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.

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.

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.

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.

Successful Kidney Transplantation From A Donor With Inherited Thrombophilia: A Case Report.

Inherited thrombophilia is a blood clotting disorder caused by genetic mutations of specific coagulation plasma factors. It is a well-established predisposing factor for venous as well as arterial thromboembolism. Thromboembolic events with renal involvement in patients with inherited thrombophilia are possible but relatively rare. On the other hand, vascular complications, including renal artery and vein thrombosis, are the main causes of early graft loss after kidney transplantation. Furthermore, there is evidence that inherited thrombophilia has a role in chronic kidney disease development. Although there are data on kidney transplantation of recipients with inherited thrombophilia, to the best of our knowledge there are no reports on kidney donation from patients with thrombophilia in the English literature. We present 2 cases of successful kidney transplantation from the same donor with inherited thrombophilia.

Hospitalization and death after recovery from acute COVID-19 among renal transplant recipients.

INTRODUCTION: Data on post-COVID-19 in renal transplant recipients (RTR) is scarce. We investigated the rate of hospitalizations, reasons for hospital admission, and mortality rate among RTR who survived acute COVID-19. METHODS: A multi-center retrospective observational cohort study measured hospital admission and death to 180 days after acute SARS-CoV-2 infection in 308 adult patients. RESULTS: The median age was 57 years, 64.9% were male. All patients had at least one comorbidity, and 26.3% had diabetes. Data on post-COVID-19 course was available for 267 patients, and 49 of them (15.9%) required hospital treatment after recovery from the acute infection. The most common indications included pneumonia (24.5%) and renal allograft dysfunction (22.4%), 7 (14.3%) had sepsis and 5 (10.2%) had thrombotic events. A median duration of the hospital stay was 12 days. Six patients (2.2%) died due to multiorgan failure, respiratory insufficiency or urosepsis. The strongest predictor for hospitalization after acute COVID-19 was hospitalization for acute SARS-CoV-2 infection, while better allograft function decreased the probability of hospitalization. CONCLUSION: Delayed consequences of acute COVID-19 are highly prevalent and the health care systems should be prepared to respond to the needs of RTR suffering from post-COVID-19 complications.

Histopathologic findings on indication renal allograft biopsies after recovery from acute COVID-19.

Current knowledge on histopathological changes occurring after COVID-19 in transplanted kidneys is limited. Herein, we present renal allograft pathology findings in patients recovered from COVID-19. Six patients underwent indication biopsy, and one required allograft nephrectomy after acute COVID-19. Demographic data, clinical characteristics, and laboratory findings were recorded. The histopathological analysis included light microscopy, immunostaining, and electron microscopy. Five patients were hospitalized for acute COVID-19, and all were diagnosed with imaging-confirmed pneumonia, one requiring mechanical ventilation, and two requiring dialysis. Two patients had mild form. Histopathologic examination of renal allograft specimens revealed collapsing, perihilar, tip-lesion and secondary FSGS in one patient each. One patient had borderline acute cellular rejection, and two had chronic antibody-mediated rejection. Histopathologic changes of glomerular tufts were accompanied by acute tubular injury in four patients. None of our patients had signs of viral inclusions in kidney cells. One patient died and one remained dialysis-dependent after the good initial response to treatment. Patients with collapsing and perihilar FSGS had further progression of their chronic allograft nephropathy still without need for dialysis. In conclusion, diverse kidney pathology may be found in SARS-CoV-2-infected renal transplant patients. It seems that viral infection may affect the immune system with triggering of glomerular diseases, while the acute tubular injury is of multifactorial etiology. Direct viral effect is less likely.

Follow-up of renal transplant recipients after acute COVID-19-A prospective cohort single-center study.

