Inhibition of Proprotein Convertase Subtilisin/Kexin-9 After Kidney Transplant: Single-Center Experience Among Patients With High Cardiovascular Risk.

OBJECTIVES: The benefits of reduction in low-density lipoprotein cholesterol by evolocumab by nearly 60% has not been evaluated among kidney transplant recipients to our knowledge. We assessed the efficacy and safety of evolocumab, a proprotein convertase subtilisin/kexin-9 inhibitor, in reducing lipids and cardiovascular events among kidney transplant recipients in a randomized controlled study. MATERIALS AND METHODS: Between June 2017 and June 2019, we enrolled 197 kidney transplant recipients with high cardiovascular risk score (>20). Patients who received evolocumab (140 mg/2 weeks) comprised group 1 (n = 98), and patients maintained on statin therapy comprised group 2 (n = 99). We followed patients clinically and with necessary laboratory investigations over 24 months. RESULTS: The 2 groups had comparable demographic characteristics (P > .05). Before enrollment in the study, smokers were significantly more prevalent in group 1, whereas posttransplant diabetes mellitus was more prevalent in group 2 (P = .033). Moreover, baseline serum creatinine was higher in group 1, whereas immunosuppression was equivalent in both groups (P > .05). We found no significant differences between the 2 groups concerning cardiovascular events, and both graft and patient outcomes were comparable (P > .05). The higher baseline cholesterol in group 1 (5.5 vs 4.7 mmol/L; P < .001) decreased significantly after 3 months and thereafter (P = .031) compared with levels in group 2 and baseline values (P < .001). We reported 2 cases of acute myocardial infarction and 1 atrial fibrillation in group 2. CONCLUSIONS: Proprotein convertase subtilisin/kexin-9 inhibitors, as an added therapy to statins, are safe and effective in treating hypercholesterolemia after kidney transplant. Evolocumab can minimize cardiovascular events after kidney transplant in patients with high events at baseline. Longer-term trials with larger number of patients are needed to confirm its beneficial effects on cardiovascular complications and patient and graft survival.

Torque Teno Virus Polymerase Chain Reaction Titer: A Promising Immunometry.

Solid-organ transplant is the treatment of choice for all patients with end-stage diseases. Long-term graft function and survival rely on suitable immunosup-pressive treatment to prevent rejection. Besides this desired effect, a reduced immunocompetence in the transplant recipient increases the risk of developing infectious diseases and malignancies. An ideal biomarker should be sensitive, allow early visibility, be accessible in peripheral blood, and be associated with a known mechanism. Torque teno virus or transfusion transmitted virus is a virus that has gained attention as a possible marker of immune function. This virus rarely causes disease in healthy individuals, but torque teno viral load in immunosuppressed patients is shown to be higher than in healthy controls. Replication of torque teno virus is inversely correlated with number and especially functions of T lymphocytes. Torque teno virus could join the current list of predictive biomarkers in transplantation to detect whether the patient is over- or under-immunosuppressed. More studies are needed to confirm or disprove this possibility.

Cystinosis in Pediatric Renal Transplant Recipients: A Case-Control Study From Kuwait.

OBJECTIVES: Cystinosis is the most frequent cause of the inherited renal Fanconi syndrome and is also potentially treatable. In this study, we have reported our single-center experience of the longterm outcomes of kidney transplant in patients with cystinosis. MATERIALS AND METHODS: Pediatric patients with cystinosis (n = 17) were compared with a matched control group without cystinosis (n = 126). The 2 groups were compared with regard to demographic data, posttransplant complications, and graft and patient outcomes. RESULTS: Most patients with cystinosis were male teenagers (52.9%) with comparable mean age (12.4 ± 4.1 vs 14 ± 3.1 years) versus the group without cystinosis. The 2 study groups were comparable with regard to type of dialysis, type of donor, blood group, and pretransplant comorbidities (P > .05). Patients with cystinosis received significantly more potent induction therapy (P < 0.05), but both groups were maintained on comparable immunosuppressive regimens (mostly tacrolimus based) (P > .05). Most grafts in both groups displayed immediate graft function. The percentage of patients with cystinosis with primary graft function was significantly higher than the percentage of those patients without cystinosis who had primary graft function (P = .024); this was associated with a relatively lower baseline creatinine level, although this was not significant (P > .05). Posttransplant complications, especially posttransplant diabetes, cytomegalovirus viremia, or BK nephropathy, were comparable (P > .05). Moreover, patient and graft survival rates were similar in the 2 groups (P > .05). CONCLUSIONS: Under standard immunosuppression, renal transplant and cysteamine therapy were safe with good long-term outcomes in patients with cystinosis. Studies that can include more patients and that have longer follow-up are needed to better understand the nature of this genetic disease and to discover the best treatment options.

