Treatment Of Renal Transplant Recipients Research Articles

Treatment of Renal Transplant Recipients with Concurrent Acute Cellular Rejection and Transplant Renal Artery Stenosis

Treatment of Renal Transplant Recipients with Concurrent Acute Cellular Rejection and Transplant Renal Artery Stenosis Hee Yeoun Kim, M.D., Jeong Hee Yun, M.D., Dong Han Kim, M.D., Jin Ho Lee, M.D., Joon Seok Oh, M.D., Seong Min Kim, M.D., Yong Hun Sin, M.D., Joong Kyung Kim, M.D. and Yong Jin Kim, M.D. Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea

Clinical Utility of Viral Load in the Management of Cytomegalovirus Infection in Solid Organ Transplant Patients in Kuwait

BackgroundInfection with human cytomegalovirus (CMV) in solid organ transplant patients remains an unresolved challenge, despite improvements in immunosuppressive therapy, post-transplantation care, viral prevention, and therapy. MethodsWe conducted quantitative real-time polymerase chain reaction (PCR) assays of CMV on plasma samples of 1,168 patients in Kuwait who received solid organ transplants from 2012 to 2014 to detect and monitor CMV DNA viral load. ResultsOf the 1,168 patients, 180 (15.4%) were positive for CMV DNA. Among the CMV DNA–positive patients, 119 (66.1%) remained without symptoms and 61 (33.9%) developed CMV-related symptoms. During the follow-up period, peak viral loads were significantly (P < .05) higher in symptomatic patients (mean 970 copies/mL; range, 15–625,000 copies/mL) than in asymptomatic patients (<150 copies/mL; range, 67–2,650 copies/mL). Many symptomatic patients (n = 57) were successfully treated, and their viral loads declined. However, some symptomatic patients had irregular viral-load kinetics, with prolonged periods of symptoms despite CMV treatment; we excluded the possibility of drug resistance in these patients, because there was no evidence of clinical resistance to treatment. ConclusionsQuantitative real-time PCR of CMV DNA is useful in monitoring CMV infection and the effectiveness of CMV treatment in renal transplant recipients in Kuwait.

Real life experience with Interferon/Ribavirin-free antiviral treatment in renal transplant recipients and endstage renal disease-patients on dialysis infected with Hepatitis C virus

Real life experience with Interferon/Ribavirin-free antiviral treatment in renal transplant recipients and endstage renal disease-patients on dialysis infected with Hepatitis C virus

P0871 : Real life experience with interferon/ribavirin-free antiviral treatment in renal transplant recipients and endstage renal disease-patients on dialysis infected with hepatitis C virus

P0871 : Real life experience with interferon/ribavirin-free antiviral treatment in renal transplant recipients and endstage renal disease-patients on dialysis infected with hepatitis C virus

Personalization of the immunosuppressive treatment in renal transplant recipients: the great challenge in "omics" medicine.

Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.

Eculizumab Therapy for Chronic Antibody-Mediated Injury in Kidney Transplantation: An Interim Assessment.

Purpose: The development of de novo donor specific antibody (DSA) following kidney transplantation is associated with worse long term graft survival. Although the mechanisms remain unclear it is believed that DSA binds to HLA expressed on graft endothelial cells (ECs) and activates complement, causing graft injury. There is no effective treatment for renal transplant recipients who have de novo DSA and worsening renal function. The current trial is designed to test if eculizumab, an antibody that blocks C5 cleavage, can ameliorate antibody-mediated injury by reducing EC injury. Methods: 10 kidney transplant recipients (4 control, 6 treatment), who had de novo DSA and had worsening renal function completed 6 months of either eculizumab therapy or observation, as a part of an ongoing clinical study. The primary endpoint is change in the trajectory of eGFR over the 6 months and secondary endpoints included pathologic changes, as well as, differential expression in endothelial cell-specific mRNAs (E-Selectin, vWf, END-1, CAV-1, CDH5 and PECAM-1) measured by qRT-PCR on kidney biopsy specimens. Results: Of the 4 control patients (3 C4d+ and 1 C4d-), 3 progressed to ESRD. Protocol biopsies showed fluctuating C4d staining and a progressive increase in IFTA grade. Of the 6 patients that received eculizumab (3 C4d+, 3 C4d-), all had stabilization of eGFR during 6 months of treatment. Five of these patients were also observed for 6 months following treatment, of which 4 patients had deteriorating renal function following cessation of eculizumab. There were no major complications associated with eculizumab therapy. Analysis of endothelial cell-specific mRNAs showed a 25 fold increase in E-Selectin expression in diseased kidneys compared to controls, however, eculizumab did not appear to affect expression of any of the endothelial cell-specific mRNA’s tested. Conclusion: Interim assessment of renal transplant patients with de novo DSA and worsening renal function show a stabilization in their renal function with eculizumab therapy. However, increased endothelial cell-specific mRNAs, possibly indicative of chronic antibody-mediated injury, may not be diminished by eculizumab therapy. DISCLOSURE:Kulkarni, S.: Grant/Research Support, Alexion Pharmaceuticals. Nancy, K.: Grant/Research Support, Alexion Pharmaceuticals. Formica, R.: Grant/Research Support, Alexion Pharmaceuticals. Moeckel, G.: Grant/Research Support, Alexion Pharmaceuticals. Pober, J.: Grant/Research Support, Alexion Pharmaceuticals.

