Disorder In Renal Transplant Recipients Research Articles

P8.038: Prevalence of Genetic Mutations Associated With Kidney Disorders in Renal Transplant Recipients – Single Centre Experience

Introduction: End-stage renal disease (ESRD) of undetermined etiology is highly prevalent and constitutes a significant clinical challenge, particularly in the context of kidney transplantation. Underlying renal conditions leading to ESRD are extremely heterogeneous and the prevalence of hereditary nephropathies among adults with ESRD is less known. To date, less than 10% of adult ESRD is thought to be genetic. Genetic analysis often reveals the cause of kidney failure in patients with unknown kidney disease. For patients awaiting renal transplantation, genetic testing prior to kidney transplant may help to understand the outcome in these patients. We studied the prevalence of genetic mutations related to kidney disease in renal transplant (RTx) recipients. Methods: It was a Single Centre, Observational, Cohort Study. Between October 2019 & July 2021, 123 RTx recipients were analyzed using Multiplex Ligation-dependent Probe Amplification (MLPA) and clinical exome sequencing for mutations related to kidney disease. Results: Mean age was 36±12 years, 96 (78%) were Males. 88 (71.5%) were undetermined and 35 (28.4 %) had established cause of CKD. 8 patients had structural or hereditary kidney disease and 27 were non-hereditary including DKD, Glomerulopathy, Obstructive uropathy and CTID diagnosed by kidney biopsy and clinical and radiological presentations. 17/88 (19.3%) patients with undetermined CKD on renal biopsy showed Glomerulosclerosis (6), CGN (8) & TMA (2). one had advanced renal damage. 32/88 (36.36%) patients had genetic mutations related to kidney disease. 20 were structural congenital or hereditary kidney disease & 10 had a mutation for Glomerulopathies. Mutations related to complement regulatory genes were found in 84/123 (68.2%). 6 patients had congenital or hereditary kidney disease, 12 were DKD, 5 were Glomerulopathy, 2 had Obstructive Kidney disease and 1 had CTID. Homozygousity and heterozygosity were seen in 14 (16.8%) and 10 (12%) patients respectively. 67/88 (80.7%) also showed CFHR1/CFHR3 gene complex duplication, reported as a variant of uncertain significance. 1 patient had a mutation for the PLG gene, previously been implicated in the pathogenesis of ahus. Conclusion: This study demonstrates 82.9% (102/123) prevalence of the genetic mutation in RTx recipients. Genetic analysis provides the etiology in 35 patients with undetermined kidney disease. The significance of complementary regulatory gene related mutation remained uncertain.

Posttransplant lymphoproliferative disorder in renal transplant recipients: Experience from a Tertiary Care Center.

Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal complications arising after solid organ or hematopoietic stem cell transplant. The most crucial factor in pathogenesis of PTLDs is either a primary infection with Epstein-Barr virus or reactivation of its latent state due to immune dysregulation. This complex pathobiology leads to a myriad of clinical manifestations due to uncontrolled lymphoproliferation that may be reactive, polymorphous or monomorphous. We report our experience at a tertiary center of six cases detected over a span of six years. All our patients were proven as high grade B-cell lymphoma on histopathology, which remains the gold standard for diagnosis. Two cases were of primary central nervous system lymphoma, two had disseminated disease, fifth showed allograft involvement, and last case presented with gastrointestinal obstruction. All the patients were managed with reduction of immunosuppression, chemotherapeutic agents, and rituximab. Five patients responded well with a follow-up period of 3-28 months since the time of treatment initiation and had preserved renal function with no episodes of disease recurrence or allograft rejection.

Using the Asseco Medical Management Solutions Program to Monitor Patients After Kidney Transplantation