Successful Management of Combined BK Nephropathy and Nocardiosis in a Renal Transplant Recipient: Case Report.

Nocardiosis is a life-threatening infection in immunocompromised patients. The prevalence of the disease ranges from 2.3% to 5% in renal allograft recipients. Here, we describe a case of BK nephropathy associating with nocardiosis with successful recovery. The 54-year-old male patient had end-stage kidney disease due to diabetic nephropathy associated with diabetic retinopathy, hypertension, and dyslipidemia. He started hemodialysis in October 2017; 2 years later, he underwent a deceased donor kidney transplant with 2 HLA mismatches and high panel reactive antibodies. He received desensitization with intravenous immunoglobulin and rituximab, received thymoglobulin as induction, and was maintained on prednisolone, mycophenolate mofetil, and tacrolimus. His serum creatinine decreased to a nadir of 90 µmol/L. He developed graft dysfunction, which was proven to be due to BK nephropathy. Therefore, mycophenolate mofetil was replaced with leflunomide in addition to intravenous immunoglobulin therapy. Ten months later, he had an accidental fall and sought an orthopedic evaluation. Magnetic resonance imaging of the lumbar spine and pelvis revealed lumbar spondylosis, avascular necrosis of the femoral head, and obturator muscle abscess. He was explored surgically, but the surgeon found no abscess or avascular hip necrosis. The patient's blood grew Nocardia, and he was readmitted and started imipenem and linezolid empirically. Brain and chest computed tomography scans ruled out any central nervous system or pulmonary involvement, but a bone scan revealed osteomyelitis of the right superior pubic ramus and prepubic swelling, which was confirmed by computed tomography to be an abscess in both obturator externus and internus. He continued the same antibiotics for 6 months based on culture and sensitivity. At follow-up, the patient has shown stable graft function (creatinine 155 µmol/L) with improved BK viremia with immunosuppression minimization. In renal transplant recipients, successful management of combined BK nephropathy and nocardiosis was feasible with minimization of immunosuppression and proper antimicrobial therapy.

Impact of Therapeutic Dose Monitoring of Mycophenolic Acid on the Outcome of Live-Donor Kidney Transplant Recipients - A Prospective Controlled Study.

Immunosuppressive therapy is the backbone to renal transplantation. Although an adequate level of immunosuppression is required to dampen the immune response to the allograft, the level of chronic immunosuppression is slowly decreased over time (as the risk of acute rejection decreases) to help lower the overall risk of infection and malignancy. Several studies have discussed the clinical use of therapeutic drug monitoring of mycophenolic acid (MPA) in kidney transplant recipients. This prospective single-center study included 88 patients with end-stage renal disease who were transplanted in Mansoura Urology and Nephrology Center from living related donors, from the beginning of February 2016 to the end of December 2016. Eight patients were excluded, the remaining 80 patients were divided into two groups; the study group (40 patients) who were followed up using therapeutic trough level monitoring of MPA and, control group (40 patients) who were followed up using the fixed-dose of Mycophenolate according to our local immunosuppressive protocol. These patients were followed up for one year posttransplantation with regard to graft function, rejection episodes, gastrointestinal (GI), and hematological side effects, the incidence of infection or malignancy, patient survival, and graft survival. Fifteen patients from the study group (37.5%) needed dose reduction of MPA, no patients needed to increase the dose. Our study showed insignificant differences regarding the patients' characteristics and demographic data. Significantly higher incidence of GI manifestations was noted in the control group (P = 0.001). Although the higher frequency of incidence of infection, anemia, leukopenia and thrombocytopenia was seen in the fixed- dose group, the difference was statistically insignificant. Regarding proteinuria and post-transplant diabetes mellitus, comparable data were obtained. Significantly higher percentage of recipients in the study group is still having normally functioning grafts (P = 0.02). Furthermore, higher percent of recipients in the control group died with functioning graft after one year of follow-up (P = 0.04). There were insignificant differences as regarding patient and graft survival. The decrease in the dose of MPA reduced the annual cost by around six thousand US dollars. Our results suggest that adopting therapeutic dose monitoring strategy during follow-up of kidney transplant recipients is adequate. Longer-term studies with a larger sample size may be needed to support this policy.

