Calcineurin Inhibitor Toxicity Research Articles

Pharmacokinetics of nirmatrelvir/ritonavir and the drug-drug interaction with calcineurin inhibitor in renal transplant recipients.

To describe the pharmacokinetic (PK) characteristics of nirmatrelvir/ritonavir in renal transplant recipients and explore the potential factors that related to the PK variance of nirmatrelvir/ritonavir and its interaction with calcineurin inhibitor (CNI). Renal transplant recipients treated with CNI and nirmatrelvir/ritonavir were prospectively enrolled. Steady-state plasma concentrations of nirmatrelvir/ritonavir were determined by high-performance liquid chromatography-tandem mass spectrometry, and the PK parameters were calculated using non-compartmental analysis. Spearman correlation analysis was used for exploring influencing factors. A total of eight recipients were enrolled; for nirmatrelvir and ritonavir, AUC/dose was 0.24179 ± 0.14495 and 0.06196 ± 0.03767μg·h·mL-1·mg-1. Red blood cell (RBC), hematocrit (Ht), hemoglobins (Hb), and creatinine clearance (Ccr) were negatively correlated with AUC/dose of nirmatrelvir, while Ccr, CYP3A5 genotype, and CYP3A4 genotype were related to the AUC/dose of ritonavir. Ccr was negatively correlated with the C0/dose of tacrolimus (TAC) after termination of nirmatrelvir/ritonavir (rs = -0.943, p = 0.008). The PK characteristics of nirmatrelvir/ritonavir vary greatly among renal transplant recipients. Factors including Ccr and CYP3A5 genotype were related to the in vivo exposure of nirmatrelvir/ritonavir. During the whole process before and after nirmatrelvir/ritonavir therapy, it is recommended to adjust the CNI basing on renal function to avoid CNI toxicity exposure.

Post-transplant CFHR5 mutation-related atypical HUS: The need for pre-transplant diagnosis

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) affecting multiple organs and can be sporadic or familial. It is most commonly caused by dysregulation of the alternative complement pathway. aHUS can occur at any age with a high rate of progression to end-stage kidney disease. We describe the case of a 24-year-old man with chronic kidney disease, severe hypertension, and antineutrophilic antibody by IF positive. On biopsy, diffuse global glomerulosclerosis with TMA and IF findings of full house pattern suggestive of lupus nephritis were present. Considering a lupus nephritis case, after 2 years of hemodialysis underwent live-related renal transplant (Father Donor). Immediate post-transplant period developed severe cortical necrosis and TMA. An etiological workup was done to ascertain the cause of post-transplant TMA. After excluding common causes of antibody-mediated rejection (C4d and donor-specific alloantibody neg), calcineurin inhibitor toxicity, and infection, we detected an abnormal complement CFHR5 mutation with an autosomal dominant pattern of inheritance. Pre-transplant diagnosis could have prevented taking the kidney from the father for transplant and further prevented recurrence. Systemic lupus erythematosus and TMA both can have alternate complement pathway dysregulation leading to full house IF pattern and misdiagnosis.

Novel non-invasive method for urine mapping: Deep-learning-enabled SERS spectroscopy for the rapid differential detection of kidney allograft injury

The kidney allograft has been under continuous attack from diverse injuries since the very beginning of organ procurement, leading to a gradual decline in function, chronic fibrosis, and allograft loss. It is vital to routinely and precisely monitor the risk of injuries after renal transplantation, which is difficult to achieve because the traditional laboratory tests lack sensitivity and specificity, and graft biopsies are invasive with the risk of many complications and time-consuming. Herein, a novel method for the diagnosis of graft injury is demonstrated, using deep learning-assisted surface-enhanced Raman spectroscopy (SERS) of the urine analysis. Specifically, we developed a hybrid SERS substrate composed of gold and silver with high sensitivity to the urine composition under test, eliminating the need for labels, which makes measurements easy to perform and meanwhile results in extremely abundant and complex Raman vibrational bands. Deep learning algorithms were then developed to improve the interpretation of the SERS spectral fingerprints. The deep learning model was trained with SERS signals of urine samples of recipients with different injury types including delayed graft function (DGF), calcineurin-inhibitor toxicity (CNIT), T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), and BK virus nephropathy (BKVN), which explored the features of these types and achieved the injury differentiation with an overall accuracy of 93.03%. The results highlight the potential of combining label-free SERS spectroscopy with deep learning as a method for liquid biopsy of kidney allograft injuries, which can provide great potential to diagnose and evaluate allograft injuries, and thus extend the life of kidney allografts.

