Factors Associated with Hyperpolypharmacy and Complex Medication Regimens in Kidney Transplant Recipients.

Background: Kidney transplantation is considered the best modality for renal replacement therapy. The use of immunosuppressive therapy and pre-existing and newly developed comorbidities predispose these patients to the use of a large number of medications. (Hyper)polypharmacy is associated with worse adherence and negative outcomes. This study aims to explore the factors correlated with hyperpolypharmacy and complex medication regimens in kidney transplant recipients. Methods: This is a cross-sectional study of outpatient kidney transplant recipients. Collected data include demographic data, complete chronic medication lists, medical history, and graft function. Linear and logistic regression were used to identify factors associated with hyperpolypharmacy and complex medication regimens. Medication regimen complexity was quantified by the Medication Regimen Complexity Index (MRCI). Results: Overall, 224 kidney transplant recipients were included, with an average time since transplantation of 8 years. Hyperpolypharmacy was present in more than two-thirds of patients; the average number of different medications was 12; and the mean MRCI score was 21.4, ranging from 6 to 50. Hypertension was almost universally present, while other frequently prescribed medication groups were hypolipemics, medication for bone-mineral metabolism disorders, gout, and antihyperglycemics. Conclusions: Factors independently associated with hyperpolypharmacy and complex medication regimens were found to be age and graft function. Studies investigating interventions aimed at reducing medication complexity and increasing adherence should focus on older patients with worse graft function.

Combination of SGLT2 Inhibitors and GLP-1 Receptor Agonists in PTDM Treatment in Kidney Transplant Recipients: Synergistic Effect With Added Value in Terms of Nephroprotection.

Post-transplantation diabetes mellitus, obesity, and metabolic syndrome are common complications after kidney transplantation. Data on using novel agents, including SGLT2 inhibitors and GLP-1 receptor agonists, in kidney transplant recipients are scarce and practice guidelines are lacking. According to available data, GLP-1 receptor agonists are efficient in terms of weight loss and glycemia control. Although improvement or no change of eGFR was observed, recently published data suggest their protective effect on graft function. Trials on SGLT2 inhibitors demonstrate improved glycemia control, weight, and blood, and stable kidney function. Given the different mechanisms of action, it has been postulated that a combination of SGLT2 inhibitors and GLP-1 receptor agonist could have beneficial effects in treating diabetes. There is some evidence in the literature postulating the beneficial effects of this treatment combination on cardiovascular outcomes in the general population and only one case emphasizing nephroprotective effect. Data on simultaneous use of SGLT2 inhibitors and GLP-1 receptor agonists in kidney transplant recipients is lacking and, here, we bring our experience.

Exploring Acute Pancreatitis in Kidney Transplant Recipients: A Multicentre Retrospective Cohort Analysis of Incidence, Causes, and Clinical Outcomes.

Background: The aim of this multicentre retrospective study is to determine the incidence, etiology, clinical characteristics, and outcomes of kidney transplant recipients diagnosed and treated for acute pancreatitis. Methods: We analyzed data from kidney transplant recipients who received kidney allografts between October 1973 and December 2023 and were diagnosed and treated for acute pancreatitis. Results: Of 2482 patients who received kidney allografts, 10 (0.4%) (5 male) were diagnosed with acute pancreatitis, with a mean age of 48.6 years. Patients were diagnosed with acute pancreatitis between 3 weeks and 24 years after the transplantation. Possible etiologies included cholecystolithiasis, COVID-19, hypercalcemia, postprocedural, use of cannabis, trimetoprim-sulphometoxasole, statins, sirolimus, tacrolimus and obesity. There was no suspected etiology in two patients. Patients were treated with aggressive hydration, pain alleviation and antibiotics if indicated. Four patients developed complications. Local complications included peripancreatic collections, pseudocyst, and abscesses formation, while systemic complications occurred in the form of Cytomegalovirus (CMV) reactivation and urinary tract infection. All patients survived with preserved kidney allograft function. Conclusions: Acute pancreatitis in kidney transplant recipients is rare. However, it may be linked to significant morbidity and mortality. While symptoms may be nonspecific and brought on by a variety of viral and non-infectious illnesses, as well as adverse effects from immunosuppressive medications, a high degree of awareness is required.

Co-occurrence of triple carbapenemase genes, blaVIM-2, blaNDM-1, and blaOXA-48 in Enterobacter hormaechei clinical isolates -first report from Croatia.