IntroductionIn Poland there is an average of 2.31 doctors per 1000 population (according to the Organization of Economic Cooperation and Development 2016), which is one of the lowest results in all of the European Union countries. With the persistent low number of specialists, the quantity of patients and their medical records keep increasing. In order to facilitate the work of doctors and to improve monitoring of the patients, most medical institutions decided to implement IT systems. At the Department of General and Transplant Surgery of Pomeranian Medical University in Szczecin, we have been using the Asseco Medical Management Solutions (AMMS) system for 5 years. The aim of this study was to evaluate the usefulness of the AMMS system in monitoring and early detection of disorders in renal transplant recipients. Materials and methodsThe retrospective study included 100 patients who underwent surgical treatments between 2012 and 2017. By analyzing the results of laboratory tests (ie, complete blood count), the concentration of creatinine and urea, potassium, and the doses of immunosuppressive drugs, we evaluated the usefulness of the AMMS system. ResultsThe clinical usefulness of the AMMS system related to the evaluation of predictors of early graft dysfunction has been confirmed. We have saved time in the analysis of medical records. ConclusionsThe AMMS system improved the management of medical records of patients after surgeries and allowed for the retrospective evaluation of the treatment and its immediate modification. The unification of medical IT systems in Poland would increase the availability of patients' data and support information transfer among all medical institutions. It would enable multifacility scientific meta-analysis.

Skin disorders in renal transplant recipients: a retrospective study.

BackgroundImmunosuppressive therapy, which is necessary to avoid graft rejection in renal transplant recipients, presents an increased risk of several pathologies, namely infectious and neoplastic.ObjectivesTo identify the most frequent skin diseases and their clinical and demographical risk factors within a population of renal transplant recipients.MethodsA retrospective study of renal transplant recipients referred to dermatology visit and observed for the first time from January 2008 to December 2014.ResultsThe study included 197 patients, 120 men (60,9%). Mean age was 50,7 years (±13,4). 12 patients (6,1%) had previous skin cancer. Infections were the most frequent reason of referral (93/197; 44%). From the total referred, 18,3% (36/197) presented pre-cancerous lesions. Malignancy was diagnosed in 36 patients (18,3%), with 29 non-melanoma skin cancers (14,7%) and 7 Kaposi sarcomas (3,6%). Ratio of basal cell carcinoma to squamous cell carcinoma was 1,1:1. Non-melanoma skin cancer was significantly associated with older age (p = 0,002), male gender (p = 0,028), history of previous skin cancer (p = 0,002) and higher duration of immunosuppressive therapy (p<0,001).Study limitationsRetrospective study, with data from the first visit in dermatology. We didn't made classification on skin-types.ConclusionsThe great incidence of cutaneous infections and skin cancer is responsible for a significant morbidity. It is important to assure the regular dermatological follow-up of renal transplant recipients, which will promote the prevention, an early diagnosis and an efficient treatment.

Management of mineral and bone disorders in renal transplant recipients.

The management of post-transplantation bone disease is a complex problem that remains under-appreciated in clinical practice. In these patients, pre-existing metabolic bone disorder is further impacted by the use of immunosuppressive medications (glucocorticoids and calcineurin-inhibitors), variable post-transplantation renal allograft function and post-transplantation diabetes mellitus. The treatment of post-transplantation bone loss should begin pre-transplantation. All patients active on transplant waiting lists should be screened for bone disease. Patients should also be encouraged to take preventative measures against osteoporosis such as regular weight-bearing exercise, smoking cessation and reducing alcohol consumption. Biochemical abnormalities of disordered mineral metabolism should be corrected prior to transplantation wherever possible, and because these abnormalities commonly persist, post transplant hypophosphatemia, persistent hyperparathyroidism and low vitamin D levels should be regularly monitored and treated. Bone loss is greatest in the first 6-12months post-transplantation, during which period any intervention is likely to be of greatest benefit. There is strong evidence that bisphosphonates prevent post-transplantation bone loss; however, data are lacking that this clearly extends to a reduction in fracture incidence. Denosumab is a potential alternative to vitamin D receptor agonists and bisphosphonates in reducing post-transplantation bone loss; however, further studies are needed to demonstrate its safety in patients with a significantly reduced estimated glomerular filtration rate. Clinical judgement remains the cornerstone of this complex clinical problem, providing a strong rationale for the formation of combined endocrinology and nephrology clinics to treat patients with Chronic Kidney Disease-Mineral and Bone Disorder, before and after transplantation.

