Viremia Negativization After BK Virus Infection in Kidney Transplantation: A National Bicentric Study

BackgroundBK virus (BKV) infection represents a potentially dreadful complication after kidney transplantation (KT). When BK viremia is detected, the best therapeutic approach remains not entirely clarified. Critical elements of BK viremia treatment are immunosuppression minimization and introduction of drugs like leflunomide, everolimus, and fluoroquinolones. The study aimed to analyze the results of the BK viremia management in 2 collaborative Italian centers.MethodsTen patients undergoing KT in the 2 collaborative Italian centers of Sapienza University of Rome and University of L’Aquila from January 2013 to December 2017 and showing a post-KT diagnosis of BK viremia were retrospectively investigated.ResultsMean time from KT to BKV positivity was 7 months (range: 1-19 months). At diagnosis, the mean viral load was 683,842 copies/mL (range: 5800-4,052,415 copies/mL), with an average zenith of 2,428,410 copies/mL (range: 6762-18,022,500 copies/mL). In the 5 patients with BKV nephropathy, we observed a switch from antimetabolite to leflunomide (n = 5), a switch from tacrolimus to everolimus (n = 3), or an introduction of fluoroquinolones (n = 3). BKV clearance was achieved in 3 patients.ConclusionsEarly BKV diagnosis and stepwise minimization of immunosuppression remain the first-line approach in patients with BK viremia. In the presence of BKV nephropathy, a combination of antiviral drugs like leflunomide and fluoroquinolones/everolimus should favor viremia clearance.     

Endoscopic Treatment for Post-Transplant Vesicoureteral Reflux

IntroductionVesicoureteral reflux (VUR) is one of the most common ureteric complications after kidney transplantation that might cause symptomatic infections which deteriorate graft function. Surgical reimplantation has been the standard treatment; recently, endoscopic injection has been an alternative approach. We report our endoscopic treatment results and analyze the long-term outcome, even in patients with less optimal graft function.Materials and methodsA total of 16 patients and 19 symptomatic VUR were diagnosed at mean time of 88.3 months after their transplantation. The distribution of VUR grade was 1, 2, 8, 6, and 2 for grade I to V, respectively, with a mean VUR grade of 3.26 according to their voiding cystourethrogram images. Endoscopic Deflux injections were performed by a single urologist via rigid cystoscope with a beveled needle system. They were followed monthly thereafter.ResultThe average number of admissions due to symptomatic urinary tract infection was 2.68/person, and the mean creatinine level before endoscopic treatment was 1.63 mg/dL. The amount of Deflux injection was 0.7 to 1.2 mL per affected ureter; the mean creatinine level after endoscopic treatment was 1.41 mg/dL. The eGFR remained stationary in both eGFR > 60 and eGFR < 60 mL/min groups with a clinical success rate of 75% in both groups.ConclusionEndoscopic dextranomer-hyaluronic acid injection is a safe and feasible treatment option for VUR after kidney transplantation. Our data showed its efficacy in recipients whose eGFR is less than 60 mL/min.     

High-Dose Intravenous Immunoglobulin Treatment of Polyomavirus Nephropathy Developing After T Cell–Mediated Rejection Treatment: A Case Report

Background

Reactivation of BK polyomavirus causes destructive virus allograft nephropathy; however, treatment options are limited. Herein, we report a case in which a patient with T cell–mediated rejection was treated with steroid therapy. The patient subsequently developed BK viremia and was successfully treated by using intravenous immunoglobulin (IVIG) after failing to respond to conventional treatment.

Differences in Pathologic Features and Graft Outcomes of Rejection on Kidney Transplant