INTRODUCTION: Although most patients recover within several weeks after acute COVID-19, some of them develop long-lasting clinical symptoms. Renal transplant recipients have an increased mortality risk from COVID-19. We aimed to describe complications occurring after COVID-19 in this group of patients. METHODS: A prospective single-center cohort study was conducted at University Hospital Centre Zagreb. Patients with two negative reverse transcriptase-polymerase chain reaction (RT-PCR) tests for SARS-CoV-2 after COVID-19 were eligible for further follow-up at our outpatient clinic. They underwent detailed clinical and laboratory assessments. The primary outcome was the development of complications after COVID-19. RESULTS: Only 11.53% of renal transplant recipients who survived acute COVID-19 were symptomless and free from new-onset laboratory abnormalities during the median follow-up of 64 days (range: 50-76 days). Three patients died from sepsis after discharge from the hospital. In 47 patients (45.2%), clinical complications were present, while 74 patients (71.2%) had one or more laboratory abnormalities. The most common clinical complications included shortness of breath (19.2%), tiredness (11.5%), peripheral neuropathy (7.7%), self-reported cognitive impairments (5.7%), and dry cough (7.7%). Most common laboratory abnormalities included shortened activated partial thromboplastin time (50%), elevated D-dimers (36.5%), elevated fibrinogen (30.16%), and hypogammaglobulinemia (24%). Positive RT-PCR for cytomegalovirus (8.7%), Epstein-Barr virus (26%), or BK virus (16.3%). Multivariate analysis identified the history of diabetes mellitus and eGFR CKD-EPI as predictors for the development of post-COVID clinical complications. Six months after acute COVID-19, elevated D-dimers persisted with normalization of other laboratory parameters. Twenty-nine patients were hospitalized, mostly with several concomitant problems. However, initially reported clinical problems gradually improved in the majority of patients. CONCLUSION: Post-COVID-19 clinical and laboratory complications are frequent in the renal transplant population, in some of them associated with significant morbidity. All patients recovered from acute COVID-19 should undergo long-term monitoring for evaluation and treatment of complications.

Novel Oral Anticoagulants in Renal Transplant Recipients: A Retrospective Cohort Study.

AIM: Data on the use of novel anticoagulant drugs (NOACc) in renal transplant recipients is scarce. The aim of our study was to investigate the safety and efficacy of NOACs in renal transplant recipients. MATERIALS AND METHODS: In a single-centre retrospective cohort study we assessed adverse reactions, thromboembolic events, and interactions of calcineurin inhibitors in patients treated with NOACs. RESULTS: Twenty-three renal transplant recipients were treated with NOACs (70% male), mean age of 65.8 ± 1.8 years. Fourteen (61%) patients were treated with rivaroxaban, apixaban was given to 8 (35%) of our patients, and dabigatran to one patient (4%). The main indications for NOAC therapy was atrial fibrillation in 61% and deep venous thrombosis in 23% of patients. Bleeding occurred in 2 patients (1 treated with rivaroxaban and 1 with dabigatran). None of our patients developed thrombosis while treated with NOAC. During the median follow-up of 24 months graft function, as well as hematological parameters, remained stable in patients that were treated with rivaroxaban and apixaban, while dabigatran was ceased after a month of therapy due to a bleeding event. CONCLUSION: Our results show that both rivaroxaban and apixaban are safe and efficient oral anticoagulant drugs in renal transplant patients. Additional studies are needed to prove these results.

Cardiorenal Syndrome in Renal Transplant Recipients: Prevalence, Clinical Presentation, Treatment, and Outcome.

BACKGROUND: Data on the cardiorenal syndrome (CRS) in renal transplant recipients (RTR) are scarce. We investigated the prevalence, clinical presentation, treatment, and outcomes of patients with CRS in our renal transplant cohort. METHODS: Charts and medical records of adult RTR were investigated to identify patients with renal allograft dysfunction and heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction. RESULTS: From December 2009 to December 2019, a total of 1,610 patients received a kidney allograft at our institution. CRS was diagnosed in 9 patients (0.56%) a median of 11 years after transplantation (4-20 years). Seven of the patients were male, and 2 were female. The median age when CRS was diagnosed was 71 years (64-80 years). The major presenting symptom was dyspnea. Five patients had HFrEF, and 4 had HFpEF. The patient's median basal creatinine clearance was 37 mL/min (range 29-77 mL/min). At hospitalization, it was decreased to 24 mL/min (range 13-45 mL/min). The patients were treated with diuretics, but 5 of them required extracorporeal fluid removal. At the 16-month follow-up (median), all patients with HFpEF were alive and had returned to initial levels of creatinine clearance. Two of the 5 HFrEF had died, and 2 needed permanent extracorporeal water removal. CONCLUSION: CRS after renal transplantation was rare (<1.0%), but CRS in HFreF patients was associated with a poor outcome.

Central nervous system infections in renal transplant recipients.