The effect of anemia on the efficacy and safety of treating chronic hepatitis C infection with direct-acting antivirals in patients with chronic kidney disease.

BACKGROUND/AIM: Chronic hepatitis-C infection is a great health burden in Egypt. The effect of anemia on the efficacy and safety of direct-acting anti-viral (DAA) therapies for those with chronic-kidney disease (CKD) has not been evaluated. PATIENTS/METHODS: This single-center retrospective study included 235 renal patients: i.e., 70-CKD patients not on hemodialysis (42 with anemia, 28 without); 40 hemodialysis patients (16 anemic; 24 non-anemic), and 125 kidney-transplant (KTx) recipients (40 anemic; 85 non-anemic). Anemia was defined by a hemoglobin level < 10.5 g/dL. Hemodialysis patients received ritonavir-boosted paritaprevir/ombitasvir. KTx patients received sofosbuvir/daclatasvir. CKD patients with eGFR > 30 mL/min/1.73 m2 received sofosbuvir/daclatasvir. Those with eGFR < 30 mL/min/1.73 m2 received ritonavir-boosted paritaprevir/ombitasvir; 64 non-anemic patients also received ribavirin therapy. RESULTS: Mean age of CKDs was 49.1 years, 43.2 years for HDs, and 45.2 years for KTx patients. Most were male; body-mass index was ~ 23.8. Anemia did not affect the efficacy of DAAs in hemodialysis, CKD, or KTx patients. Most patients achieved a rapid virologic response (RVR), and a 12- and 24-week sustained viral response. Worsening of anemia among the non-anemic group was mostly related to ribavirin therapy in hemodialysis patients (11/16 patients). Acute kidney injury in CKDs occurred more frequently within the anemic group (59.5%) compared to the non-anemic group (32.1%). For KTx, graft impairment was more common among the anemic group (7/40) compared to the non-anemic group (2/85). CONCLUSION: Hemoglobin levels of < 10.5 g/dL prior to DAA treatment did not affect the virological response in renal patients but was associated with increased serum creatinine among KTx and those with CKD.

Detection of Hepatis C Virus-Related Immunologic Markers and Their Impact on Outcomes of Living-Donor Kidney Transplant Recipients.

OBJECTIVES: Liver disease is an important cause of morbidity and mortality among recipients of transplanted organs. In addition to the liver, hepatitis C virus infection has a significant prevalence among recipients of kidney transplant and is related to worse graft and recipient survival as the kidney is an important component of the hepatitis C virus clinical syndrome. MATERIALS AND METHODS: This retrospective single center study included 336 patients with end-stage renal disease who received a kidney transplant at the Mansoura Urology and Nephrology Center from January 1992 to December 1995. Of 336 patients, 63 were excluded, and the remaining 273 patients were divided into 3 groups: viremic active (72 patients), viremic inactive (108 patients), and nonviremic (93 patients). Division of patients was based on hepatitis C virus RNA complement level (C3 and/or C4 consumption), circulating cryoglobulins, and rheumatoid factor detection. RESULTS: Our study showed insignificant differences regarding patient characteristics and demographic data among the study groups but significantly higher incidence of transaminitis in viremic (active and inactive) patients. Nonsignificant differences were found regarding proteinuria among the 3 groups, including among those who had levels in either nephrotic or nonnephrotic ranges. Biopsy-proven acute rejection episodes among the 3 groups of recipients were statistically comparable, with significantly higher frequency of chronic rejection episodes among viremic active patients. Nonviremic recipients had significantly lower serum creatinine levels than viremic (active and inactive) recipients. Patient and graft survival results were comparable among the groups. CONCLUSIONS: Presence of hepatitis C virus immunologic markers does not have a significant effect on patient and graft survival; however, it may be a clue for long-term incidence of chronic rejection.