Impact of nonspecific allograft biopsy findings in symptomatic kidney transplant recipients

A for-cause biopsy is performed to diagnose the cause of allograft dysfunction in kidney transplantation. We occasionally encounter ambiguous biopsy results in symptomatic kidney transplant recipients. Yet, the allograft survival outcome in symptomatic recipients with nonspecific allograft biopsy findings remains unclear. The purpose of this study was to analyze the impact of nonspecific for-cause biopsy findings in symptomatic kidney transplant recipients. We retrospectively collected records from 773 kidney transplant recipients between January 2008 and October 2021. The characteristics of transplant recipients with nonspecific findings in the first for-cause biopsy were analyzed. Nonspecific allograft biopsy findings were defined as other biopsy findings excluding rejection, borderline rejection, calcineurin inhibitor toxicity, infection, glomerulonephritis, and diabetic nephropathy. The graft outcome was compared between recipients who had never undergone a for-cause biopsy and those who had a first for-cause biopsy with nonspecific findings. The graft survival in recipients with nonspecific for-cause biopsy findings was comparable to that in recipients who did not require the for-cause biopsy before and after propensity score matching. Even in symptomatic kidney transplant recipients, nonspecific allograft biopsy findings might not be a poor prognostic factor for allograft survival compared to recipients who did not require the for-cause biopsy.

A292 IMPACT OF SIROLIMUS PROTEINURIA FOLLOWING LIVER TRANSPLANTATION

Abstract Background Sirolimus (Sr) is a potent immunosuppressant used in liver transplant recipients to prevent rejection in settings of calcineurin inhibitor toxicity and in transplanted hepatocellular carcinoma (HCC) patients. Sr can cause proteinuria, which can lead to poor renal function and survival. The significance of proteinuria is poorly understood, with a lack of studies assessing its risk factors and their impact on clinical outcomes. Aims We evaluated the incidence of proteinuria and its impact on clinical outcomes among liver transplant (LT) recipients who were Sr users compared with non-sirolimus (nonSr) users. Methods We analyzed patients with their first LT between 2001 and 2020. Data were gathered from Organ Transplant Tracking records and chart reviews. Sr users received Sr for at least 6 consecutive months in the first year post-LT. We studied demographics, pre-LT comorbidities, and immunosuppression use. We evaluated the development of proteinuria, renal dysfunction, and new comorbidities including features of metabolic syndrome and cardiovascular disease. Data on post-LT infections, graft rejection, and patient survival were collected. Results We analyzed 359 Sr and 762 non-Sr users (73.5% vs. 65% male). The average ages of Sr and non-Sr users were 54.9±9 and 51.7±11.6 years, respectively (pampersand:003C0.001). Of Sr users, 40.4% had HCC (pampersand:003C0.001). Among non-Sr users, 95% were on tacrolimus and 67.8% were on mycophenolate. Higher frequency of pre-LT hypertension (HTN) was observed in Sr users (27.2% vs. 18.2%; pampersand:003C0.001). There were no differences in pre-LT chronic kidney disease (CKD), cardiovascular disease (CVD), dyslipidemia (DLD), diabetes mellitus (DM) prevalence, creatinine levels, or proteinuria. Sr users had a higher incidence of proteinuria (13.1% vs. 7.9%, p=0.006). Protein-creatinine ratios and albumin-creatinine ratios 12 months post-LT were not significantly different in Sr and non-Sr users ([40.1±105.6 vs. 57.5±169.9 mg/g, p=0.39], and [56.2±101.4 vs. 54.6±166.8 mg/g, p=0.268], respectively). Pre-LT creatinine (OR1.5; pampersand:003C 0.001) and DM (OR2.7; pampersand:003C 0.001) were associated with an increased risk of proteinuria. Sr users had higher (pampersand:003C0.001) incidence of post-LT CVD (24% vs. 14.8%), DM (20.4% vs. 12.6%), HTN (41.5% vs. 30.3%), and DLD (41.3% vs. 20.3%). There was no difference in post-LT CKD between Sr vs non-Sr (41% vs. 47%; p =0.119). Sr users had a lower frequency of post-LT infection (43.1% vs. 53%, p=0.007). Higher incidence of graft rejection was seen in Sr users (43.5% vs 27.8%, pampersand:003C0.001). There was no difference in median graft (15.2 ± 0.40 vs. 14.4±0.30 years; p = 0.681) or patient survival (12.5±0.44 vs. 12.5±0.33 years; p = 0.536). Conclusions Although Sr users were less likely to develop CKD post-LT, they had significantly higher rates of proteinuria, CVD, HTN, and DLD. However, no significant difference was observed in graft or patient survival rates. Funding Agencies None

The Role of Protocol Allograft Biopsies in Postrenal Transplantation: A Systematic Review and Meta-analysis