Post-transplant Hyperuricemıa as a Cardıovascular Risk Factor

PurposeUric acid is known to impair endothelial cell function and to stimulate the development of renal interstitial fibrosis. The aim of this study was to evaluate the association between first-year hyperuricemia with graft dysfunction and the development of cardiovascular risk disorders in renal transplant recipients. MethodsOne hundred kidney transplant recipients (31 female, 45.9 ± 9.6 post-transplantation months) with normal graft functions were enrolled. The clinical biochemical parameters in the first post-transplantation year were retrospectively recorded and searched for the predictive value in yearly determined graft function and association with cross-sectionally analyzed cardiovascular parameters, including body composition analyses, ambulatory blood pressure monitoring data, and pulse wave velocity. Hyperuricemia was defined as an uric acid level of ≥ 6.5 mg/dL that persisted for at least 2 consecutive tests. ResultsOne year after transplantation, 37% of subjects had hyperuricemia. According to cross-sectional data, sagittal abdominal diameter (P = .002) and hip circumferences (P = .013) were significantly higher in hyperuricemic patients than in normouricemic ones. Hyperuricemic patients had higher fat (P = .014) and muscle mass (P = .016) than normouremic patients. Hyperuricemic patients had significantly higher mean systolic BP (P = .044) than normouremic patients. Hyperuricemic patients had significantly higher pulse wave velocity levels (P = .0001) and left ventricular mass index (P = .044) than normouremic patients. The yearly decline in estimated glomerular filtration rate levels was significantly higher in hyperuricemic patients (P = .0001) than in normouricemic ones. ConclusionPost-transplantation hyperuricemia is associated with hypertension, arterial stiffness, and dyslipidemia; it should be accepted not only as a marker for renal allograft dysfunction but also as a cardiovascular risk factor in renal transplant recipients.

N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP) Assessment in the First Year After Renal Transplantation and Its Relationship With Graft Function and Left Ventricular Hypertrophy

BackgroundNT-proBNP is a natriuretic neurohormone released mainly from ventricular cardiomyocytes in conditions of volumetric or pressure overload; it is suitable for use as a marker of left ventricular hypertrophy (LVH), a common disorder in renal transplant recipients. The study objective here was to assess NT-proBNP levels in the 1st year after renal transplantation (RT) and its relationship with graft function and LVH. MethodsSixty patients (age, 49 ± 16.9 y; male, 58%) were subjected to prospective 1-year follow-up. Basic blood tests and NT-proBNP level measurements were performed twice (in the early period and at 1 year after transplantation). Cardiac echography was performed in 40 patients. LVH was diagnosed when left ventricular mass index was >95 g/m2 in women and >115 g/m2 in men. Statistical analyses were performed with the use of the R Package. ResultsAt 1 year after RT, the NT-proBNP level decreased >2-fold compared with the early period (median 171 pg/mL [interquartile range (IQR), 104.5–283] vs 368 pg/mL[IQR, 170–629]; P = .00008). In the early post-transplantation period, NT-proBNP correlated with the patient's age, body mass index, estimated glomerular filtration rate (eGFR), and left ventricular end-diastolic dimension, and at 1 year after transplantation its correlation with the eGFR range (patients with eGFR ≥60 mL min−1 1.73 m−2 had significantly lower NT-proBNP levels than those with eGFR <60 mL min−1 1.73 m−2), with age,and with ejection fraction was found. Patients with LVH had higher NT-proBNP levels than those without LVH in the early period (median 511 pg/mL [IQR, 190–736] vs 380 pg/mL [IQR, 217–511]; P = .09), and at 1 year (median 269 pg/mL [IQR, 155–474] vs 133 pg/mL [IQR, 99–134]; P = .057). At NT-proBNP >480 pg/mL in the early period and >280 pg/mL at 1 year, LVH occurred with a 68% probability (P = .05 and P = .03, respectively). ConclusionsDuring the 1st year after RT, NT-proBNP levels decrease ≥2-fold and are primarily related to eGFR. NT-proBNP measurements are useful in identifying patients with LVH.

Hyperuricemia as a Cardiovascular Risk Factor in Renal Transplant Recipients.

