Calcineurin Inhibitor Toxicity Research Articles

Association of gut microbiota with allograft injury in kidney transplant recipients: a comparative profiling through 16S metagenomics and quantitative PCR.

Introduction. The existence of a mutual relationship between gut microbiota and immune homeostasis highlights its importance in the context of kidney transplantation.Gap statement. The translational utility of gut microbiota as a biomarker for allograft injury has not been assessed before.Aim. In this study, we aimed to characterize the gut microbial diversity in kidney transplant recipients and investigate the alterations in the gut microbial composition in association with allograft injury such as histopathological graft rejection and calcineurin inhibitor toxicity. In addition, we compared the gut microbial quantitation using 16S metagenomics and quantitative PCR (qPCR) to assess its translational utility.Methodology. In this prospective longitudinal cohort study, we enrolled 38 kidney transplant recipients and collected serial faecal specimens (n=114), once before the induction therapy, and twice after transplant, during the first and third month. We characterized the gut microbial composition through 16S rRNA sequencing and qPCR from the DNA isolates of the samples. The recipients were clinically followed up for a median of 600 days post-transplant. Histopathological evidence of allograft rejection and calcineurin inhibitor toxicity were used for the correlational analysis with gut microbial diversity.Results. Significant differences in the gut microbial diversity were observed between the pre- and post-transplant samples. Pre-transplant gut microbiota revealed a higher relative abundance of phylum Bacteroidetes in the allograft rejection group, and a higher relative abundance of phylum Firmicutes was observed in the histopathological features of calcineurin inhibitor toxicity (hCNI toxicity) group. We found a high concordance between 16S metagenomics and qPCR outputs for assessing the gut microbial diversity. Furthermore, the receiver operating characteristic curve analysis has also proven that the pre-transplant levels of gut microbial dysbiosis, as a potential predictive biomarker for allograft injury.Conclusion. Our pilot study found a strong statistical association of gut microbial dysbiosis with kidney allograft injury, highlighting the potential of gut microbiota as a predictive biomarker and that qPCR serves as a more reliable and economic tool for assessing dysbiosis paving the way for its translational utility.

Defining the Etiology of Renal Allograft Dysfunction Using Banff 2019 Classification: Correlation with Post-Transplant Duration and Creatinine Levels-A Comprehensive Analysis of 200 Renal Biopsies at a Tertiary Care Medical Center Hospital.

Chronic kidney disease is a growing global health issue, contributing significantly to morbidity and mortality. The incidence of end-stage renal disease (ESRD) is approximately 100 per million population. Renal transplantation remains the cornerstone treatment for ESRD, with a projected 20-year survival rate of 60%. We aim to define the etiology of renal allograft dysfunction using the Banff 2019 classification by analyzing 200 renal allograft biopsies in correlation with creatinine levels across post-transplant time frames. 200 renal allograft biopsies are analyzed using the recent Banff 2019 classification with creatinine levels and post-transplant duration correlation. The study included 150 (75%) male patients and 50 (25%) female patients, with the majority 78 (39%) representing the age group of 16-30 years. 36 (18%) biopsies were within 3-month post-transplant, while 92 (46%) were 2-year post-transplant. According to the Banff 2019 classification, 92 (46.0%) transplant rejection biopsies were identified, with most 54 (27%) exhibiting antibody-mediated rejection (Category 2), including 40 (20%) active acute antibody-mediated rejection (ABMR) and 14 (7.0%) chronic active ABMR. T-cell-mediated rejection (TCMR; Category 4) represented 12 (6%) biopsies, including 10 (5%) acute TCMR and 2 (1%) chronic active TCMR. Category 5, the miscellaneous group, represented 100 (50%) biopsies, out of which 32 (16%) exhibited calcineurin inhibitor (CNI) toxicity, 38 (19%) acute tubular necrosis, and 8 (4%) thrombotic microangiopathy. A notable variation in the dysfunction distribution across different post-transplant time frames indicated a temporal evolution in the underlying causes of allograft dysfunction. Specific Banff categories showed a robust association with renal dysfunction, potentially contributing to the elevation of creatinine levels and renal function deterioration. Our study highlights the intricate pathophysiology of renal allograft dysfunction. Most biopsies were attributed to ABMR whereas one-third of biopsies exhibited mixed lesions (ABMR and TCMR or ABMR and calcineurin inhibitor toxicity (CNIT)). Additionally, this study suggests that renal allograft rejection remains a significant contributor to graft dysfunction. A complex interplay between histological findings, Banff classification, and renal function is noted. A significant difference in the distribution of dysfunction across post-transplant time frames is noted suggesting a temporal evolution in the etiology of allograft dysfunction. Certain Banff categories demonstrate a stronger association with renal dysfunction that may influence creatinine level increase and renal function deterioration. In correspondence to the recent Banff 2019 guidelines for diagnosing ABMR, we emphasize the role of C4d staining on immunofluorescence or immunohistochemistry in allograft biopsies as imperative for timely diagnosis and immunosuppressant therapy adjustment, ultimately enhancing graft survival. Further research is needed to elucidate the underlying mechanisms driving renal dysfunction in different Banff categories, ultimately informing personalized management strategies for patients with renal allograft dysfunction. In line with the Banff 2019 guidelines for diagnosing ABMR, this study highlights the critical role of C4d staining through immunofluorescence or immunohistochemistry in allograft biopsies for early diagnosis and timely adjustment of immunosuppressive therapy, ultimately improving graft survival.