Clinical management of patients receiving cell‐based immunoregulatory therapy

Administering immunoregulatory cells as medicinal agents is a revolutionary approach to the treatment of immunologically mediated diseases. Isolating, propagating, and modifying cells before applying them to patients allows complementation of specific cellular functions, which opens astonishing new possibilities for gain-of-function antigen-specific treatments in autoimmunity, chronic inflammatory disorders, and transplantation. This critical review presents a systematic assessment of the potential clinical risks posed by cell-based immunotherapy, focusing on treatment of renal transplant recipients with regulatory macrophages as a concrete example.

DI-044 Late discontinuation of sotrastaurin: loss in efficacy and safety of renal transplantation?

BackgroundRenal transplant recipients previously treated by sotrastaurin (STA) had their immunosuppressive regimen changed because the STA development programme was interrupted. It is not established in the literature which immunosuppressive regimen...

Impact of CYP 3 A 5 and ABCB 1 polymorphisms on drug switching from cyclosporine to tacrolimus for individualized treatment of renal transplant recipients

Objective To investigate the impact of CYP3A5 and ABCB1polymorphisms on the initial individualized treatment with tacrolimus(FK506)in renal transplant recipients during switching from cyclosporine(CsA)to FK506.Methods Polymerase chain reaction and restriction fragment length polymorphism method(PCR-RFLP)was employed to investigate CYP3A5(A6989G)and ABCB1(exon12[C1236T],exon21G[A]2677Tand exon26[C3435T])genotype data.The initial trough concentration/dose(C0/D)values were compared among different CYP3A5 genotypes in renal transplant recipients switching from CsA to FK506 using one-way ANOVA.In addition,the initial C0/D values were also compared among different ABCB1(exon12[C1236T],exon21G[A]2677Tand exon26[C3435T])genotypes and their haplotypes using one-way ANOVA.Results The FK506C0/D values were significantly different between different CYP3A5genotypes(AA,AG and GG)at the7 th,14th,21 th and 28 th day of conversion from CsA to FK506 in renal transplant recipients(P0.05).Only on the 28 th day ofconversion,when the FK506 Din CYP3A5AA group was 3.5-fold that of CYP3A5 GG group([0.14±0.03]mg·kg-1·d-1 vs[0.04±0.01]mg·kg-1·d-1,P=0.00)and the FK506 Din CYP3A5AG group was 1.75-fold that of CYP3A5 GG group([0.07±0.03]mg·kg-1·d-1 vs[0.04±0.01]mg·kg-1·d-1,P=0.00),the FK506C0 in different CYP3A5 genotypes reached the same target concentration.The initial FK506C0/D was not associated with different ABCB1(exon12 [C1236T],exon21G[A]2677T and exon26 [C3435T])genotypes or their haplotypes in renal transplant recipients.ConclusionAppropriate initial daily dose of FK506 should be selected according to CYP3A5 genotype in order to quickly achieve the target immunosuppression in renal transplant recipients who are switching immunosuppressive regimen from CsA to FK506.