Two Enterobacter hormaechei isolates harbouring three carbapenemase genes each, were isolated from two patients from different ICUs at University Hospital Centre Zagreb, Croatia, which is to our knowledge, the first report of triple carbapenemase (blaVIM-2, blaNDM-1, and blaOXA-48) co-existence in E. hormachei strains and also among Enterobacterales members in Croatia. Antimicrobial susceptibility testing showed susceptibility only to colistin and amikacin. The production of carbapenemases was phenotypically tested by immunochromatographic assay and confirmed by PCR. Detailed analysis by Whole Genome Sequencing (WGS) of short reads by Illumina and long reads by Oxford Nanopore Technologies (ONT) was additionally performed and showed that both isolates belonged to ST200. They were separated by 98 Single Nucleotide Polymorphisms (SNPs) having variations in the number of blaVIM-2 genes on the chromosome, the number of blaNDM-1 genes on the plasmid, non-identical blaNDM-1 plasmids, different plasmid content in general, and only one isolate carried a 94 kb prophage.

Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis.

The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans' heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.

Immunomodulatory Effect of COVID-19 on HLA-Antibody Profile in Renal Transplant Recipients.

Background/Objectives: The novel coronavirus disease 2019 (COVID-19) has led to significant morbidity and mortality among kidney transplant recipients. SARS-CoV-2 has been hypothesized to cause an unusual immunological dysregulation triggering alloimmunity and leading to graft rejection. Methods: This prospective observational cohort study assessed 321 kidney transplant recipients who had COVID-19 infection. After the infection, patients' sera were tested for the presence of anti-HLA de novo DSA and non-DSA specificities. Logistic regression analysis and a stepwise multivariable logistic regression analysis were used to analyze the independent risk factors associated with the development of antibodies, adjusting for known confounders. The variables evaluated were acute COVID-19 characteristics (i.e., presentation, and need for hospitalization), demographic characteristics (i.e., age, gender, and primary renal disease), clinical characteristics (i.e., various comorbidities), and post-COVID-19 sequelae. Results: Anti-HLA de novo DSA developed in 18.7% of patients, while anti-HLA class I and class II non-DSA antibodies developed de novo in 84 (26.3%) and 83 (25.9%) patients, respectively. The development of DSA, HLA-DQ, and HLA-DR antibodies was predicted by the history of graft rejection. Obesity appeared to be protective against the emergence of de novo DSA. De novo DSA and HLA-DR antibody formation was positively linked with intravenous immunoglobulin use, CMV-hyperimmune globulin use, and decreased doses of immunosuppression during acute infection. Better allograft function during the acute disease was a protective factor against the formation of HLA-DQ and HLA-DR antibodies. Positive predictors of de novo DSA development were graft biopsy and the reactivation of EBV after infection. Conclusions: These findings suggest that the SARS-CoV-2 virus has an immunomodulatory effect and may be associated with an increased mortality in this population.

Acute pancreatitis as a complication of acute COVID-19 in kidney transplant recipients.

BACKGROUND: Acute pancreatitis is a rare extrapulmonary manifestation of coronavirus disease 2019 (COVID-19) but its full correlation with COVID-19 infection remains unknown. AIM: To identify acute pancreatitis' occurrence, clinical presentation and outcomes in a cohort of kidney transplant recipients with acute COVID-19. METHODS: A retrospective observational single-centre cohort study from a transplant centre in Croatia for all adult renal transplant recipients with a functioning kidney allograft between March 2020 and August 2022 to record cases of acute pancreatitis during acute COVID-19. Data were obtained from hospital electronic medical records. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was proven by a positive SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction on the nasopharyngeal swab. RESULTS: Four hundred and eight out of 1432 (28.49%) patients who received a renal allograft developed COVID-19 disease. The analyzed cohort included 321 patients (57% males). One hundred and fifty patients (46.7%) received at least one dose of the anti-SARS-CoV-2 vaccine before the infection. One hundred twenty-five (39.1%) patients required hospitalization, 141 (44.1%) developed pneumonia and four patients (1.3%) required mechanical ventilation. Treatment included immunosuppression modification in 233 patients (77.1%) and remdesivir in 53 patients (16.6%), besides the other supportive measures. In the study cohort, only one transplant recipient (0.3%) developed acute pancreatitis during acute COVID-19, presenting with abdominal pain and significantly elevated pancreatic enzymes. She survived without complications with a stable kidney allograft function. CONCLUSION: Although rare, acute pancreatitis may complicate the course of acute COVID-19 in kidney transplant recipients. The mechanism of injury to the pancreas and its correlation with the severity of the COVID-19 infection in kidney transplant recipients warrants further research.

A Machine Learning-Driven Virtual Biopsy System For Kidney Transplant Patients.

In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.