Early CYP3A5 Genotype-Based Adjustment of Tacrolimus Dosage Reduces Risk of De Novo Donor-Specific HLA Antibodies and Rejection among CYP3A5-Expressing Renal Transplant Patients.

Our previous retrospective single-center cohort study found, at 3-year follow-up, a trend toward low tacrolimus trough levels and an increased risk of de novo donor-specific anti-HLA antibodies (DSAs) and of antibody-mediated rejection (ABMR) in CYP3A5-expressing patients. Determining CYP3A5-expression status immediately after renal transplant would allow early genotype-based dosage adjustment of tacrolimus and might prevent the occurrence of de novo DSAs and ABMR, improving transplant outcome. 160 renal allograft recipients who underwent renal transplant at the University Hospital Essen between May 2019 and May 2022 were genotyped for the CYP3A5 rs776746 polymorphism within the first two weeks after transplant, and genotype-based dose adjustment of tacrolimus was performed for the follow-up of 2 years. CYP3A5 expression was detected in 33 (21%) of the 160 patients. Tacrolimus trough levels were similar in CYP3A5 expressers and nonexpressers over the entire 2-year follow-up period. However, we observed a trend toward slightly higher tacrolimus trough levels in CYP3A5 expressers, who, as expected, required tacrolimus dosages twice as high as did nonexpressers during follow-up. Calcineurin inhibitor (CNI) nephrotoxicity-free survival rates were comparable between CYP3A5 expressers and nonexpressers (p = 0.49). Rejection-free survival rates (p = 0.89), de novo anti-HLA antibody-free survival rates (p = 0.57) and de novo DSA-free survival rates (p = 0.61) did not differ between the two groups. Early detection of CYP3A5-expression status and resultant genotype-based adjustment of tacrolimus dosage after renal transplant protected patients from transplant rejection and de novo DSA formation and was not associated with increased incidence of CNI toxicity among CYP3A5 expressers.

Rifampin as Rescue Therapy for Paxlovid-Associated Calcineurin Inhibitor Toxicity

Rifampin as Rescue Therapy for Paxlovid-Associated Calcineurin Inhibitor Toxicity

Acute Kidney Injury after Liver Transplantation

Abstract Liver transplantation is the only curative treatment for terminal liver failure. Advances in immunosuppressive therapy and improvements in surgical techniques have improved patient survival in the post-transplant period. At the same time, however, the incidence of late complications is increasing, which has been contributed to by the broadening of the indication criteria in liver allocation. The most common complications include chronic kidney disease, the aetiology of which is multifactorial with a predominance of calcineurin inhibitor toxicity in the post-transplant period. The prevalence ranges from 30% to 90% depending on the definition used and the methodology used to measure renal function. Early detection of risk factors and early intervention lead to a significant improvement in the quality of life of recipients in the post-transplant period.

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.

