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 previously common post-kidney transplant Kaposi sarcoma has become non-existent for a decade: an Egyptian experience.

BACKGROUND: De novo malignancy is a worrying complication after kidney transplantation; the type of which may vary due to factors such as the prevalence of viral infection and race. Kaposi sarcoma used to be the most common malignancy among our patients constituting more than one-third of cancers. Nevertheless, we noticed that Kaposi sarcoma has not been observed for a long period. Therefore, we conducted this study to explore such observation. METHODS: Data of all kidney transplant recipients were retrieved and retrospectively analyzed. Their total number was 3126 patients. Their mean age was 28.71 ± 10.97 years and of them, 823 (26.3%) were females. The pattern of Kaposi sarcoma throughout the last decade as well as the preceding three decades was studied. The possible relation between the disappearance of Kaposi sarcoma and three paradigm shifts in our practice, namely the use of mTOR inhibitors, steroid-free regimen and CMV prophylaxis was explored. RESULTS: Since 2010, no new cases of Kaposi sarcoma have been observed. In addition, patients who have been transplanted after 2006 did not develop such malignancy. Patients who received CMV prophylaxis and/or were maintained on mTOR inhibitor or steroid-free regimens have not developed Kaposi sarcoma. Moreover, CMV prophylaxis had a statistically significant difference when compared to a homogenous group without CMV prophylaxis. However, Kaplan-Meier analysis of patients of the three policies and their counterpart groups showed comparable results. CONCLUSION: Kaposi sarcoma, which was previously the most common malignancy, is no longer observed for almost a decade among our kidney transplant recipients. m-TOR inhibitors, steroid-free regimen and CMV prophylaxis policy are possible contributing factors. Nevertheless, only CMV prophylaxis policy had a statistically significant relation to the disappearance of Kaposi sarcoma.

CYP3A5 Gene-Guided Tacrolimus Treatment of Living-Donor Egyptian Kidney Transplanted Patients.

BACKGROUND: Tacrolimus is an approved first-line immunosuppressive agent for kidney transplantations. Part of interindividual and interethnic differences in the response of patients to tacrolimus is attributed to polymorphisms at CYP3A5 metabolic enzyme. CYP3A5 gene expression status is associated with tacrolimus dose requirement in renal transplant recipients. MATERIALS AND METHODS: In this study, we determined the allelic frequency of CYP3A5*3 in 76 renal transplanted patients of Egyptian descent. Secondly, we evaluated the influence of the CYP3A5 gene variant on tacrolimus doses required for these patients as well on dose-adjusted tacrolimus trough-concentrations. RESULTS: The CYP3A5*3 variant was the most frequent allele detected at 85.53%. Additionally, our results showed that, mean tacrolimus daily requirements for heterozygous patients (CYP3A5*1/*3) were significantly higher compared to homozygous patients (CYP3A5*3/*3) during the first year after kidney transplantation. CONCLUSION: This is the first study in Egypt contributing to the individualization of tacrolimus dosing in Egyptian patients, informed by the CYP3A5 genotype.

Efficacy and safety of the new antiviral agents for the treatment of hepatitis C virus infection in Egyptian renal transplant recipients.

PURPOSE: Hepatitis C virus (HCV) infection in kidney transplant recipients (KTRs) is common and can impact on patient and graft survival rates. The efficacy and safety of direct-acting antivirals (DAAs) to treat genotype-4 HCV-infected KTRs have not been fully established. METHODS: A prospective, single-arm, single-center study was conducted at Mansoura Urology/Nephrology Center (Mansoura University, Egypt). 114 HCV RNA(+) genotype 4 KTRs were enrolled in this study after a hepatology consultation and consented to start treatment with interferon-free DAAs. A sofosbuvir-based regimen was given to 109 recipients that had creatinine clearance (Crcl) of > 30 mL/min/1.73 m2. Ritonavir-boosted paritaprevir/ombitasvir was prescribed to five recipients with Crcl < 30 mL/min/1.73 m2. RESULTS: The mean age of the cohort was 45.2 ± 11.2 years; most were male. The mean duration with a transplant was 14.2 ± 3.5 years, with different immunosuppressive regimens, mostly based on calcineurin inhibitors. A rapid virological response (RVR), i.e., clearance of viral load, was achieved in 100% at 4 weeks after starting treatment. All patients had a sustained virological response (SVR) at 12 and 24 weeks posttreatment, with one exception. During DAA therapy serum creatinine increased in 12 patients. In three, this was concomitant with elevated calcineurin inhibitor and sirolimus trough levels. Graft biopsies were performed in 8 of these 12 patients: these revealed an acute rejection in 4 cases (acute cellular rejection grade-1A: n = 2, and grade-1B: n = 2). The rejection episodes occurred at 4-6 weeks after starting treatment. CONCLUSION: DAAs were highly efficacious and safely treated genotype-4 HCV-infected KTRs and had no significant adverse effects on graft function/survival.