Introduction: Kidney transplantation is the preferred treatment for end-stage kidney disease, offering improved outcomes compared to dialysis. However, factors such as immunological rejection, drug toxicity, and infections limit its success. Incorporating protocol biopsies (PBs) into standard care for kidney transplant recipients varies widely. This study aims to review the literature on the practice, histopathological findings, and benefits of performing PB on allograft function. Materials and Methods: A systematic review was conducted using PubMed, ScienceDirect, and other databases from 2000 to 2023. Studies describing findings of PBs within 2 years posttransplant were included. Data extraction covered study design, immunosuppression, biopsy timing, incidence of subclinical rejection (SCR), clinical rejection, and allograft function measures. Statistical analysis was performed using R and RevMan software. Results: Among 25 studies (3384 patients) included, 8 were randomized controlled studies. Protocol biopsy timing varied, with the highest number performed at 1 year (44.84%). The pooled incidence of SCR was 13%, with heterogeneity across estimates. Subgroup analysis did not reveal significant differences in SCR rates between high- and low-immunologic risk patients. Patients who underwent PBs had lower clinical rejection rates (12.64% vs. 20.17%) and better allograft function. Incidence of calcineurin inhibitor toxicity ranged from 1.2% to 63.4%, and BK virus nephropathy ranged from 0% to 5.9% in included studies. Conclusion: Performing PB at 6 months, 1 year, and 2 years posttransplant can reveal SCR and potentially improve long-term graft outcomes. Treatment of SCR may reduce clinical rejection episodes. However, further research, particularly comparing PB with noninvasive methods, is needed to better understand their efficacy and complications in the modern transplant landscape.

Thrombotic microangiopathy after kidney transplantion

Background and objectives: Thrombotic microangiopathy after kidney transplantation is rare but serious complication. The purpose of this study is to describe the cases of thrombotic microangiopathy after kidney transplantation. Patients and Methods: This retrospective study used the reports of all kidney transplant biopsies that were done in Kurdistan region from January 2017 to April 2022. The biopsy reports with diagnosis of Thrombotic microangiopathy were extracted from this total number and the patients, and pathological data included in the reports were recorded. Results: The total number of 1635 graft biopsies, of which 82 (5.01%) were found to have Thrombotic microangiopathy features. The mean age of studied patients with Thrombotic microangiopathy was (38.2 years) and male to female ratio as 2.3:1. We found 67.1% of cases of Thrombotic microangiopathy were associated with calcineurin inhibitor toxicity, 35.4% with rejection, 15.9% were recurrent thrombotic microangiopathy, and 40.2% were associated with other miscellaneous causes. Conclusions: Thrombotic microangiopathy after kidney transplantation is rare but debilitating complication. The cause is multifactorial in most cases in the light of coexistence of multiple risk factors in the kidney transplant recipients. Further studies are required to disentangle these overlapping risk factors. And allow for better prevention and treatment of this condition.

Aurora Kinase a Inhibition for Gvhd and Relapse Prevention after Allogeneic HCT: Phase I Trial in Combination with Ptcy/Sirolimus

Introduction: With the wider use of post-transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis, there is interest in replacing tacrolimus (TAC) with sirolimus (SIR, mTOR inhibitor) to avoid calcineurin inhibitor toxicity, maintain excellent GVHD control, and potentially allow for a greater graft-versus-tumor effect. mTOR and Aurora kinase A (AURKA) mediate CD28 costimulation in alloreactive T cells. SIR can only partially block CD28 costimulation. Adding selective AURKA inhibition to SIR following PTCy fully suppresses CD28 signal transduction, with synergistic GVHD prevention in mice (see ASH 2023 abstract ID 173376). AURKA inhibitors also have direct anti-leukemia activity. Here, we present the phase 1 dose escalation portion of a first-in-human clinical trial of PTCy plus SIR and VIC-1911 (VIC), a selective oral AURKA inhibitor, for GVHD and relapse prophylaxis after myeloablative allogeneic hematopoietic cell transplantation (alloHCT). Methods: This single-arm phase I dose escalation trial (NCT05120570) is designed to evaluate the pharmacodynamic potency of AURKA pathway suppression and the safety of PTCy/SIR/VIC. The primary endpoint of phase I is to identify the lowest biologically active dose of VIC, defined as <54% pH3ser10+ CD4+ T cells at day +21 (the lower confidence interval of the normal, pre-transplant frequency of pH3ser10+ CD4+ T cells - a marker of AURKA activity), that is safe with PTCy/SIR. Patients aged 18-60 years receive myeloablative conditioning of TBI alone at a dose of 1320 cGy. PTCy is given as 50 mg/kg on days +3 and +4, SIR on day +5 with levels targeting 8-12 ng/ml and tapered after day +100, and VIC given on days +5 to +45 at doses of 25, 50, or 75 mg BID. Patients undergoing myeloablative TBI-based alloHCT with PTCy/SIR plus mycophenolate mofetil (MMF), without VIC on a separate protocol, served as a control. Results: Proof-of-concept experiments with PTCy/SIR/alisertib (AURKA inhibitor) demonstrate synergistic protection against xenogeneic GVHD and tumor (Raji cells) in mice, compared to PTCy/TAC (median survival: 45 days v undefined, 9 mice/group, 2 experiments, P<0.0001). Unlike alisertib, VIC-1911 is not myelosuppressive, providing rationale for this trial. In vitro studies show killing of multiple leukemia cells lines at physiologically achievable VIC-1911 concentrations. VIC 75 mg BID is the lowest biologically active dose suppressing AURKA activity below the primary endpoint target of <54%, with reduced mean frequency of day +21 pH3ser10+ CD4+ T cells at 23.7% compared to 58.5% with PTCy/SIR/MMF (Figure 1A, P=0.0091). PTCy/SIR/VIC also suppresses mTOR activity in donor T cells (3.9% v 16.6% pS6+ CD4+ T cells, P=NS; pS6 frequency in healthy donor T cells is ~30-40%), concurrently ablating CD28 signal transduction. Data trends show greater Tregs at day +21 with PTCy/SIR/VIC, compared to PTCy/SIR/MMF controls (40.2% v 10.5%, P=NS). Patient characteristics are detailed in Figure 1B. Neutrophil engraftment occurred in 9/9 evaluable patients at a median of 18 days. Platelet engraftment occurred in 8/9 evaluable patients at a median of 21 days; one patient is awaiting platelet engraftment. No dose-limiting toxicities have been observed during dose escalation. Patient 1 died of non-COVID coronavirus during initial hospitalization; he received high-dose methylprednisolone for ARDS beginning on day +17, which made him unevaluable for the primary pharmacodynamic endpoint. Conclusions: A VIC-1911 dose of 75 mg BID from day +5 to day +45 effectively suppresses AURKA activity as determined by a low frequency of pH3ser10+ CD4+ T cells, ablating CD28 T cell costimulation when combined with sirolimus, resulting in no dose-limiting toxicities. VIC 75 mg BID will be studied further in an expanded phase I cohort to obtain estimates of efficacy in preventing both GVHD and relapse in PTCy-based myeloablative alloHCT.