Kidney Biopsy Findings After Lung Transplantation

The early diagnosis of histological kidney damage after lung transplantation (LT) is of paramount importance given the negative prognostic implications of kidney disease. Three pathologists analyzed all kidney biopsies (KBs) (N= 100) performed from 2010 to 2021 on lung transplant patients in 4 Paris transplantation centers. The main indication for biopsy was chronic renal dysfunction (72% of patients). Biopsies were performed at a median of 26.3 months after transplantation and 15 months after a decline in estimated glomerular filtration rate (eGFR) or the onset of proteinuria. Biopsies revealed a wide spectrum of chronic lesions involving the glomerular, vascular, and tubulointerstitial compartments. The 4 most frequent final diagnoses, observed in 18% to 49% of biopsies, were arteriosclerosis, acute calcineurin inhibitor (CNI) toxicity, thrombotic microangiopathy (TMA) and acute tubular necrosis (ATN). TMA was significantly associated with a combination of mTOR inhibitors (mTORi) or CNIs with biological signs present in only 50% of patients. The eGFR was poorly correlated with most lesions, particularly percent glomerulosclerosis, and with the risk of end-stage renal disease (ESRD). Thirty-four patients progressed to ESRD at an average of 20.1 months after biopsy. Three factors were independently associated with the risk of ESRD: postoperative dialysis, proteinuria >3 g/g and percent glomerulosclerosis >4%. Given the great diversity of renal lesions observed in lung transplant recipients, early referral to nephrologists for KB should be considered for these patients when they present with signs of kidney disease.

#2487 Deleterious renal outcome in patients with thrombotic microangiopathy after lung transplantation: the lung TMA trial

Abstract Background and Aims Thrombotic microangiopathy (TMA) is a rare but severe complication following lung transplantation. The pathogenesis is poorly understood, involving endothelial damage and various risk factors, including calcineurin inhibitor (CNI) toxicity. We aimed to evaluate diagnostic accuracy, identify risk factors for and assess the renal and overall survival of TMA in this patient group. Method We performed a retrospective study of patients with TMA after lung transplant between 01/01/2000-01/01/2021. Matching controls were selected based on underlying lung disease, age, gender, CMV risk, and immunosuppressive regimen. Overall survival and baseline data (age, gender) were collected for the whole lung transplant group. Results A total of 29 TMA cases (2.9%) were identified out of 1025 lung transplantations. 48% of patients had a complete hematological assessment with Coombs testing as the most frequent (52%) missing test. The median time from transplantation to TMA was 5.9 months. 76% of the episodes occurred before 12 months. 77% of patients had organ damage with acute kidney injury in 72%. At the time of TMA 38% of patients had a cytomegalovirus (CMV) infection. Arterial hypertension was found in 31% and acute rejection in 11%. The immunosuppressive scheme consisted of tacrolimus/mycophenolate mofetil and corticosteroids in the majority of cases (56%). Tacrolimus (n = 22) and cyclosporine (n = 7) trough levels were respectively 11.8 and 207 µg/l at the time of TMA. Treatment consisted of change in immunosuppressive regimen (72%), 31% received plasmapheresis. When comparing the TMA patients with the control group a higher rate of donor specific antibodies were found (11% vs 1%), a lower median time till chronic lung allograft dysfunction (37 m vs 91 m) and a higher prevalence of end-stage renal disease (24% vs 6%) and overall death (97% vs 44%) with mortality being significantly higher (p < 0.01). Fig. 1 illustrates the overall outcome. Conclusion This study illustrates the clinical characteristics and outcomes of TMA after lung transplantation. Even though the prevalence is low the effects are deleterious with acute kidney injury in the majority of cases and higher risk of end-stage renal disease and mortality. Our study emphasizes the need for higher further research into risk factors, and therapeutic strategies to prevent and improve patient outcomes. Furthermore, the findings underscore the importance of vigilant monitoring and tailored interventions for TMA in lung transplant patients.

#2645 Clinical features and outcomes of steroid resistant focal sclerosing glomerulosclerosis (FSGS) in a single tertiary nephrology centre in Malaysia

Abstract Background and Aims Steroid resistant FSGS is defined as persistence of proteinuria with <50% reduction from baseline despite prednisolone 1 mg/kg/d for at least 16 weeks. We aim to study the clinical presentations, treatment, treatment response and kidney survival among steroid resistant FSGS patients. Method This retrospective study included all patients who had undergone renal biopsy in HSIS and had documented diagnosis of steroid resistant FSGS from January 2007 until December 2022. Data was collected and analysed using SPSS version 17. Results are expressed in mean ± standard deviation (SD) unless stated otherwise. Results A total of 74 patients had primary FSGS out of which 15 were identified as steroid resistant. Median age was 33 years old with 53% being female. Median weight at diagnosis was 73.7kg with BMI of 28kg/m2. One third had no co-morbid disease while 4 patients had underlying diagnosis of minimal change disease. Proteinuria on presentation was 7.6g with albumin levels of 16 g/L. No difference was seen between steroid resistant and steroid sensitive cohort with regards to age, proteinuria, GFR and laboratory parameters. Median duration of steroid was 38.8 months with duration of high dose steroids were 5 months and complications often set in by 2 months of therapy. Steroid toxicity occurred in 13 patients with most common complication seen was Cushingoid features (8/13) followed by acne (2/13) and diabetes mellitus (2/13). There were more steroid complications in steroid resistant cohort compared to the steroid sensitive. Second line was initiated in all patients but one with cyclosporin A being the most common choice (11/14) followed by Azathioprine (2/14) and cyclophosphamide (3/14). The median duration of second line agent was 22 months with CNI specifically being for 18 months. 3 patients developed CNI toxicity and was given cyclophosphamide while one patient developed CNI resistance and was given IV Rituximab. 4 (%) patients went on to achieve complete remission, 8 had partial remission while the rest did not achieve remission. 9 patients had normal renal function, while 3 developed chronic kidney disease. One patient went on to become end stage renal disease while 2 patients died. There was no difference in terms of renal or patient outcome between steroid resistant and steroid sensitive FSGS. Conclusion Steroid resistant FSGS is a challenging entity of FSGS that warrants close monitoring for complications and management. The outcomes were not different between steroid sensitive and steroid resistant FSGS however, the steroid complications were more common in steroid resistant FSGS.