Effect of Periodontal Treatment in Renal Transplant Recipients

Objective: To evaluate the effect of periodontal treatment on gingival overgrowth in a group of renal transplant patients. Subjects and Methods: Twenty-five renal transplant recipients receiving immunosuppressive therapy with cyclosporine A (CsA) were randomly assigned to 2 groups. Group 1 (n = 15) included patients who had been specifically referred to a dental clinic to prevent gingival overgrowth and were given full periodontal therapy. Group 2 (n = 10) was comprised of patients who did not receive any professional periodontal cleaning. Patients from both groups were examined to determine their periodontal status before and after 3, 6 and 12 months in terms of their plaque index, gingival index and gingival overgrowth. During the examination, their overall health was stable. Results: For group 1, the scores were 1.89 (baseline), 0.98 (6 months) and 0.56 (12 months), and hence there were significant reductions (p = 0.0001). The gingival indices were 1.71 (baseline), 0.76 (6 months) and 0.35 (12 months), and the reductions were also significant (p = 0.0001). A significant association was observed between poor oral hygiene and the degree of gingival overgrowth. The 1-year post-treatment follow-up showed that patients in group 1 did not develop gingival overgrowth due to the use of CsA as group 2 did without prior periodontal therapy. Conclusion: Oral hygiene status was the most important variable related to the development and degree of gingival overgrowth due to the use of CsA.

Cardiovascular disease: Prevention and treatment in renal transplant recipients

Abstract Despite improved survival, renal transplant recipients remain at a high risk of increased mortality and mortality from cardiovascular disease. Both traditional cardiovascular disease (CVD) risk factors and those unique to this population add to the burden of disease, making their CVD risk 50 times that of the general population. This article discusses our present understanding of cardiovascular disease, the risk factors, including dyslipidemia, hypertension, allograft rejection and dysfunction, anemia, proteinuria and new onset diabetes after transplantation (NODAT), as well as prevention and management of these risk factors. Cardiovascular interventions as well as future considerations are also briefly discussed.

Endovascular Abdominal Aortic Aneurysm Repair in Patients with Renal Transplants: Reports of Two Cases

The artery and vein of the transplanted kidney are generally anastomosed to the external iliac artery and vein, respectively. Therefore, in open abdominal artery aneurysm (AAA) repair in renal transplant patients, kidney ischemia due to a proximal aortic clamp is a serious problem. We successfully performed endovascular aneurysm repair (EVAR) of AAA without aortic clamping in two renal transplant recipient cases. The two patients were diagnosed with large AAAs following the renal transplant, and EVAR was performed. To protect the renal function, we used N-acetylcysteine premedication and hydration before the operation, and we could then reduce the iodine contrast medium by using echography of the artery during the operation. In this report, a case where EVAR with renal function protection is a useful treatment for renal transplant recipients with AAA is described.

Perioperative Therapeutic Plasmapheresis

Perioperative Therapeutic Plasmapheresis

Safety and efficacy of peginterferon-α2a plus ribavirin treatment in renal transplant recipients with chronic hepatitis C

Interferon (IFN)-based therapy in chronic hepatitis C virus (HCV)-infected renal transplant (RT) recipients has been associated with a high risk of acute allograft rejection (AAR) and poor efficacy. We assessed the safety and efficacy of PegIFNα-2a and ribavirin (RBV) combination therapy in HCV-infected RT recipients. Thirty-two adult RT recipients of >12-month duration, infected with HCV genotypes 1 (62.5%) and 4 (37.5%), and significant fibrosis (Metavir ≥ F2) were recruited in an open-label trial with PegIFNα-2a 135-180 μg/week, plus RBV 200-1200 mg/day for 48 weeks, based on the estimated glomerular filtration rate. Safety assessments were performed weekly for 4 weeks, 2-weekly for 8 weeks, and 6-weekly for 36 weeks. Study end points were sustained virologic response (SVR) or development of AAR. Allograft biopsies were performed for 20% increase in creatinine from pretreatment levels, or optionally at week 12 on surveillance protocol. Renal safety was compared with matched untreated historical controls (n=31). None of the treated patients showed AAR when biopsied for raised creatinine (12.5%) or during surveillance (37.5%), with incremental and sustained creatinine increases occurring in 6.3% of treated patients and 16.1% of untreated controls (p=0.148), by week 72 assessment. Mean pretreatment and end-of-assessment creatinine in treated patients remained similar (106.8 ± 32.0 vs. 113.4 ± 62.8, respectively; p=0.140), while levels increased significantly in the controls (106.6 ± 35.6 vs. 142.5 ± 93.0, respectively; p=0.013). Rapid, early virologic response (EVR) and SVR occurred in 12.5%, 56.3%, and 37.5% of cases, respectively. SVR was similar in both genotypes (p=1.000). PegIFN and RBV dose reductions were required in 34.4% and 78.1%, respectively; discontinuation was required in 12.5%. Binary logistic regression identified only EVR (OR, 20.4; 95% CI: 2.2-192.6; p=0.008) as an independent predictor of SVR. PegIFN/RBV therapy is not associated with AAR in RT recipients at low risk for rejection but has modest efficacy in the treatment of HCV.