Purpose: Uric acid is known to impair endothelial cell function and to stimulate the development of renal interstitial fibrosis and the production of inflammatory cytokines. The aim of this study is to evaluate the association between hyperuricemia with graft dysfunction and development of cardiovascular risk disorders in renal transplant recipients. Methods: One hundred kidney transplant recipients (31 female, 38.7±11 years with 45.9±9.6 months post-transplantation period) with normal graft functions (creatinine <2mg/dl) were enrolled. The clinical biochemical parameters including the uric acid levels in the third year of post transplantation period were retrospectively recorded and searched for the association in yearly determined graft function and cardiovascular parameters including body composition analyses, ambulatory blood pressure monitoring data (ABPM), pulse wave velocity (Pwv). Hyperuricemia was defined as uric acid level of ≥ 6.5 mg/dl that persisted for at least two consecutive tests. Results: Hyperuricemia was 37% at the third year after transplantation. Hyperuricemic patients (n:27) had significantly higher glucose (p:0.037), LDL (p:0.037), triglyceride (p:0.042), total cholesterol (p:0.007)and PTH (p:0.003) levels than normouricemic patients. According to antropoemetric data sagittal abdominal diameter (p:0.002), triceps skin fold thickness (p:0.022), waist (p:0.001) and hip circumferences (p:0.013);body weight (p:0.001), fat mass (p:0.014), muscle mass (p:0.016), visceral fat rating (p:0.001)and BMI (p:0.001)were significantly higher in hyperuricemics than normouremic patients. Hyperuricemic patients had significantly higher mean systolic BP (p:0.044), day-time mean systolic BP (p:0.022), night time mean systolic BP (p:0.031), day-time and night time mean arterial pressure than normouremic patients according to ABPM data. Hyperuricemic patients had significantly higher PWv levels (p:0.0001) and LVMI (p:.044) than normouremic patients. Yearly decline in eGFR levels were significantly higher in hyperuricemic patients (7.6% vs. 9.6%, p:.0001) than normouricemic ones. Conclusions: Post-transplant hyperuricemia had a strong impact on decline in renal function and associated with cardiovascular risk predictors as hypertension, arterial stiffness and left ventricular hypertrophy.

Mucocutaneous disorders in renal transplant recipients receiving sirolimus‐based immunosuppressive therapy: a prospective, case–control study

Sirolimus (SRL) has some dermatologic complications including acneiform eruptions, edema, aphthous ulceration, and onychopathy. However, controlled studies reporting the prevalence and clinical characteristics of mucocutaneous disorders are scarce. To investigate the prevalence and clinical spectrum of mucocutaneous disorders in renal transplant recipients (RTRs) receiving SRL and to compare the findings with those in RTRs not receiving SRL. Fifty RTRs (35 men, 15 women; mean age, 34.6 ± 11.6 yr) receiving SRL, 50 RTRs (36 men, 14 women; mean age, 34.4 ± 11.3 yr) not on SRL were screened for mucocutaneous disorders. In RTRs receiving SRL, skin infection (78%) was the most common dermatologic disorder followed by facial hyperpigmentation (50%) and acneiform eruption (46%). Herpes simplex virus infections (14%) and seborrheic dermatitis (38%) were significantly more common in RTRs on SRL (p < 0.05); the frequencies of edema, aphthous ulceration, acne, and longitudinal nail ridging were similar in both groups (p > 0.05). This study had a small sample size. The investigator was not blinded to immunosuppressive treatment protocols. Renal transplant recipients receiving SRL are more likely to develop seborrheic dermatitis and herpes simplex virus infections than those not taking SRL. Whereas, they are not more prone to edema, aphthous ulceration, acne, or longitudinal nail ridging.

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Dyslipidemia following kidney transplantation: Diagnosis and treatment

Lipid abnormalities are a common complication of kidney transplantation, occurring in up to 60% of patients. In fact, impairment of lipid metabolism is often present before renal transplantation due to the uremic state. After transplantation and recovery of renal function, lipid disturbances usually persist but show a different profile due to the various effects of immunosuppressive drugs on lipid metabolism. Actually, steroids, calcineurin inhibitors, and mammalian target of rapamycin inhibitors usually lead to quantitative and qualitative abnormalities of very low-density, low-density, and high-density lipoproteins. As cardiovascular diseases remain the leading cause of death in renal transplant recipients, management of dyslipidemia and other traditional risk factors, such as smoking, arterial hypertension, diabetes mellitus, and obesity, is of great importance to prevent cardiovascular complications and chronic allograft dysfunction. This review addresses the causes of dyslipidemia, the role of immunosuppressive drugs, and current recommendations to manage lipid disorders in renal transplant recipients.