Tacrolimus Intrapatient Variability on Graft Outcomes inAdherent Renal Transplantation Patients: A Cross-SectionalStudy.

Tacrolimus is the mainstem of immunosuppressive therapy in kidney transplant patients. It has high intrapatient variability (Tac-IPV), which has been reported to affect graft function by predisposing patients to rejection or nephrotoxicity. We conducted this study with the aim of assessing the influence of Tac-IPV on 2-year graft function, biopsy-proven rejection, and infections in compliant renal recipients. In this single-center retrospective analytic cross-sectional study, 250 patients who underwent transplantation from March 21, 2018, to March 20, 2020 and had at least three outpatient tacrolimus trough levels on the same daily dose 6 to 12 months after transplantation were recruited. Tac-IPV was defined as a coefficient variation of > 15%. Graft function, biopsy-proven rejection, cytomegalovirus (CMV) and BK virus viremia, and calcineurin inhibitor (CNI) toxicity were evaluated. Of 202 transplant recipients, 128 were included with a mean age of 45.48 ± 13.14 years. The median Tac-IPV was 13.28% with 43.75% of patients with Tac-IPV > 15%. There were no significant differences in graft function, rejection, CNI toxicity, and CMV viremia among the groups during the 24-month study (P > .05). However, BK viremia was significantly higher among patients with Tac-IPV > 15% (13 vs. 2.9%, P = .042). The risk of antibody mediated rejection alone (22.7 vs. 2.9%) or any kind of rejection (22.7 vs. 11.8%) was significantly higher in patients with higher Tac-IPV, and in those who had mean trough levels below 7 ng/mL (P = .015, .032; respectively). Tac-IPV is low in adherent patients (with the median of 13.28%) and maintaining tacrolimus trough level above 7 ng/mL can overcome the adverse graft outcome of Tac-IPV in compliant kidney transplant recipients. DOI: 10.52547/ijkd.7815.

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.

Mucormycosis-Associated Colon Perforation in the Early Postrenal Transplant Period

The incidence of colon perforation in the posttransplant period is 1.3% based on various single-center studies. We report the case of a 32-year-old male, a known case of chronic kidney disease and end-stage renal disease who received a live-related ABO-compatible transplant. The patient was started on tacrolimus, mycophenolate mofetil, and steroids; no induction was given. The patient had a delayed graft function, and his creatinine was persistently high. Hence, a biopsy was done on postoperative day 4, which revealed an acute tubular injury with features of calcineurin inhibitor toxicity. His tacrolimus dose was reduced and his output improved until day 13, after which his renal function worsened. The repeat tacrolimus level was low. Hence, the patient was started on pulse steroids and discharged after the patient improved symptomatically (discharge creatinine: 2.1). The patient was readmitted 3 days after discharge with severe abdominal pain. The patient’s blood pressure was 90/30 mmHg; he was drowsy and tachypneic. His abdomen was distended. Computed tomography of the abdomen revealed pneumoperitoneum, and the patient was subjected to an explorative laparotomy. There was colonic perforation. The peritoneum and colon revealed multiple punched-out lesions and a right hemicolectomy was done. A biopsy revealed suppurative inflammation involving all three layers with multiple giant cells, and tissue staining revealed ribbon-like aseptate hyphae with 90° angulation suggestive of mucormycosis. The patient expired in the immediate postoperative period. The final diagnosis of mucormycosis-associated colon perforation was made. Only one such case has been reported previously.

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.