets of CsA activity and found that Fn14 (tumor necrosis factor receptor superfamily 12A), the receptor for TWEAK, is a highly CsA-inducible gene in these cells. Correlating with this, CsA pretreatment sensitized tubular epithelial cells specifically to the pro-inflammatory activities of recombinant TWEAK in vitro. Moreover, injection of rTWEAK alone into mice induced moderate disease similar to CsA, and rTWEAK combined with CsA resulted in synergistic nephrotoxicity. These findings support the importance of tubular epithelial cells as cellular targets of CsA toxicity and introduce TWEAK as a critical contributor to CNT pathogenesis.

Peritoneal Dialysis in Orthotopic Liver Transplantation Recipients.

In many dialysis programs, there is resistance to initiating peritoneal dialysis (PD) in liver transplant patients needing renal replacement therapy. This retrospective study reviews the outcome of PD in liver transplant patients at a major transplantation and dialysis center. We performed a retrospective cohort study in patients who underwent liver transplants and received PD between 1991 and 2016. Patient demographics, laboratory parameters, and adverse events were collected from our electronic database. Between 1991 and 2016, 14 patients underwent liver transplants and subsequently received PD. The mean age was 59.0 ± 7.1 years; 42.8% women; the mean time from transplant to PD initiation was 9.7 ± 2.8 years; average follow-up on PD was 31.3 months (range: 9 - 87 months). Hepatitis C was the main cause of liver failure necessitating the transplant (8 patients). Calcineurin inhibitor toxicity was the lead cause of end-stage renal disease (ESRD) (12 patients). The overall peritonitis rate was 39.8 patient-months (0.3 episodes per year at risk). There was 1 patient with relapsing peritonitis, and 1 patient had severe peritonitis and died. Mean survival was 58.9 ± 11.3 months, 4 patients died, 4 received a kidney transplant, 1 patient was transitioned to hemodialysis due to poor ultrafiltration, 1 patient was transferred to another program, 2 remained on PD and 2 patients recovered renal function. Eight patients underwent liver biopsies during their time on PD without complication. There appears to be no specific concern related to liver transplant patients undergoing PD. Peritonitis and mortality rates were no different from other solid organ recipients or even from the general PD population. The hepatic graft was never threatened, even during peritonitis. Therefore, these patients should not be denied the option of PD.

Spectrum of renal allograft biopsy: A five-year experience at a tertiary care center of Eastern India

Renal allograft dysfunction (RAD) can have myriad causes and presentations. Allograft biopsy remains the gold standard for optimum management. This is a retrospective study carried out at a tertiary care institute from August 2011 to March 2016. Details of the renal allograft biopsy requisitions were recorded and analyzed. Two hundred and two patients had undergone kidney transplantation (KT) during the study period. One hundred and twenty-six had undergone renal biopsy for RAD. The acute asymptomatic rise of serum creatinine was the most common clinical presentation (47.61%) followed by chronic RAD (CRAD) (19.84%), proteinuria (15.87%), immediate graft dysfunction (10.31%), and persistent active urinary sediments (6.34%) in that order. The incidence of delayed graft function was 1.98%. The overall incidence of biopsy-proven rejection was 8.41% within oneyear and 8.91% beyond oneyear of transplant. Acute cellular rejection (ACR) [with or without antibody-mediated rejection (AMR)] was found in 65%; AMR was found in 40% and 15% had both ACR and AMR. Borderline acute cell-mediated rejection was found in 22.5% of biopsies. CRAD was due to chronic rejection and chronic calcineurin inhibitor toxicity in only about one-fourth of the cases. Incidence of glomerulo-nephritis was 10.89% and most of these occurred two years after KT. Renal allograft biopsy was associated with minor complications in 3.17% of cases. Clinical presentations do not reliably distinguish the various causes of RAD. Allograft biopsy is a mainstay in the diagnosis of RAD and is safe. Results of live donor first transplantation using complement-dependent cytotoxi-city crossmatch are comparable to those programs using newer methods like solid-phase assays. However, the direct comparison of these results with other studies may not be completely applicable.