SAT254 Elevated Vitamin D 1,25-Dioh Leading To The Diagnosis Of Diffuse Large B-cell Lymphoma With Excessive Vitamin D Intake Confounding The Clinical Picture

Abstract Disclosure: R. Barai: None. C. Hurtado: None. We present a patient with acute-onset hypercalcemia in the setting of excessive vitamin D intake, found to have elevated vitamin D 1,25-DiOH and PTHrP, eventually resulting in a diagnosis of diffuse large B-cell lymphoma. 76-year-old man with PMH of idiopathic pulmonary fibrosis s/p left lung transplant, CKD secondary to calcineurin inhibitor toxicity, hypothyroidism, HTN, type 2 DM, and OSA presented with progressively worsening fatigue for four weeks, found to be hypercalcemic to 15.3 mg/dL on presentation with low-normal intact PTH, 14 pg/mL. Three weeks prior to admission, patient had normal calcium, 9.9 mg/dL, with sudden increase to 12.8 mg/dL one week prior to admission, which was not treated. Patient reported taking 5,000 IU of vitamin D PO daily for 5 years, which confounded the clinical picture as the etiology was initially thought to be secondary to excessive vitamin D intake in the setting of frankly elevated vitamin D 25(OH)D of 160 ng/mL. Further work-up revealed elevated 1,25-DiOH of 339 pg/mL with elevated PTHrP of 5 pmol/L and low ACE level of <10 U/L, which was inconsistent with vitamin D intoxication and was concerning for malignancy as the etiology of the hypercalcemia. Patient was treated with 4 doses of calcitonin, fluids and 2 low-doses of pamidronate in the setting of AKI on CKD with only modest improvement in hypercalcemia during the hospitalization. Patient was discharged with calcium 11.4 mg/dL. On CT chest, patient was found to have an enlarged R epicardiac lymph node, prompting PET/CT that demonstrated extensive intensely FDG avid nodular thickening of the right pleura and peritoneum with FDG avid thoracic and abdominopelvic lymphadenopathy and two FDG avid liver masses. US-guided biopsy of a peritoneal nodule was consistent with diffuse large B-cell lymphoma (DLBCL). Colonoscopy demonstrated 5 cm cecal mass with DLBCL, and transverse colonic mass with adenocarcinoma. Liver biopsy flow cytometry was consistent with DLBCL. Patient’s calcium has since normalized with further treatments of denosumab, calcitonin, zoledronic acid and treatment of DLBCL with rituximab, high-dose prednisone, and cyclophosphamide with plan for surgical resection of colon adenocarcinoma. It is important to highlight that elevated 1,25-DiOH would not be typical of hypervitaminosis D as the activity of 1-alpha-hydroxylase (the enzyme that converts the inactive form of vitamin D, 25(OH)D, to the bioactive form, 1,25-DiOH) would be low with hypercalcemia. With the elevated 1,25-DiOH and PTHrP, we were concerned for granulomatous disease or malignancy as the etiology, and we recommended investigation for causes of hypercalcemia other than excessive vitamin D intake. The diagnosis of lymphoma was made due to the incongruity of the history of excessive vitamin D intake and the elevated 1,25-DiOH. Hypercalcemia, in our patient’s case, was due to lymphoma-induced vitamin D activation. Presentation: Saturday, June 17, 2023

Long-term Course of Kidney Function in Uterus Transplant Recipients Under Treatment With Tacrolimus and After Transplantectomy: Results of the First Clinical Cohort.