BackgroundRejection is still a barrier to long-term allograft survival, but there are not many reports of clinical outcomes according to rejection types. The purpose of this study was to investigate differences in pathologic features and graft outcomes of rejection on kidney transplant (KT).Materials and MethodsWe retrospectively analyzed 139 kidney transplant recipients diagnosed to rejection by allograft biopsy results between 2006 and 2018. We divided kidney transplant recipients into 3 groups as follows: T cell–mediated rejection (TCMR), antibody-mediated rejection, and mixed rejection. We investigated clinical characteristics, pathologic findings, death-censored graft survival rates, and patient survival rates among the 3 groups.ResultsMean follow-up duration was 113.5 (SD, 80.6) months. The mixed rejection group was the youngest significantly. There were no significant differences of the proportion of sex, KT type, KT number, number of HLA mismatches, induction immunosuppressant, and maintenance immunosuppressant among the 3 groups. In pathologic findings, microvascular inflammation and C4d were significantly different among the 3 groups. Death-censored graft survival of mixed rejection was the least. In multivariate analysis, recipient age, TCMR, and positive C4d were the risk factors associated with graft failure. However, patient survival rates showed no significant differences among the 3 groups.ConclusionsOur study showed that mixed rejection had poor prognosis in comparison with TCMR and antibody-mediated rejection groups, and TCMR and positive C4d were the most important risk factors for graft survival. Therefore, constant monitoring through allograft biopsy and early treatment for rejection are very important in post-transplant clinical outcomes.     

Acute Inflammatory Syndrome Paradoxically Induced by De Novo Purine Inhibitors Synthesis Before Renal Transplantation: A Case Report and Review of the Literature

Background

Mycophenolate mofetil (MMF) and mizoribine (MZR) are increasingly used as immunosuppressive agents for organ transplantation and chronic inflammation. We report a patient with rheumatoid arthritis who had an acute inflammatory syndrome triggered by preoperative immunosuppression therapy with both MMF and MZR.

Clinical Significance of Mycophenolate Mofetil Withdrawal in Kidney Transplant Recipients

IntroductionThe most effective immunosuppressant protocol in kidney transplantation (KT) is the combination of a calcineurin inhibitor, steroid, and mycophenolate mofetil (MMF) until now. However, MMF withdrawal (MW) is performed for many reasons, and the clinical course of the KT recipients after MW is not clearly known. The purpose of this study was to investigate the clinical outcomes of KT after MW.Materials and MethodsWe retrospectively analyzed the medical records of 626 KT recipients between 2000 and 2016. We evaluated the incidence of biopsy-proven acute rejection (BPAR), graft and patient survival rates, and risk factors related with graft failure.ResultsThe proportion of MW was 33.2% (208 of 626 patients). The median time between KT and MW was 6.4 months (range, 3.2–32.1 months). The common causes of MW were infection (70.7%), hematologic abnormalities (9.1%), and gastrointestinal trouble (7.7%). The incidence of BPAR was significantly higher in the MW group compared with the MMF continuation group (27.4% vs 8.9%, respectively, P < .001). Death-censored graft survival and patient survival rates were significantly lower in the MW group compared with the MMF continuation group (P < .001; P < .001, respectively). In the multivariate analysis, BPAR after MW was an independent risk factor for graft failure (hazard ratio 6.058, 95% confidence interval, 3.172–11.569, P < .001).ConclusionsThe incidence of rejection, graft failure, and patient mortality in KT were high after MW. Therefore, MW should be considered carefully.     

Renal Function Impairment in Kidney Transplantation: Importance of Early BK Virus Detection

Background

BK virus allograft nephropathy is a major complication of kidney transplantation that markedly reduces graft survival (50% graft failure 24 months after being diagnosed). BK virus replication can occur at any time posttransplantation. Viruria detection is a signal of virus reactivation and precedes viremia. Only viremia has been related to BK nephropathy. Early detection appears to be important in the prevention of BK nephropathy.

Clinical Significance of Postoperative Nutritional Status as a Prognostic Factor in Kidney Transplant Recipients

BackgroundDespite advancements in the management of kidney transplantation (KT), kidney transplant recipients (KTRs) have a higher risk of mortality than the age-matched general population. Improvement of long-term graft and patient survival is a significant issue. Therefore we investigated the effects of postoperative nutritional status on graft and patient survival and explored the predictive factors involved in nutritional status.MethodsOur retrospective study included 118 KTRs who underwent KT at our hospital. Clinical and laboratory data were obtained from medical charts. The prognostic nutritional index (PNI) was used to assess nutritional status. Changes in nutritional status after KT were monitored and the effect of nutritional status on graft and patient survival was investigated. The variables involved in nutritional status were also explored.ResultsThe KTRs in this cohort comprised 66 men and 52 women with a median age of 47 years at KT. There were 16, 32, and 22 cases of cadaveric, preemptive, and ABO-incompatible KTs, respectively. Postoperative PNI gradually improved and was stable from 6 months after KT. Although graft survival was regulated by ABO-compatibility, independent predictors for patient survival were history of dialysis, PNI, and serum-corrected calcium levels. Preemptive KT and inflammatory status contributed to PNI.ConclusionsNutritional status of KTRs improved over time after KT and could contribute to patient survival. Optimal nutritional educational programs and interventions can lead to better outcomes in KTRs. Further studies are needed to validate our results and develop appropriate nutritional educational programs, interventions, and exercise programs.     