Analytical and clinical performance characteristics of the Simplexa BK virus quantitative PCR assay for the diagnosis of polyomavirus-associated nephropathy in renal transplant recipients using plasma and urine specimens

BackgroundPolyomavirus-associated nephropathy is a significant cause of kidney rejection in renal transplant recipients. Quantification of BK viral load in plasma and urine can predict the development of polyomavirus-associated nephropathy, though each assay requires careful evaluation of analytical and clinical performance characteristics for optimal use. ObjectivesThis study evaluated the analytical and clinical performance characteristics of the Simplexa BK virus quantitative PCR assay. Study designAnalytical validation was performed using commercial standards, BK virus stock culture, and patient specimens. Clinical performance was evaluated using biopsy-proven BK nephropathy as the gold standard. ResultsThe Simplexa BK virus quantitative PCR assay was linear over a range of 2.7–10.4log10copies/mL. Limit of detection was 2.7–2.8log10copies/mL in plasma and urine samples. Sensitivities were 100% and 100% and specificities were 84% and 86% for plasma and urine samples, respectively, when compared to a reference BK assay. Clinical cutoff values of 4.0log10copies/mL (plasma) and 7.5log10copies/mL (urine) yielded 100% sensitivity and specificities of 87.5% and 85%, respectively, for biopsy-proven polyomavirus nephropathy. ConclusionsThe Simplexa BK virus quantitative PCR assay has high sensitivity and acceptable analytical characteristics for clinical use. The clinical cutoff values presented here provide a rational approach to the monitoring and treatment of renal transplant recipients for polyomavirus-associated nephropathy.

Determination of optimal cholecalciferol treatment in renal transplant recipients using a population pharmacokinetic approach

No information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30-80 ng/mL during the first year post-transplantation. Four months after renal transplantation, 49 patients received four oral doses of 100,000 IU cholecalciferol every 2 weeks (intensive phase), then every 2 months until 1 year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment-model with first-order formation and elimination and basal concentration. The mean population parameter estimates and the associated between-subject variability were: formation rate constant (k(f)), 0.11 day(-1); clearance (CL/F), 2.5 L/day (0.42); central volume of distribution (V(C)/F), 237 L; basal concentration (C(0)),12.82 ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80 ng/mL, cholecalciferol dosing should be six successive administrations of 100,000 IU at 2-week intervals, followed by 100,000 IU once a month until the end of the first year. We present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients.

Emergency Endovascular Repair in a Patient With Abdominal Aortic Aneurysm With Pelvic Transplant Kidneys: Case Report

Abdominal aortic aneurysms after a kidney transplant are becoming treated more frequently owing to the extension of renal transplant in severely arteriosclerotic older patients. Renal transplant recipients with autosomal dominant polycystic kidney disease are prone to develop abdominal aortic aneurysms. We present the case of a ruptured abdominal aortic aneurysm that occurred in a renal transplant patient with autosomal dominant polycystic kidney disease. The patient was treated with emergency endovascular repair because open surgery could not be performed successfully owing to the presence of massive polycystic native kidneys and a liver that was occupying the entire peritoneal cavity. His postoperative course was uneventful without complications. The important lessons to be learned from our case are 2-fold: (1) Autosomal dominant polycystic kidney disease renal transplant recipients should be screened annually for abdominal aortic aneurysms to prevent ruptures and (2), emergency endovascular repair may be a preferred treatment in renal transplant recipients owing to its low surgical risk and success.