P31-A150†SARS-CoV-2 real time polymerase chain reaction testing of corneas from post-mortem SARS-CoV-2 positive donors.

PURPOSE: Possible transmission of SARS-CoV-2 from donors to recipients via cornea grafts is still a concern of the transplantation community. Current recommendations are to avoid corneal transplants from donors with ongoing SARS-CoV-2 infection or those recently exposed to it. During pandemic period in Croatia 21/1113; (1,9%) corneas were procured from donors positive for SARS-CoV-2 by postmortem nasopharyngeal swab tests. That tissue was discarded. Due to the lack of knowledge about the infectivity of such corneas, we started prospective study of SARS-CoV-2 presence in cornea tissue. Here we show our first results. METHODS: In the study period we had four corneas procured from two post-mortem SARS-CoV-2 positive donors. For the presence of SARS-CoV-2, analysis is performed on donor serum, hypothermic storage medium and cornea tissue lysate. Corneas were stored in hypothermic condition for 8 to 10 days, after which tissue was macerated and washed with PBS. The intracellular content was released by incubation with lysis buffer, followed by centrifugation. Next, tissue lysate, serum and hypothermic storage medium were in parallel subjected to fully automated nucleic acid isolation and RNA expression was analyzed by qRT-PCR. During isolation, RNasaP was used as internal control for successful nucleic acids isolation. RESULTS: No SARS-CoV-2 RNA was detected in the donors serum, storage medium and cornea tissue from donors who were SARS-CoV-2-positive upon tissue procurement. In nasopharyngeal swabs of post mortem positive donors cycle threshold values of viral copies were high (CT>34), indicating that there was small number of viral particles in infected donors that could have impact on negative results in tested tissue. CONCLUSION: Our data suggested that corneas may not be SARS-CoV-2 permissive if the donor was postmortem positive. Further research is required to gain more coherent insight into SARS-CoV-2 transmission via corneal transplantation.

Histopathological Features of Time-Zero Kidney Biopsy Are Predictive Factors for Posttransplant Anemia.

INTRODUCTION: Posttransplant anemia (PTA) is a common complication of kidney transplantation, associated with reduced graft survival and higher mortality. We aimed to determine the association of PTA with histopathological characteristics of time-zero allograft biopsy and donor clinical characteristics. METHODS: We conducted a retrospective, observational cohort study that included 587 patients who underwent kidney transplantation in our center. Hemoglobin levels were assessed at 6 and 12 months after transplantation, and anemia was defined according to World Health Organization criteria. The kidney allograft time-zero biopsy has been done in all investigated cases. The evaluated histopathological parameters of the kidney allografts included glomerulosclerosis, arteriolar hyalinosis (AH), vascular fibrous intimal thickening (CV), interstitial fibrosis, tubular atrophy, and interstitial fibrosis and tubular atrophy. The Banff Classification of Allograft Pathology criteria were followed to assess the allograft histopathological changes. RESULTS: The prevalence of anemia was 31.3% at 6 months after transplantation and 23.5% at 12 months. There was an association between 20-50% glomerulosclerosis and PTA in both time points, independently from estimated glomerular filtration rate. AH and interstitial fibrosis were identified as independent risk factors for anemia 6 months after transplantation. CONCLUSION: Histopathological features of time-zero kidney biopsy may be predictors of PTA. Among them, our study recognized 20-50% degree of glomerulosclerosis, AH, and CV as the most significant risk factors for PTA.

Autoantibodies in COVID-19, a possible role in the pathogenesis of the disease.

OBJECTIVES: In this study, we investigated whether SARS-CoV-2 stimulates autoantibody production. METHODS: The study included 91 patients hospitalized due to COVID 19, with no previous history of immunological diseases. Immunofluorescence assays were performed to detect antinuclear antibodies (ANAs) and antineutrophil cytoplasmic antibodies (ANCAs), along with tests for specific autoantibodies. RESULTS: The median age (57% male) was 74 years (range 38-95 years). Autoantibodies were positive in 67 (74%), ANA in 65 (71%), and ANCA in 11 (12%) patients. Female gender (p = 0.01), age (p = 0.005), and Charlson comorbidity index (p = 0.004) were significant predictors for the development of ANA/ANCA antibodies (p = 0.004). Nuclear mitotic apparatus (NuMA)-like, positivity was the strongest predictor of acute kidney injury (AKI), together with noninvasive ventilation and eGFR (χ2 = 49.01, P < 0.001). CONCLUSION: Positive autoantibodies in a large proportion of patients suggest a role of autoimmunity in the pathophysiology of acute COVID-19 disease. NuMA was the strongest predictor of AKI.