Long-term Clinical Significance of Tacrolimus Trough Level at the Early Period After Kidney Transplantation

BackgroundThe stable immunosuppressant level at the early period after kidney transplantation (KT) is one of the most important factors for the prognosis of KT. However, the extent of immunosuppression varies according to the policies of each KT center. We investigated the relationship between the clinical outcome and tacrolimus trough level (TTL) at the early post-transplant period.Materials and MethodsWe retrospectively analyzed medical records of patients who underwent KT between July 2007 and June 2016. We investigated TTLs at 3 months after KT. We evaluated the incidence of biopsy-proven acute rejection (BPAR), cytomegalovirus infection, and graft survival according to the TTLs.ResultsA total of 426 patients who received KT during the study period were enrolled. The mean age of KT recipients was 46.3 ± 11.5 years, and 55.5% of patients were men. The incidence of BPAR within 1 year after KT was significantly higher when TTLs at 3 months were less than 4.0 ng/mL (P = .020). Death-censored graft survival rates were significantly lower in KT recipients with BPAR and TTL less than 4.0 ng/mL (P < .001, P < .001, respectively). In multivariate analysis, BPAR and TTL less than 4.0 ng/mL at 3 months after KT were independent risk factors for graft failure.ConclusionBPAR and TTL less than 4.0 ng/mL at 3 months after KT are important risk factors for allograft failure. Therefore, TTL should be kept at least 4.0 ng/mL or more at 3 months after KT to reduce the incidence of BPAR within 1 year after KT.     

Plasma Homocysteine and Glutathione Are Independently Associated With Estimated Glomerular Filtration Rates in Patients With Renal Transplants

BackgroundElevated levels of plasma homocysteine could, through homocysteine oxidation, induce the overproduction of reactive oxygen species, leading to a reduction in glutathione-related antioxidants, and may impair graft functions in patients with renal transplants. The purpose of this study was to determine whether plasma homocysteine, glutathione, or its related antioxidants were related to graft functions in patients with renal transplants.Patients and MethodsWe recruited 66 patients (mean age 48.4 years) with renal transplants (mean transplant duration 8.3 years). Patients were divided into 2 groups, based on their estimated glomerular filtration rate (eGFR): the moderate graft function group (eGFR ≥ 60 mL/min/1.73 m², n = 37) and low graft function group (eGFR < 60 mL/min/1.73 m², n = 29). We then determined their fasting levels of the following: malondialdehyde (MDA), homocysteine, cysteine, pyridoxal 5′-phosphate (PLP), glutathione (GSH), oxidized glutathione (GSSG), GSH/GSH ratio, glutathione peroxidase (GSH-Px) activity.ResultsWe found in the low graft function group significantly higher levels of plasma homocysteine, cysteine, GSH, and GSH/GSSG ratios. But an intergroup difference was not found regarding levels of MDA, PLP, GSSG, and GSH-Px activity. After adjusting for potential confounders, the increased plasma homocysteine and GSH levels were independently associated with lower eGFR. No interaction existed between homocysteine and GSH levels in association with eGFR.ConclusionIncreased plasma homocysteine and GSH levels appeared to be independent indicators of decreased graft functions in patients with renal transplants.     