Chronic kidney disease is common after non-renal solid organ transplantation, mainly secondary to calcineurin inhibitors toxicity. Uterus transplantation (UTx) is an innovative treatment for women with absolute uterine factor infertility. UTx is exclusive because it is transient with the absence of lifelong immunosuppression and is performed in young healthy participants. Therefore, UTx provides a unique setting for evaluating the effect of time-limited calcineurin inhibitors treatment on recipients' kidney function. In the first UTx cohort worldwide, we studied kidney function using estimated glomerular filtration rate (eGFR) in 7 women over a median follow-up of 121 (119-126) mo. Median eGFR (mL/min/1.73 m2) of the cohort was 113 at UTx, which declined to 74 during month 3, 71 at months 10-12, 76 at hysterectomy (HE), and 83 at last follow-up. Median duration of tacrolimus exposure was 52 (22-83) mo, and median trough levels (µg/L) were 10 during month 3 and 5.8 at HE. Between UTx and month 3, decline in kidney function was observed in all 7 participants with a median eGFR slope for the whole cohort of -24 mL/min/1.73 m2, which declined further by -4 mL/min/1.73 m2 until months 10-12. Thereafter, eGFR slope improved in 3 participants, remained stable in 3, and worsened in 1 until HE/tacrolimus discontinuation, after which it improved in 2. Eventually, between UTx and last follow-up, 4 of 7 participants had a decline in their eGFR, the median annual eGFR slope being negative at -1.9 mL/min/1.73 m2/y for the whole group. Kidney function declined in all recipients early after UTx followed by a persistent long-term decrease in majority, despite transplantectomy and discontinuation of immunosuppression. Thus, UTx may incur an increased risk of chronic kidney disease even in this young and healthy population, highlighting the importance of close surveillance of kidney function and minimization of tacrolimus exposure.

Thrombotic microangiopathies after kidney transplantation in modern era: nosology based on chronology

BackgroundThrombotic microangiopathies (TMAs) are rare but can be severe in kidney transplant.recipients (KTR).MethodsWe analysed the epidemiology of adjudicated TMA in consecutive KTR during the.2009–2021 period.ResultsTMA was found in 77/1644 (4.7%) KTR. Early TMA (n = 24/77 (31.2%); 1.5% of all KTR) occurred during the first two weeks ((median, IQR) 3 [1–8] days). Triggers included acute antibody-mediated rejection (ABMR, n = 4) and bacterial infections (n = 6). Graft survival (GS) was 100% and recurrence rate (RR) was 8%. Unexpected TMA (n = 31/77 (40.2%); 1.5/1000 patient-years) occurred anytime during follow-up (3.0 (0.5–6.2) years). Triggers included infections (EBV/CMV: n = 10; bacterial: n = 6) and chronic active ABMR (n = 5). GS was 81% and RR was 16%. Graft-failure associated TMA (n = 22/77 (28.6%); 2.2% of graft losses) occurred after 8.8 (4.9–15.5) years). Triggers included acute (n = 4) or chronic active (n = 14) ABMR, infections (viral: n = 6; bacterial: n = 5) and cancer (n = 6). 15 patients underwent transplantectomy. RR was 27%. Atypical (n = 6) and typical (n = 2) haemolytic and uremic syndrome, and isolated CNI toxicity (n = 4) were rare. Two-third of biopsies presented TMA features.ConclusionsTMA are mostly due to ABMR and infections; causes of TMA are frequently combined. Management often is heterogenous. Our nosology based on TMA timing identifies situations with distinct incidence, causes and prognosis.

Secondary thrombotic microangiopathy following CNI and mTOR inhibitor toxicity after COVID-19 therapy with nirmatrelvir/ritonavir in a kidney transplant patient.

Secondary thrombotic microangiopathy following CNI and mTOR inhibitor toxicity after COVID-19 therapy with nirmatrelvir/ritonavir in a kidney transplant patient.