Topical treatment of cutaneous Kaposi sarcoma with imiquimod 5% in renal-transplant recipients: a clinicopathological observation

Kaposi sarcoma (KS) is a vascular neoplasm pathogenetically linked to human herpesvirus 8. Transplant recipients, in particular renal-transplant recipients (RTRs) are at higher risk for post-transplant (P)-KS which affects 0.2-11% of RTRs. The course of P-KS is influenced by the post-transplantation immunosuppressive treatment. Reduction of immunosuppressive drugs can result in tumour regression, and is the treatment of choice for P-KS, but is associated with the risk for transplant rejection. Imiquimod is a topically applied immunomodulator without relevant systemic absorption, and may thus represent a promising treatment for cutaneous KS in RTRs. The aim of this study was to investigate the clinical and histological effects of imiquimod in two RTRs with cutaneous KS. Imiquimod resulted in complete clinical and histologically proven remission in one patient, but in the second patient, although there was clinical remission, histological persistence of KS was found. Imiquimod may represent an effective treatment for RTRs with cutaneous P-KS. However, clinical remission does not necessarily indicate complete tumour regression, as shown in one of our patients, who had a persisting tumour, as shown by biopsy examination. Thus, histological confirmation is crucial to confirm complete response.

Mineral metabolism in renal transplant recipients discontinuing cinacalcet at the time of transplantation: a prospective observational study

The calcimimetic cinacalcet is approved for treating secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Biochemical profiles and clinical outcomes in patients discontinuing cinacalcet at the time of transplantation are scarce. We performed a prospective observational cohort study, including 303 incident renal transplant recipients, of whom 21 were on cinacalcet treatment at the time of transplantation. Parameters of mineral metabolism and incidence of parathyroidectomy and nephrocalcinosis in patients discontinuing cinacalcet at the time of transplantation patients ("cinacalcet +") were compared to cinacalcet-naïve patients ("cinacalcet -"). Mean follow-up was 35.6 ± 15.8 months. At the time of transplantation, parameters of mineral metabolism were similar in both groups. Conversely, at month 3, serum ionized calcium (p = 0.0007), calcitriol (p = 0.02), biointact parathyroid hormone (p = 0.06) levels and urinary fractional excretion of phosphorus (p = 0.06) were higher, while serum phosphorus levels (p = 0.06) were lower in "cinacalcet +." Analysis based on matching at the time of initiation showed that the course of post-transplant mineral metabolism in cinacalcet-treated patients (median treatment period 12.5 months) vs. cinacalcet-naïve patients was identical. "Cinacalcet +" patients are characterized by a high-incidence proportion of both post-transplant nephrocalcinosis (45% at month 3) and parathyroidectomy (28.6%). No difference in renal function was observed between "cinacalcet +" and "cinacalcet-" patients. Cinacalcet does not affect the course of secondary hyperparathyroidism in patients awaiting kidney transplantation. Biochemical profiles and a high parathyroidectomy rate suggest rebound hyperparathyroidism in renal transplant recipients discontinuing cinacalcet at the time of transplantation, which may be related to the short exposure time specific to this population. Risk/benefit studies are urgently required to define the role of continued calcimimetic treatment in renal transplant recipients and to determine the optimal treatment of secondary hyperparathyroidism in patients listed for transplantation.

Posttransplantation Proteinuria

Proteinuria is a common problem encountered in the treatment of renal transplant recipients, occurring in up to 45% of patients. Proteinuria from native kidneys falls rapidly after renal transplantation, and persistent or worsening proteinuria is usually indicative of allograft pathology. Biopsy studies of transplant patients with proteinuria have confirmed that transplant-specific diagnoses (transplant glomerulopathy, interstitial fibrosis and tubular atrophy, and acute rejection) are more commonly found than other proteinuric conditions, such as glomerulonephritis. As in the nontransplant setting, proteinuria is associated with worse clinical outcomes, including an increased risk for death, cardiovascular events, and graft loss. Blockade of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers will reduce proteinuria, but the long-term effect of these medications on patient and graft survival remains unknown.