Impact of Sex Disparities on Outcomes of Living-Donor Kidney Transplant in Egypt: Data of 979 Patients.

OBJECTIVES: Renal transplant is the criterion standard for treatment of end-stage renal disease. The effects of disparities between men and women on renal transplant outcomes have been evaluated in many studies but with debatable results. It has been suggested that female kidney donors have poor outcomes after transplant compared with male kidney donors, especially when implanted in a male recipient. The aim of the study was to evaluate the effects of sex on living-donor kidney transplant outcome. MATERIALS AND METHODS: The data of 979 patients who underwent living-donor kidney transplant from January 2000 to December 2010 at a single center were reviewed retrospectively. The patients were divided into 4 groups according to recipient and donor sex: male donor-to-male recipient (n = 307), male donor-to-female recipient (n = 132), female donor-to-male recipient (n = 411), and female donor-to-female recipient (n = 129). We compared the demographic characteristics, posttransplant rejection and complications, and graft and patient survival rates among the groups. RESULTS: Male recipients were older than female recipients, whereas male donors were younger than female donors (P < .001). No statistically significant differences were shown regarding recipient body mass index, ischemia time and time to diuresis, and acute and chronic rejection rates between the groups. Graft (P = .947) and patient (P = .421) survival rates were comparable between groups. CONCLUSIONS: Donor and recipient sex had no significant effect on outcomes of living-donor renal allograft recipients.

Comparative analysis for optimizing the modified release tacrolimus (Advagraf) after kidney transplantation: A prospective randomized trial.

Immunosuppression management in clinical transplantation aims to balance delivery of efficacy against adverse reactions using therapeutic drug monitoring. Adherence to posttransplant immunosuppressive medications and minimizing variability in drug exposure are important considerations in preventing rejection and maximizing overall transplant outcomes. The availability of once-daily tacrolimus may add a potential benefit by simplifying immunosuppressive regimens, though improving compliance among transplant recipients. The aim of our study is to investigate the safety and efficacy of the once-daily formulation of tacrolimus (Advagraf) against the usually used twice daily tablets (Prograf). A prospective randomized trial 1:2 was designed for 99 consecutive live-related renal transplant recipients who received their grafts at a single center (study group, Advagraf, 33 recipients and control group, Prograf, 66 recipients). The demographic data were homogeneous among both groups regarding donors and patients' characteristics. Posttransplant hypertension, infection, malignancy, and diabetes mellitus were comparable among both groups. Renal function and rejection episodes showed no statistical significance among recipients of both groups. Despite slight higher Advagraf unit doses, there was no statistical difference regarding the tacrolimus trough levels, between the two groups. Our singlecenter experience revealed that the availability of once-daily tacrolimus formulation could give potential benefit of improved medication compliance and better allograft outcomes by decreasing pill burden and thereby simplifying dosing schedule, Advagraf was non-inferior to twice-daily tacrolimus regarding safety and efficacy. Although being nonsignificant, a trend for better kidney function was noted in this short-term study in the Advagraf group, so long-term follow-up is needed to verify this.

Enhanced Recovery Open vs Laparoscopic Left Donor Nephrectomy: A Randomized Controlled Trial.