#3385 A STUDY OF CLINICAL SPECTRUM AND THE OUTCOME IN LIVE KIDNEY TRANSPLANT RECIPIENTS IN A TERTIARY CARE CENTRE OF INDIA

Abstract Background and Aims Kidney transplantation has become the treatment of choice for end-stage renal disease as it leads to longer survival and superior quality of life. There is a remarkable disparity in the access and outcome of kidney transplant across the world. Limited health care resources, difficulty in access or sometimes non availability of appropriate medications, difficulties with transportation, limited availability of Nephrologists are common challenges in developing countries and also within a country like India due to diverse socioeconomic and cultural backgrounds. We present the pattern of infection, various causative organisms, causes of allograft dysfunction and the clinical outcome of the admitted live kidney transplant recipients in Nephrology department of a tertiary care center from North-East India. Method This was a single center retrospective observational study carried out in Nephrology Department of Gauhati Medical College, Guwahati, India. The data were collected from the medical records. All the admissions of live renal allograft recipients during the period May 2017- May 2022, were included in the study. Results Out of a total of 156 admissions of renal transplant recipients, male to female ratio was 3.7: 1. Among the live KTRs basic disease, most common was chronic glomerulonephritis (44.8%) followed by CTID (23.9%). Infection related complications were present in 72 (46.1%) cases. Among infection UTI (n = 29, 16.6%) was most common followed by pneumonia (n = 24, 15.4%). Various causes of graft dysfunction (biopsy proven) were ATI (Acute tubular injury), CNI toxicity, chronic ABMR, acute ABMR, recurrence of basic disease, acute TCMR and chronic TCMR. NODAT was found in 14 (9%) of the cases. Out of theses 4 cases, 1 had bacterial pneumonia and 3 had UTI. Of 72 admissions with infection, total 8 patients succumbed to their illness with mortality rate of 11.1%. The most common cause of mortality was sepsis due to UTI. Conclusion The number of admissions of renal transplant cases has increased significantly in last 5 years, indicating the increased availability and affordability of renal transplantation in our country. Of 156 admitted live KTRs, infection was seen in 46.1% (n = 72) cases. UTI remained the most common infection (n = 29, 16.6%) followed by pneumonia (n = 24, 15.4%). Graft dysfunction was seen in 33.9% (n = 53) cases. Chronic ABMR was the most common cause (n = 30, 19.2%) for graft dysfunction. Neglect of necessary hygiene, ignorance of regular follow up and dysregulated immunosuppressive doses have contributed to high infection rate. Lack of regular follow up in post-transplant period due to logistic issues or lack of education and awareness, lack of access to immunosuppressive drugs, etc. are major contributing factors for graft dysfunction in our set up. The condition worsens with the difficult terrain, repeated floods, and lack of transportation from remote areas in Nort Eastern part of India.

#6147 BELATACEPT OUTCOMES IN PEDIATRIC KIDNEY TRANSPLANTATION: AN INTERNATIONAL MULTICENTER STUDY

Abstract Background and Aims Belatacept is a co-stimulation blocker associated with better long-term outcomes in adult patients compared to CNI based regimens. Data on its use in older children and young adults are lacking. We are the 1st to report outcomes for 45 pediatric kidney transplant recipients converted to belatacept. Method 45 patients were included from 4 centers (USA and France) between 05/2018 and 12/2021. Patients received an induction with basiliximab (n = 39) or ATG (n = 6). Maintenance immunosuppression included CNI, MMF +/− steroids. Patients’ viral status (EBV, CMV) were monitored monthly and allograft biopsies were performed prior and ∼6 months after starting belatacept. The first 5 belatacept injections were administered at 5 mg/kg/dose (10 mg/kg/dose if early conversion) every 2 weeks, then monthly. CNI were progressively reduced and stopped. MMF doses were also increased at CNI withdrawal. Results Median age at conversion was 17.7 y (range 10.3-20.6). 7/45 patients received an early conversion (median: 1 month post-transplant, IQR 0.5-1.2): 6 patients because of delayed graft function and 1 to avoid CNI toxicity (post-transplant diabetes). 38/45 patients were converted after a median of 4.1 years post-transplant (IQR 1.7-6.0). Conversion indication was based on the need for long term CNI avoidance: either because of toxicity (histology, post-transplant diabetes, tremors; n = 13) or sub-optimal creatinine (n = 12) or to improve adherence (e.g. monthly IV-treatment, n = 13). CNI were withdrawn in 42/45 patients by a median of 2.4 months (IQR 1.4-6.0). GFR was stable or improved over a median follow-up time of 1.6 years (IQR 1.1-2.4), Fig 1 A. Rejection episodes were observed in 10/45 patients (22%) after a median of 10.2 months (IQR 6.1-15.8) and included 7 TCMR, 2 ABMR and 1 mixed rejection. None of these patients were converted early (<3 m), 5 had been converted for non-adherence, 4 had pre-existing DSA and 4 had prior history of rejection. Evolution of GFR in rejectors is shown in Fig 1 B. CNI were reintroduced for 6/10 and belatacept stopped for 3/10. Regarding viral complications, 1 severe BKv nephropathy required the discontinuation of belatacept. All patients were EBV+ at conversion (4 were EBV- at the time of transplant). No EBV replication was observed. Conclusion Selected pediatric kidney recipients benefit from long-term CNI toxicity avoidance, but selection criteria need to be refined to avoid rejection under costimulation blockade.