Posttransplantation Lymphoproliferative Disorders in Renal Transplant Recipients: Report of Over 20 Years of Experience

Introduction Despite the benefits of immunosuppressive medications to improve graft function, they have several adverse effects, such as development of neoplasms in renal transplant recipients. Posttransplantation lymphoproliferative disorders (PTLDs) are not uncommon complications, so we conducted a study to evaluate the characteristics of affected patients. Methods We enrolled 2117 kidney recipients from June 1984 to March 2004 in order to find pathological and clinical evidence of neoplasms. We collected and analyzed all data on PTLD patients. Results Overall there were 46 recipients with different types of neoplasms, among which the most common types were diseases of the skin (24 cases, 52.2%), Kaposi’s sarcoma (15 cases, 32.6%), and PTLD (14 cases, 30.4%). The mean (± SD) age of PTLD patients at the time of transplantation was 37.86 ± 9.67 years and 42.8% were women. Median and mean (± SD) time interval to PTLD diagnosis were 38.5 and 50.35 ± 41.7 months, respectively (range 1 to 146 months). Types of PTLD in these patients were kidney lymphoma (14.3%); gastrointestinal (14.3%); brain lymphoma; tonsils; palatine; Hodgkin’s lymphoma, large cell lymphoma, and acute lymphoblastic lymphoma (each 7.1%), with 28.6% unspecified types. The 1-, 5-, and 10-year patient survival rates after transplantation were 71.4%, 51.4%, and 44.3%, respectively. Despite discontinuing immunosuppressive therapy in PTLD patients, five of six surviving had graft function up to a mean time of 105.4 ± 57.6 months after transplantation. Conclusion Our findings showed that the prevalence of PTLD was 0.66%, which was less than reports from Western countries. The fact that there were surviving grafts for a considerable time despite discontinuing immunosuppressive therapy is of great importance.

Ganciclovir and Acyclovir Reduce the Risk of Post‐Transplant Lymphoproliferative Disorder in Renal Transplant Recipients

Given its association with Epstein-Barr virus (EBV), there is considerable interest in assessing the impact of prophylactic anti-viral therapy on post-transplant lymphoproliferative disorder (PTLD). A recently completed multi center case-control study assessed the impact of immunosuppressive therapy on PTLD risk among renal transplant patients and collected information on the use of anti-viral therapy. Biopsy-confirmed PTLD cases (n = 100) were matched to 375 controls by center, date of transplant, and age. Data were collected on immunosuppression and rejection therapies, demographics, pre-transplant viral status, number of rejections, and anti-viral use. With adjustment for known risk factors, prophylactic anti-viral use was associated with up to 83% reduction in the risk of PTLD, depending on the anti-viral agent. These results were stronger for the first year post-transplant. For every 30 days of ganciclovir treatment, risk of PTLD during the first year was lower by 38% (Odds Ratio [OR]= 0.62; 95% confidence interval [CI]= 0.38-1.0); acyclovir effects were less striking (OR = 0.83; 95% CI = 0.59-1.16). Anti-viral therapy appears to play a role in reducing the risk of PTLD in renal transplant patients. Ganciclovir may be more potent than acyclovir.

Analysis of Factors that Influence Survival with Post-Transplant Lymphoproliferative Disorder in Renal Transplant Recipients: The Israel Penn International Transplant Tumor Registry Experience

Significant mortality is associated with post-transplant lymphoproliferative disorder (PTLD) in kidney transplant recipients (KTX). Univariate/multivariate risk factor survival analysis of US PTLD KTX reported to Israel Penn International Transplant Tumor Registry from November 1968 to January 2000 was performed. PTLD presented 18 (median) (range 1-310) months in 402 KTX. Death rates were greater for those diagnosed within 6 months (64%) versus beyond 6 months (54%, p = 0.04). No differences in death risk for gender, race, immunosuppression, EBV, B or T cell positivity were identified. Death risk increased for multiple versus single sites (73% vs. 53%, hazards ratio (HR) 1.4). A 1-year increase in age increased HR for death by 2%. Surgery was associated with increased survival (55% vs. 0% without surgery) (p < 0.0001). Patients with allograft involvement, treated with transplant nephrectomy alone (n = 20), had 80% survival versus 53% without allograft removal (n = 15) (p < 0.001). Overall survival was 69% for allograft involvement alone versus 36% for other organ involvement plus allograft (n = 19 alive) (p < 0.0001). Death risk was greater for multiple site PTLD and increasing age, and risks were additive. Univariate analysis identified increased death risk for those not receiving surgery, particularly allograft involvement alone.

Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin

Introduction After renal transplantation, the incidence of premalignant and malignant skin lesions is high. Treatment with acitretin improves the number and aspect of actinic keratoses and appears to reduce the incidence of squamous cell carcinomas, but treatment is hampered by frequent side effects. No optimal long-term dosing advice is available. Methods A total of 26 long-term renal transplant recipients were randomized to 1-year treatment with acitretin, either 0.4 mg/kg/d throughout the whole year or 0.4 mg/kg/d during the first 3 months followed by 0.2 mg/kg/d for the remaining 9 months. At 9 different time points, the number of actinic keratoses and tumors was counted, and erythema and thickness of the lesions, and severity of side effects were scored. Patient's judgment was recorded using visual analog scores. Results In both groups, the number of actinic keratoses decreased by nearly 50%, but the number of new malignant tumors during the study year was similar to the number of tumors in the year before the study. Thickness of the keratoses decreased significantly in both groups. Acitretin dose had to be reduced in most patients because of the frequent occurrence of mucocutaneous side effects, such as cheilitis, excessive peeling of the skin, and hair disorders. In the 14 patients randomized to continuous treatment with a dose of 0.4 mg/kg/d, this dose could be maintained in 3 of 14 patients only. Temporary interruption of acitretin therapy was necessary in 7 of 26 patients. Patients' contentment about the aspect of their skin increased significantly, with no differences between groups. Conclusions Acitretin therapy decreased the number of actinic keratoses in renal transplant recipients at a low maintenance dose of 0.2 mg/kg/d and significantly decreased the degree of thickness of the lesions. However, the incidence of new skin malignancies remained unchanged. Despite the high incidence of mucocutaneous side effects, patient's contentment with the aspect of their skin increased significantly.

Increased susceptibility for CsA-induced hepatotoxicity in kidney graft recipients with chronic viral hepatitis C.

CsA-induced hepatotoxicity is a rare disorder in renal transplant recipients when low doses are administered and whole blood trough levels of CsA are regularly monitored. However, there is controversy about the clinical value of measuring CsA-metabolites, whose contribution to immunosuppression and toxicity is not fully understood. To assess the relation between low-dose CsA therapy and hepatotoxicity, we studied 128 renal transplant recipients attending our nephrology clinic. Eight of these patients had markedly elevated liver function tests. Three patients while receiving very low doses of oral CsA (< 3.8 mg/kg of body weight) presented marked derangements of CsA metabolism with abnormally increased CsA-metabolite levels. Parent drug levels were in the normal range. All 3 patients had chronic infection with hepatitis C virus and revealed histomorphologic evidence of hepatotoxicity. Hepatic dysfunction normalized when CsA was withdrawn or reduced by 50%. It is likely that hepatitis C virus infection interferes with CsA metabolism and/or biliary CsA-excretion and thus is responsible for CsA and/or metabolite-induced hepatotoxicity despite very low doses of CsA.

Lipid Disorders in Renal Transplant Recipients

Plasma cholesterol, triglyceride, lipoprotein and phospholipid levels were higher in 76 transplant recipients than in normal age-matched controls. 22 patients exhibited a normal lipid pattern; 12 a type IIa, 12 a type IIb, and 30 a type IV hyperlipidemia. Lipid abnormalities were not related to serum creatinine, parathyroid hormone (PTH), serum albumin, plasma glucose, transplant age, relative body weight or steroid administration schedule. Only plasma triglyceride level was related to mean prednisone dosage. In order to reduce the apparent cardiovascular risk posed by these changes in plasma lipid concentration, hypocaloric diet was administered to 16 patients with hypertriglyceridemia or mixed hypertriglyceridemia and hypercholesterolemia. With these dietary measures, plasma lipid concentrations returned to normal and remained stable during the period of observation (6--18 months).