OBJECTIVE: To compare recovery outcomes between laparoscopic donor nephrectomy (LDN) and open donor nephrectomy within a specified enhanced recovery program (ERP) for left kidney donations. PATIENTS AND METHODS: A phase III randomized trial was conducted between January 2013 and June 2015; eligible left-side donors were randomized to laparoscopic or open donor nephrectomy in a 1:1 ratio with recovery optimized within a standardized ERP. The primary outcome was patient-reported measure of physical fatigue, as measured by the physical fatigue domain of the translated Multidimensional Fatigue Inventory 20. Secondary outcomes included other donor recovery outcomes, postoperative pain scores, hospital stay, perioperative complications, and graft outcomes. RESULTS: A total of 224 donors (laparoscopy, n = 113; open surgery, n = 111) were randomly allocated. Six weeks postoperatively, physical fatigue domain scores in Multidimensional Fatigue Inventory 20 were significantly lower in the LDN group (mean: laparoscopy, 8.2 ± 3.2 vs open surgery, 13.05 ± 2.9) (P = .007). Median total hospital stay was also significantly shorter in the LDN group (median: laparoscopy, 2; interquartile range, 1-5 vs open surgery, 4; interquartile range, 2-9 days) (P = .002). LDN was associated with less pain scores and less non-opioid analgesic requirements. Warm ischemia times were not significantly different in both groups (mean: laparoscopy, 2.5 ± 0.8 vs open surgery, 2.2 ± 0.6) (P = .431). CONCLUSION: Even when optimized within an ERP, LDN was associated with less general and physical fatigue and better physical function at 6 weeks postoperatively when compared with open surgery for left kidney donations.

Optimizing Immunosuppressive Regimens Among Living-Donor Renal Transplant Recipients.

OBJECTIVES: We review different immunosuppressant protocols used for living-donor kidney transplant recipients at our center. MATERIALS AND METHODS: Many prospective randomized studies from our center have been reported between March 1976 and 2016, with more than 2700 renal transplant procedures conducted. The first study was a prospective randomized trial of azathioprine versus cyclosporine. The second study compared triple therapy (prednisolone + azathioprine + cyclosporine) versus conventional therapy (prednisolone + azathioprine). The third study was a cost-saving study, in which 100 patients received ketoconazole along with the triple regimen. Another trial demonstrated the advantages of a microemulsion form of cyclosporine. A subsequent trial compared calcineurin inhibitor minimization versus avoidance protocols. Rescue therapies were carried out to intensify immunosuppressive regimens after repeated rejection. In addition, steroid-free regimens were evaluated during both short- and long-term treatment. A recent trial reported a step-forward avoidance protocol with a calcineurin inhibitor and a steroid-free regimen, whereas another current study is the TRANSFORM one. The rationale behind antibody therapy was tho roughly evaluated among living-donor renal trans plant recipients with different agents, including basiliximab, daclizumab, antithymocyte globulin, and alemtuzumab. RESULTS: Earlier studies have demonstrated the efficacy of conventional regimens without induction therapy, especially in longer follow-up. The standard triple therapy has emerged with intensified immunosuppressive and lowered dose of each drug, especially cyclosporine. In minimization studies, no significant differences were encountered regarding patient and graft survival, even in the long-term. Steroid avoidance was safe and effective. Calcineurin inhibitors and steroid-free regimens have shown comparable patient and graft survival. Induction therapy has lowered the incidence and severity of acute rejection. CONCLUSIONS: A better 5-year graft survival and less posttransplant complications have been achieved with steroid avoidance after induction with basiliximab. Induction therapy did not affect graft and patient survival rates despite lowered incidence and severity of acute rejections.

Challenges for Renal Retransplant: An Overview.

Despite many achievements in renal transplant in the past few years regarding immunosuppression and tissue matching, the rates of early and late graft loss and return to dialysis are still high. Many of those with primary graft failure will be listed for a kidney retransplant, as this allows for better quality of life than dialysis. Many challenges face those requiring renal retransplant, including first graft nephrectomy and whether site of retransplant should be ipsilateral or contralateral, whether to conduct preemptive retransplant or wait while on dialysis, additional immunologic factors, immunosuppression after retransplant, cancer risk, BK virus infection, and retransplant in pediatrics. Despite the increased relative risks associated with retransplant, patients receive a significant survival benefit, better quality of life, and low health care costs versus remaining on dialysis after a failed transplant.

Frequency of the Original Kidney Disease and Its Effect on the Outcome of Kidney Transplant in the Urology-Nephrology Center Mansoura University.