#4762 PREGNANCY-RELATED ACUTE KIDNEY INJURY: 10-YEAR SERIES OF A NEPHRO-OBSTETRIC CLINIC

Abstract Background and Aims Pregnancy-related acute kidney injury (P-AKI) is a rare complication of pregnancy associated with significant maternal and fetal morbidity and mortality. Its incidence has progressively decreased worldwide with the improvement of obstetric care, but recently some developed countries have noticed an increase in its incidence. Adjusted definition of AKI in pregnancy is lacking, making its incidence difficult to ascertain. Herein, the authors retrospectively evaluated the causes and outcomes of P-AKI patients surveilled by the nephro-obstetric clinical team. Method Retrospective analysis of maternal, obstetric and perinatal outcomes of P-AKI patients, that were followed by the Nephro-obstetric clinical team between 2011 and 2022. Results We evaluated 29 patients, with mean age of 32 ± 6 years [17 – 42], 19 Caucasian and 9 Black, 17 nulliparous, 16 hypertensive, 7 diabetic, 1 with HIV, and 1 with systemic lupus erythematosus. Only 12 patients had CKD and 3 were renal transplant patients. In 2/29 patients P-AKI occurred before 20 weeks [15-17] due to obstructive uropathy and pregnancy hyperfiltration in a CKD G3 patient. After 20 weeks of gestation, P-AKI occurred in 27/29 patients (mean 32 weeks; range 21-41weeks), with mean SCr of 3,1 mg/dl [1,8-4,5] in previously CKD patients and mean SCr of 2.4mg/dl (1,2-58mg/dl) in the patients with normal renal function. Regarding the severity of P-AKI, 16/7/6 patients developed AKI stage 1/2/3 (KDIGO), respectively. Causes of P-AKI after 20 weeks in patients with normal renal function were preeclampsia (PE; 8/14), HELLP syndrome (1/14), hemolytic uremic syndrome (1/14), sepsis (3/14), renal obstruction (1/14), severe hypercalcemia (1/14), cortical necrosis due to hemorrhagic shock (2/14), hypovolemia and nephrotoxic agents (1/14). All patients had full renal recovery. In renal transplant patient P-AKI was related to PE (2/3), sepsis (1/3) and probable calcineurin inhibitor toxicity (1/3). Regarding CKD patients, P-AKI was caused by PE (6/10), hyperfiltration of pregnancy (3/10) and allergic interstitial nephritis (1/10). The need for renal replacement therapy occurred in 7/29, and only 2/7 became dialysis dependent (both with previous CKD diagnosis). De novo or worsening proteinuria occurred in 15/29 (3975 g/day; 431-14000 g/day) and 10/29 patients (mean 6227 mg/day; 681-14937 mg/day), respectively. Regarding fetal outcomes, there were 2 stillbirths, mean gestation duration was 33 weeks (25-41weeks), mean birth weight 1947 g (550-3950 g) and mean Apgar 1/5/10 was 8/9/10, respectively. Cesarean was performed in 19/27 patients and 7 newborns were admitted to the neonate care unit due to prematurity. Conclusion In a tertiary referral center, P-AKI was associated to a wide range of causes, frequently required a multidisciplinary approach and was associated to significant worse maternal, obstetric and perinatal outcomes.

Rituximab/Mycophenolate Combination Therapy in Children with Calcineurin Inhibitor-Resistant FSGS.

There is a paucity of data and therapeutic options nationally and internationally on calcineurin inhibitor (CNI)-resistant forms of focal segmental glomerulosclerosis (FSGS) in children. CNI (tacrolimus or cyclosporine) are proven monotherapy in children with FSGS with a steroid-dependent (SD) or steroid-resistant (SR) course. We analyzed a novel therapeutic option in CNI-resistant FSGS by using the dual therapy of rituximab and mycophenolate to maintain remission. This is a retrospective analysis of clinical, therapeutic profile, and treatment outcomes (sustained remission versus no remission) in subjects with CNI-resistant FSGS who received dual rituximab therapy along with mycophenolate as maintenance therapy for a minimum of 1 year. The median age of presentation of 13 recruited children was 7.8 years (range: 2.4-17.6 years); nine (69.2%) were males. Ten (76.9%) of them had an SD course and three (23.1%) had an SR course. Four (30.7%) had evidence of acute/chronic CNI toxicity, and the remaining nine (69.3%) showed no response to CNI therapy despite adequate trough levels. Post dual therapy, 11 (84.6%) had sustained remission for at 1 year and two (15.4%) children did not show remission. None reported adverse reactions or infections, and all had preserved renal functions. Dual combination therapy with rituximab and mycophenolate among children with CNI-resistant FSGS can emerge as a promising and efficacious treatment strategy to ensure sustained remission in this subset of patients.