Clinical Course of Renal Disease in Recipients of Liver Transplant Who Required Peritransplant Dialysis

PurposeRenal dysfunction is a common complication and one of the factors that affects the outcomes of liver transplantation (LT). The aim of this study was to review the clinical course of recipients of LT who needed peritransplant dialysis at our center.MethodsWe compared the clinical demographics, morbidity, and mortality between patients who required and those who did not require peritransplant dialysis among 26 recipients of LT from May 2015 to February 2018 at our center.ResultsAmong the recipients, 9 had pretransplant or posttransplant dialysis and 17 did not. The patients who underwent dialysis had a higher pretransplant Model for End-Stage Liver Disease score (42 vs 13; P < .001), older donor age (41 vs 24 years; P < .001), and longer post-LT hospital stay (37 vs 20 days; P < .001). However, there was no significant difference in the serum creatinine level between the 2 groups (1.36 vs 0.93 mg/dL; P = .187) at 2 weeks (1.10 vs 0.96 mg/dL; P = .341), 1 month (1.06 vs 0.86 mg/dL; P = .105), and 3 months after LT (0.92 vs 0.94 vs 0.89 mg/dL; P = .825). Mortality was higher in the peritransplant dialysis group (P = .043). The pre-LT dialysis duration was significantly related to post-LT dialysis (P = .028) and mortality (P = .011).ConclusionsThe pre-LT dialysis duration is considered an important factor in the survival and recovery of kidney function after LT. Therefore, if the patient has started dialysis, it may be beneficial to proceed to LT as soon as possible.     

Effective and Safe Reduction of Conventional Immunosuppressants Using Everolimus in Maintenance Kidney Transplant Recipients

Background

Adverse events due to conventional immunosuppressive therapy decrease both graft and patient survival. We aimed to establish a new protocol using everolimus (EVR) to safely minimize conventional immunosuppressants in maintenance kidney transplant recipients.

Do Antithymocyte Globulin-Free Acute Rejection Therapies Increase the Risk of Polyoma Nephropathy in Renal Transplant Recipients?

IntroductionBK virus nephropathy is a serious complication that can lead to allograft kidney loss. Excessive immunosuppression increases the risk. We aimed to evaluate whether there is an increased risk of BK viremia and nephropathy in patients who underwent high-dose immunosuppression because of the development of acute rejection in the early period after kidney transplantation.MethodsThis retrospective cohort study was performed between April 2015 and March 2016. Twenty-nine patients who had biopsy-proven acute rejection in the first 3 months were evaluated for BK viremia and nephropathy. Thirty patients who had transplantations at the same period were the control group. Plasma BK-DNA values were examined at 1, 2, 3, 6, 9, and 12 months after the rejection treatment and at 3, 6, 9, and 12 months in the control group. Presence of polyoma nephropathy was examined with surveillance biopsies at the 6 and 12 months.ResultsAcute rejection treatment was started on the 12th day after transplantation (2–37 days). Seventeen cellular rejections and 12 humoral rejections were reported by biopsy. Two of the 12 humoral rejections were suspicious. Only pulse steroid (PS) (n = 18); PS, plasmapheresis, and intravenous immunoglobulin (n = 8); PS and intravenous immunoglobulin (n = 2); and PS and plasmapheresis (n = 1) treatments were performed. In 21 patients in the rejection group and 25 patients in the control group, BK-DNA was not positive at all. Two patients had graft loss at 11 and 36 months in the rejection group. Graft losses were secondary to rejection.ConclusionsTreatment with antithymocyte globulin-free regimens after acute rejection episodes did not lead to an increase in BK viremia.     

In Vitro Study Evaluating the Effect of Different Immunosuppressive Agents on Human Polyomavirus BK Replication

BackgroundHuman polyomavirus BK (BKPyV) is the etiologic agent of polyomavirus-associated nephropathy, a leading cause of kidney transplant dysfunction. Because of the lack of antiviral therapies, immunosuppression minimization is the recommended treatment. This strategy offers suboptimal outcomes and entails a significant risk of rejection. Our aim was to evaluate the effect of different immunosuppressive drugs (leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus) and their combinations in an in vitro model of BKPyV infection.MethodsHuman renal tubular epithelial cells were infected with BKPyV and treated with leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus, administered alone or in some combination thereof. Viral replication was assessed every 24 hours (up to 72 hours) by BKPyV-specific quantitative real-time polymerized chain reaction for the VIRAL PROTEIN 1 sequence in cell supernatants and by western blot analysis targeting the viral protein 1 and the glyceraldehyde 3-phosphate dehydrogenase on total protein lysates. Results were described as viral copies/mL and compared between treatments at any prespecified time point of the study.ResultsThe highest inhibitory effects were observed using leflunomide or everolimus plus mycophenolic acid (mean BKPyV replication log reduction 0.28). The antiviral effect of everolimus persisted when it was used in combination with tacrolimus (mean BKPyV replication log reduction 0.27).ConclusionsOur experience confirms that everolimus has anti-BKPyV properties and prompts future research to investigate possible mechanisms of action. It also provides a rational basis for targeted clinical trials evaluating alternative immunosuppressive modification strategies.     