BACKGROUND: The aim of this study is to determine the incidence, etiology, clinical characteristics, and outcomes of renal transplant recipients diagnosed and treated for central nervous system (CNS) infection at our institution. METHODS: We analyzed data from all renal transplant recipients between January 2007 and December 2019 that were diagnosed and treated for CNS infections at our institution. RESULTS: Of 1374 patients who received renal allografts, 13 were diagnosed with CNS infections (9 males), with a mean age of 53.5 years. Patients were diagnosed with CNS infections between 2 months and 11 years after the transplantation. Causative agents included JC virus, Streptococcus pneumoniae, Cryptococcus neoformans, Herpes zoster virus, Mycobacterium tuberculosis, Listeria monocytogenes, and West Nile virus. One patient had concomitant Nocardia and Neisseria infection. Immunosuppression was reduced in all patients. The patient with JC encephalitis and the patient with concomitant Neisseria and Nocardia meningitis died. One patient was returned to dialysis. Other patients recovered with differing levels of neurologic sequelae. CONCLUSION: Central nervous system infections in renal transplant recipients are rare. However, they are associated with significant morbidity and mortality. A high level of awareness is needed: neurological symptoms may be nonspecific and caused by non-infectious conditions related to the underlying disease, or side-effects of immunosuppressive drugs.

A Comparison of Different Valgancyclovir Formulations in the Universal 6-Month Prophylaxis Against CMV Infection in Renal Transplant Recipients: A Randomized Single-Centre Study.

INTRODUCTION: Cytomegalovirus (CMV) is the most common opportunistic infective pathogen in kidney transplant recipients. Valganciclovir (VAL) is commonly used for prophylaxis, especially in high-risk recipients. Generic VAL formulations have become available, but the data about their safety and efficacy are lacking. METHODS: Consecutive de novo kidney transplant patients were randomized to generic VAL Valganciklovir Teva® (VT group)(24 patients) or Alvanocyte® (A group), Alvogen (19 patients) or to Valcyte® (V group), Roche (23 patients) in a 18-month open-label study. Universal prophylaxis was used for 6 months after the transplantation. CMV DNA levels were measured at 1,3,6,9,12 and 18 months after the transplantation. All positive measurements of CMV DNA were recorded. RESULTS: Groups did not differ regarding the clinical characteristics or the risk for developing CMV infection in the post-transplant period. CMV replications were most common at 9 months after the transplantation with rates of 9% for the V, 13% for the VT and 26% for the A group (p=0.26). At 12 months, positive CMV DNA was recorded in 22%, 8% and 11 % of patients taking V, VT and A, respectively (p=0.37). Rates of biopsy-proven acute rejection, adverse events, and serious adverse events were similar for all formulations. Lymphocele occurred most commonly in the V group (35%) compared to 17% in VT and 17% in the A group (p=0.23). One patient from each of the A and VT groups developed CMV disease. Additionally, they were the only two patients with CMV DNA copies above 656 IU/ml. Glomerular filtration rates were similar in all groups at all time points, while proteinuria was significantly higher at 12 months in patients who received V 0.32 g/day (0.18 - 0.42), compared to patients on VT 0.2 (0.1 - 0.2), or A 0.2 (0.2 - 0.3), p=0.04. CONCLUSION: Valgancyclovir efficacy and safety in this limited data set is similar with early administration of V, VT and A after kidney transplantation. Additional studies aimed at elucidating the effectiveness of this treatment regimen in patients who are at high risk for developing CMV infection are necessary to draw further conclusions.

BMP-7 PROTEIN EXPRESSION IS DOWNREGULATED IN HUMAN DIABETIC NEPHROPATHY.

Bone morphogenetic protein-7 (BMP-7) is expressed in all parts of the normal kidney parenchyma, being highest in the epithelium of proximal tubules. It protects kidney against acute and chronic injury, inflammation and fibrosis. Diabetic nephropathy is the leading cause of chronic kidney disease, and is characterized by decreased expression of BMP-7. The aim of our study was to analyze whether the expression of BMP-7 is significantly changed in advanced stages of human diabetic nephropathy. Immunohistochemical analysis of the expression of BMP-7 was performed on archival material of 30 patients that underwent renal biopsy and had confirmed diagnosis of diabetic nephropathy. Results showed that BMP-7 was differently expressed in the cytoplasm of epithelial cells of proximal tubules and podocytes among all stages of diabetic nephropathy. At early stages of diabetic nephropathy, BMP-7 was strongly positive in proximal tubules and podocytes, while low expression was recorded in the majority of samples at advanced stages. In conclusion, increased expression of BMP-7 at initial stages of diabetic nephropathy with subsequent decrease at advanced stage highlights the role of BMP-7 in the protection of kidney structure and function. Further investigations should be focused on disturbances of BMP-7 receptors and signaling pathways in patients with diabetic nephropathy.