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus Advagraf™ in liver transplant recipients

BackgroundGraft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients.MethodsThe EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus Advagraf™ (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period.DiscussionC/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022.Trial registrationThis trial has been registered (4 May 2020) in the EU Clinical Trials Register, EudraCT-Nummer: 2020–000796-20. Additionally, this trial has been registered (22 January 2021) at ClinicalTrials.gov: NCT04720326. The trial received a favourable opinion from the concerned lead ethics committee at the University of Regensburg, under the reference 20–1842-112.

Skin cancer in solid organ transplant recipients: still an open problem.

In the last two decades, the optimization of organ preservation and surgical techniques, and the personalized immunosuppression have reduced the rate of acute rejections and early post-transplant complications. However, long-term graft survival rates have not improved over time, and evidence suggest a role of chronic calcineurin inhibitor toxicity in this failure. Solid organ transplant recipients may develop chronic dysfunction/damage and several comorbidities, including post-transplant malignancies. Skin cancers, mostly non-melanoma skin cancers (squamous cell carcinoma and basal cell carcinoma), are the most common malignancies in Caucasian solid organ transplant recipients. Several factors, together with immunosuppression, may contribute to the susceptibility for skin cancers which, although often treatable, could be associated with a much higher mortality rate than in the general population. The rapid identification and treatment (including reduction of immunosuppression and early surgical treatments) have an important role to avoid an aggressive behavior of these malignancies. Organ transplant recipients with a history of skin cancer should be followed closely for developing new and metastatic lesions. Additionally, patient education on the daily use of sun-protective measures and the recognition of the early signs (self-diagnosis) of coetaneous malignancies are useful preventive measures. Finally, clinicians should make themselves aware of the problem and build, in every clinical follow-up center, collaborative network involving transplant clinicians, dermatologists and surgeons who should work together to easily identify and rapidly treat these complications. In this review, we discuss the current literature regarding the epidemiology, risk factors, diagnosis, preventive strategies and treatments of skin cancer in organ transplantation.

Renal biopsy - indication and its implications in management of children admitted at a tertiary care hospital, Mangalore

Background: Percutaneous renal biopsy is an established diagnostic tool for identification of renal pathology required for diagnosis, treatment, and prognostication. The present study was conducted to know the common indications and histopathological findings of renal biopsy, impact of biopsy report on treatment, and complications of procedure. Methods: This was a retrospective observational study conducted in the paediatric ward of a tertiary care level hospital. Indications of renal biopsy as suggested by medical records were noted down. Any treatment changes happened after final histopathological report were recorded. Statistical analysis was made using statistical package for the social sciences (SPSS) version 20.0 (IBM, NY). Results: The mean age of patients at which biopsy was done was 9.83±5.31 years. Most common indications of renal biopsy were nephritic onset nephrotic syndrome (34.8%), steroid-resistant nephrotic syndrome (21.7%), steroid-dependent nephrotic syndrome requiring calcineurin inhibitors (CNI) (17.4%), lupus nephritis (8.7%), nephrotic syndrome with later age of onset (8.7%), acute kidney injury (AKI) stage 3 (4.3%) and for evidence of calcineurin inhibitor toxicity (4.3%). Focal segmental glomerulosclerosis (26.1%), minimal change disease (21.7%) and membranoproliferative glomerulonephrosis (17.4%) were the most common histopathological findings. Conclusions: This study reiterates the fact that renal biopsy is one of the decisive and diagnostic procedures and has good prognostic value in further management of medical renal disease.

Evaluation of T-Cell Immune Status of Reduced-Dose Cyclosporine and Everolimus Combination Therapy in Kidney Transplant Patients

Kidney transplantation (KT) outcomes have significantly improved with calcineurin inhibitors (CNIs) administration. In recent years, the dose of CNIs has been reduced, and everolimus (EVR) has been used in combination with CNIs to avoid complications from the long-term use of CNIs. However, T-cell immune responses to these protocols have not been fully evaluated. This study evaluated the anti-donor T-cell responses to our CNI-sparing regimen. Fifty-five de novo KT patients were enrolled. Three months after KT, the patients were randomly assigned to either the EVR group, which received low-dose cyclosporine (CsA) (n=28), or the standard-exposure CsA control group (n=27), which was treated with both mycophenolate mofetil and methylprednisolone. Graft function, adverse events, and immunologic status were evaluated 3 years after KT. Mixed lymphocyte reaction (MLR) assays were performed to evaluate anti-donor T-cell responses in KT patients. Both groups maintained graft function well, but total cholesterol levels tended to increase annually in the EVR group. The incidence of cytomegalovirus (CMV) infection tended to be lower in the EVR group, regardless of the CMV serologic status. Immunologic evaluation by MLR assay showed that anti-donor T-cell responses were adequately maintained in both groups. EVR starting 3 months after KT can reduce the trough levels of CsA without affecting graft function or compromising the immunosuppressive effects. The EVR combination protocol is expected to reduce CNI toxicity and improve long-term prognosis after KT.