Successful Treatment of Focal Segmental Glomerulosclerosis Recurrence in a Second Kidney Transplant Patient: A Case Report

Background

Recurrence of focal segmental glomerulosclerosis (FSGS) in renal allograft recipients after first transplant occurs in the second graft in virtually all patients. There is little evidence regarding optimal treatment.

Urine Albumin Creatinine Ratio May Predict Graft Function After Kidney Transplant

BackgroundThe albumin to creatinine ratio (ACR) has been shown to be an important prognostic marker in kidney disease. The ACR has been shown to predict graft failure and patient death after kidney transplant.MethodsFrom March 1, 2011, to December 31, 2013, we checked the urine ACR and blood for highly sensitive C-reactive protein in 93 kidney recipients who regularly follow up at out institute. We tested the linear correlations of these parameters with estimated glomerular filtration rate. Furthermore, we used multivariate linear regression to examine its value in predicting graft function. Finally, we used receiver operating characteristic curve analysis to validate their predictive value on creatinine clearance > 45 mL/min.ResultsWith multivariate linear regression, the latest estimated glomerular filtration rate has a strong linear relationship with initial ACR (B = ?0.032; P = .02), suggesting each unit rise in ACR with a decrease in creatinine clearance by 0.032 mL/min. To investigate their value in predicting good functional graft defined as creatinine clearance >45 mL/min, a receiver operating characteristic curve analysis was applied on these parameters. The area under curve for age is 0.496, for body weight is 0.539, and for highly sensitive C-reactive protein is 0.582, which are all around the chance of 0.5 by flipping coins. The area under ACR curve is 0.825, better than above parameters, and only second to serum creatinine level.ConclusionsUrine ACR is a simple and effective measure to predict graft function after a kidney transplant. It has similar independent strong correlations to creatinine clearance comparing with serum creatinine without requirement of a blood draw.     

Effectiveness of Thymoglobulin Induction Therapy in Kidney Transplant From Deceased Donor With Mild to Moderate Acute Kidney Injury

BackgroundThe clinical benefit of rabbit antithymocyte globulin (Thymoglobulin) compared with basiliximab for induction therapy in kidney transplant (KT) resulting from acute kidney injury (AKI) donors remains controversial. In cases of severe AKI, the degree of kidney injury is too great to reveal influence of different induction therapies on clinical outcomes. We aimed to compare clinical outcomes of Thymoglobulin and basiliximab induction therapy in KTs from deceased donors (DDs) with mild to moderate AKI.MethodsWe retrospectively studied 147 patients who received KTs from DDs between 2009 and 2017 in our center; 91 patients received kidneys from AKI donors. The AKI severity was classified based on the Acute Kidney Injury Network (AKIN) staging, and patients with AKIN stage 3 (43 patients) were excluded. Clinical outcomes were compared according to the type of induction therapy.ResultsThymoglobulin and basiliximab induction groups showed no significant differences in demographic and baseline characteristics except donor age and follow-up period. The Thymoglobulin group had lower incidences of acute rejection and a trend toward a lower incidence of delayed graft function and better graft survival than the basiliximab group. There was no significant difference in BK infection rate; however, cytomegalovirus infection rate showed a trend toward a lower incidence in the basiliximab group.ConclusionsIn cases of KT from AKIN stage 1 and 2 donors, Thymoglobulin showed better clinical outcomes than basiliximab, although it had a somewhat high rate of cytomegalovirus infection. It seems beneficial to use Thymoglobulin induction therapy in KTs from DDs with mild to moderate AKI.     