Race-free estimated glomerular filtration rate equation in kidney transplant recipients: development and validation study.

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients. DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials). PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021. MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P30 (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation. RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient's creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys. TRIAL REGISTRATION: ClinicalTrials.gov NCT05229939.

Collapsing Focal Segmental Glomerulosclerosis After Kidney Transplantation: Is It a Consequence of Viral Infections?

BACKGROUND: The aim of this case study was to explore the possible link between viral infections and collapsing focal segmental glomerulosclerosis (cFSGS) in patients who underwent kidney transplantation. METHODS: This case study included 3 case reports of patients who underwent kidney transplantation. The case reports were presented clinically and pathohistologically with cFsGS as a possible consequence of viral infections. RESULTS: The first patient developed cFSGS after polymerase chain reaction for SARS-CoV2 was positive twice. He gradually developed terminal stage chronic kidney disease. The second patient developed cFSGS with high range proteinuria after cytomegalovirus infection, which has been treated with 3 lines of antiviral medicaments. The third patient developed cFSGS as a possible consequence of hepatitis B virus infection. CONCLUSIONS: This case study highlighted the importance of viral etiology in the pathway of cFSGS. Pathogenic links between viral infections and concomitant glomerulopathies are challenging, especially in immunocompromised transplanted patients.

Association of multiple retinal nodular hamartomas and "confetti" skin lesions with end-stage renal disease in patients with tuberous sclerosis.

PURPOSE: The main purpose of this study is to explore characteristics of patients with chronic kidney disease in tuberous sclerosis (TSC) and to underline differences in clinical characteristics between end-stage renal disease (ESRD) patients and patients in earlier stages of chronic kidney disease. METHODS: This multicentric, retrospective study included data for 48 patients from seven South-Eastern European countries (Albania, Bosnia and Herzegovina, Croatia, Greece, Montenegro, Serbia, Slovenia) in the period from February to August 2020. Researchers collected data from local and national nephrological and neurological registries and offered clinical and laboratory results from medical histories in follow-up periods. RESULTS: This study enrolled 48 patients with a median age of 32.3 years (range, 18-46 years), and predominant female gender (60.45%). The percentage of patients with chronic kidney disease (CKD) diagnosis of the total number of patients was 66.90%, with end-stage renal disease development in 39.6%. The most prevalent renal lesions leading to chronic kidney disease were angiomyolipomas (AMLs) in 76.6%, while multiple renal cysts were present in 42.6% of patients. Nephrectomy was performed in 43% of patients, while the mTOR inhibitors were used in 18 patients (37.5%). The majority of patients had cutaneous manifestations of tuberous sclerosis-83.30% had hypomelanotic cutaneous lesions, and 68.80% had angiofibromas. Multiple retinal nodular hamartomas and "confetti" skin lesions were more frequent in end-stage renal disease (ESRD) than in patients with earlier stages of chronic kidney disease (p-0.033 and 0.03, respectively). CONCLUSION: Our study has also shown that retinal hamartomas and "confetti" skin lesions are more frequent in end-stage renal diseases (ESRD) patients than in other chronic kidney disease (CKD) patients. Usage of mTOR inhibitors can also reduce the number of complications and associated with tuberous sclerosis, such as dermatological manifestations and retinal hamartoma, which are more common in the terminal stage of chronic kidney disease.

Kidney Transplantation in Patients With the History of SARS-CoV-2 Infection.

BACKGROUND: The aim of this study is to present the experience and results of kidney transplantation in patients with the history of SARS-CoV-2 infection. METHODS: We retrospectively analyzed waitlisted patients who had a history of SARS-CoV-2 infection and offered a kidney transplant between March 2020 and December 2021. RESULTS: Of the 97 waitlisted potential kidney transplant recipients who were offered a kidney, 13 (13.4%) had a history of SARS-CoV-2 infection. All patients were tested negative for SARS-CoV-2 at the time of the kidney offer. Successful transplantation was performed in 9 patients (5 male; average age was 40.8 years), with the average time between SARS-CoV-2 infection and transplantation of 8 months. Four of 13 patients with a history of SARS-CoV-2 infection were finally not transplanted, with 2 patients not eligible for transplantation due to significant post-COVID findings in routine pretransplant chest CT scans, and 2 patients were not transplanted because of poor donor organ quality. CONCLUSIONS: Kidney transplantation after SARS-CoV-2 infection is possible in a setting of full recovery from acute infection, negative PCR test, and no pneumonic infiltrates on chest CT scan. A growing number of waitlisted patients with a history of SARS-CoV-2 infection imposes the need for decision-making tools and guidelines for risk/benefit assessment in these patients.