OBJECTIVES: Renal allograft function and graft survival depends on many factors, including the source of the graft, immunologic matching between donor and recipient, incidence of acute rejection, and recurrence of the original kidney disease. This work aimed to evaluate the effects of the original kidney disease on patient and graft survival. MATERIALS AND METHODS: This was a retrospective, single-center study that included 2189 kidney transplant recipients who were transplanted at The Urology and Nephrology Centre, Mansoura University, between 1976 and 2010. Of 2189 recipients, 1350 patients with unknown original kidney disease were excluded, with the remaining 839 patients divided into 4 groups according to their original kidney disease. RESULTS: We found pretransplant dialysis and blood transfusion to be statistically significant among the 4 groups. Regarding induction immunosuppressive therapy, a statistical significance was found between the 4 groups regarding the presence and type of induction therapy, with no statistical significance regarding the type of maintenance immunosuppression. There was no statistical significance between the 4 groups regarding the incidence of acute and chronic rejection. We also found recurrence of original kidney disease to be statistically significant in the 4 groups, particularly in the group that included patients with glomerular disease, where the highest rate of recurrence was reported in patients with focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis, and patient and graft survival was also statistically significant. CONCLUSIONS: The original kidney disease has an effect on renal allograft function and graft and patient survival.

Effect of pretransplant hepatitis C virus on the development of new-onset diabetes mellitus after transplant in Egyptian living-donor renal allotransplant recipients at Mansoura Urology and Nephrology Center.

OBJECTIVES: New-onset diabetes mellitus after transplant is a common complication in renal allograft recipients. Recently, a high prevalence of diabetes mellitus has been reported in patients with chronic hepatitis C virus. The association between hepatitis C and diabetes mellitus is well demonstrated in the general population, but some controversy still exists. This work aimed to study the effect of pretransplant hepatitis C virus on the development of new-onset diabetes mellitus after transplant in Egyptian living-donor renal allotransplant recipients. MATERIALS AND METHODS: This retrospective single center study included 913 kidney transplant recipients who were transplanted at Mansoura Urology and Nephrology Center between 2000 and 2010. The patients were divided into 4 groups according to their hepatitis C virus serology and diabetic status. RESULTS: Pretransplant dialysis duration and number of blood transfusion units were statistically significant among both viremic and nonviremic groups. With respect to induction therapy, a highly statistical significance was observed between the 4 groups regarding presence and type of adjuvant therapy (P < .001). With respect to maintenance immunosuppression, high statistically significant results were observed regarding steroid and rapamycin between the 4 groups (P < .001) with lower significance regarding mycophenolate mofetil (P = .04) but no significance regarding azathioprine, cyclosporine, or tacrolimus therapy. Incidence of new-onset diabetes mellitus after transplant was statistically higher in the viremic than nonviremic group (P < .001). CONCLUSIONS: There was a positive correlation between incidence of new-onset diabetes mellitus after transplant and positive pretransplant hepatitis C virus status.

The Long-Term Effect of Hepatitis C Virus on the Outcome of Live-Donor Kidney Transplant Recipients. A Retrospective Study.

OBJECTIVES: Hepatitis C virus infection occurs frequently among end-stage renal disease patients. Moreover, its effect on long-term patient and renal graft survival is controversial. This study was performed to assess the long-term effect of hepatitis C virus on the outcome of kidney allografts. MATERIALS AND METHODS: We retrospectively analyzed 273 hepatitis B negative renal transplant recipients who were transplanted at Mansoura Urology and Nephrology Center, for whom hepatitis C virus RNA polymerase chain reaction results were available before transplant, and followed them for at least 17 years after transplant. We compared graft and patient survival rates between viremic group (study group) and nonviremic group (control group). We also studied posttransplant hepatic function, graft performance, and incidence of posttransplant diabetes mellitus. RESULTS: Hepatitis C virus was detected in sera of 195 patients (71%). No statistically significant increased risk for graft failure (P = .29) or patient death (P = .47) was found among the groups. Hepatitis C virus viremic transplant recipients had significantly greater frequencies of biochemical chronic liver disease (P = .01). However, we did not report significant differences regarding incidence, quantity of proteinuria, biopsy-proven acute rejection, chronic allograft nephropathy, and incidence of posttransplant diabetes mellitus between the studied groups. CONCLUSIONS: Hepatitis C virus infection was shown to increase the incidence of chronic hepatitis posttransplant. However, no statistically significant adverse effect on long-term renal graft and patient survival was noted.