Gout Severity in Recipients of Kidney Transplant

PurposeThis retrospective analysis of medical chart data was performed to compare severity and treatment of gout in patients with or without a history of kidney transplantation (KT).MethodsVia an online survey, a panel of board-certified US nephrologists (N = 104) provided the following deidentified chart data for their 3 most recent patients with gout: age, sex, serum uric acid, numbers of swollen or tender joints, visible tophi, gout flare events (prior 12 months), gout drug treatment history, and KT history. The presence of “severe, uncontrolled gout” was defined as: serum uric acid ≥ 7.0 mg/dL, ≥1 tophi and ≥2 flares in the last 12 months, and history of xanthine oxidase inhibitor treatment.ResultsTwenty-five out of 312 (8.0%) gout patients had a history of KT. Univariate analysis found that patients with gout and history of kidney transplants had: greater prevalence of severe uncontrolled gout (27% vs 8%, P = .007) and tophi (36% vs 17%, P = .030), and higher rates of failure or physician perceived contraindication to allopurinol (44% vs 23%, P = .028).ConclusionThis study provides preliminary evidence that gout in patients with history of KT is more severe and poses greater challenges to pharmacologic management. Although gout has been linked to worse outcomes among kidney recipients in the literature, there are presently no publications on gout severity among patients with KT in comparison to other patients with gout. Further investigation of disease severity and appropriate, effective treatment options in recipients of kidney transplant with a diagnosis of gout, especially prior to the transplant, is warranted.     

Randomized controlled trial assessing the impact of everolimus and low‐exposure tacrolimus on graft outcomes in kidney transplant recipients

This was a single‐center, randomized controlled trial assessing the impact of a 3‐month (10‐16 weeks) conversion to everolimus with low‐exposure tacrolimus, as compared to remaining on full exposure tacrolimus with mycophenolate (NCT 02096107). Adult kidney transplant recipients with a functioning graft were eligible for participation. Goal troughs in the intervention arm were 2‐5 ng/mL for tacrolimus and 3‐8 ng/mL for everolimus, with tacrolimus maintained at 5‐12 ng/mL in the control arm; 60 were randomized (30 in each arm) and were well matched at baseline; mean age was 51 years and 57% were African‐American. At 12‐months, fibrosis scores (27.8% tacrolimus/mycophenolate vs 22.9% tacrolimus/everolimus, P = .391), acute rejection rates (7% tacrolimus/mycophenolate vs 3% tacrolimus/everolimus, P = .554), and graft function (mean eGFR tacrolimus/mycophenolate 56 ± 15 vs tacrolimus/everolimus 59 ± 14 mL/min/1.73 m², P = .465) were similar between arms. The everolimus arm had significantly lower rates of CMV infection, severe BK infection, and improved BK viral clearance kinetics, as compared to the MPA arm. In this population, including a significant number of African‐Americans, an immunosuppression regimen of everolimus with low‐exposure tacrolimus provided similar efficacy to tacrolimus and mycophenolate, with significantly lower rates of BK and CMV.     

Trough Level of Mycophenolic Acid Did Not Affect De Novo DSA Development in Kidney Transplantation

IntroductionMycophenolate mofetil has improved long-term outcomes of kidney transplantation. However, the impact of mycophenolic acid (MPA) trough level on the development of de novo donor-specific anti-HLA antibody (DSA) is unclear. We examined the relation between MPA trough level and de novo DSA development.MethodWe retrospectively studied 617 kidney recipients whose MPA trough level and de novo DSA data were available. All patients underwent primary kidney transplant from living donors from 2008 to 2014, and were chronically treated with a calcineurin inhibitor, mycophenolate mofetil, and +/- steroids. They were equally divided into 4 groups according to the mean trough level of MPA (mMPA) at 1 year post-transplantation: Group 1, mMPA < 2.14 ng/mL (n = 152); Group 2, mMPA 2.14-2.83 ng/mL (n = 157); Group 3, mMPA 2.83-3.57 ng/mL (n = 153); and Group 4, mMPA ≥ 3.57 ng/mL (n = 155). The groups were compared by incidence rate of de novo DSA, graft survival rate, and renal function.ResultsThe incidence rates of de novo DSA were 33.3% in Group 1, 23.7% in Group 2, 22.9% in Group 3, and 30.3% in Group 4 (P = .158). Although there was no significant difference in graft survival rates, a significant difference of renal functions was noted: the higher the renal function, the lower the MPA trough level.ConclusionThe mMPA trough level at 1 year post-transplantation was not statistically associated with the incidence rate of de novo DSA after kidney transplantation.