Treatment of hepatitis C infection among Egyptian hemodialysis patients: the dream becomes a reality.

BACKGROUND AND AIMS: New direct-acting antiviral drugs have become the corner-stone treatment for HCV infection: they show promising results with accepted side-effects and low dropout rates. One of the available regimens is paritaprevir/ombitasvir/ritonavir (PTV/OMV/RTV). Our aim was to study the efficacy and safety of this drug regimen among HCV-positive hemodialysis patients. METHODS: This prospective single-center study was performed in the Urology and Nephrology Center, Mansoura University, Egypt. Ninety-six maintenance hemodialysis patients were screened for HCV antibodies. Positive results were found in 46 patients (47.9%). HCV PCR was assessed in all HCV-antibody-positive patients; positive results were found positive for 38 (82%); all patients were HCV genotype 4. Four patients were excluded due to advanced liver cirrhosis, liver malignancy, or metastatic breast cancer. Thirty-four patients were prescribed PTV/OMV/RTV for 3 months to treat HCV. RESULTS: Mean age was 43.2 ± 11.9 years. Most patients were male (67.6%). There was a rapid response to treatment: HCV PCR became negative by 4 weeks after starting treatment. By 12 and 24 weeks post-DAA therapy, there was a sustained viral response (SVR 12, SVR 24) in 100% of patients with improved liver-enzyme levels. CONCLUSION: The PTV/OMV/RTV regimen was safe and effectively treated Egyptian HCV-positive genotype-4 hemodialysis patients.

Diabetic Nephropathy Following Posttransplant Diabetes Mellitus.

Diabetic nephropathy is one of the main long-term diabetic microangiopathies that can complicate type 1 and 2 and other secondary forms of diabetes mellitus, including posttransplant diabetes mellitus. Posttransplant diabetes mellitus was initially reported in the 1960s, with case reports of recurrent and de novo diabetic nephropathy after kidney transplant reported in the early 2000s, mostly as a result of same-risk and precipitating factors of diabetic nephropathy as in native kidneys. The disease may appear early in view of the hyperfiltration risk of being a single grafted kidney. Here, we discuss risk factors, early serologic and genetic biomarkers for early detection, and strategies to avoid and delay the progression of diabetic nephropathy after posttransplant diabetes mellitus. In this overview of published literatures, we searched PubMed and MEDLINE for all articles published in English language between January 1994 and July 2018. Included studies reported on the prevalence, incidence, or determinants of post-transplant diabetes among renal transplant recipients and studies reporting diabetic nephropathy in their cohorts. Our review showed that avoidance or good control of posttransplant diabetes is the cornerstone in management of posttransplant diabetes mellitus and hence diabetic nephropathy. Control and avoidance can be commenced in the preparatory stage before transplant using validated genetic markers that can predict posttransplant diabetes mellitus. The use of well-matched donors with tailored immunosuppression (using less diabetogenic agents and possibly steroid-free regimens) and lifestyle modifications are the best preventative strategies. Tight glycemic control, early introduction of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and possibly conversion to less diabetogenic regimens can help to delay progression of diabetic nephropathy.

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.

Posttransplant Erythrocytosis Among Egyptian Living-Donor Kidney Transplant Recipients.

OBJECTIVES: The goal when treating patients with end-stage renal disease is to increase patient survival and to provide a better quality of life, both of which can be achieved by kidney transplant. Identifying problems associated with kidney transplant is an essential step toward improved graft function. Here, we evaluated posttransplant erythrocytosis, a frequent complication among kidney transplant recipients. MATERIALS AND METHODS: In this single-center retro-spective study, we identified 1850 kidney transplant recipients who were transplanted at the Mansoura Urology and Nephrology Center (Mansoura University, Mansoura, Egypt) from 1990 and 2013. From these patients, we identified 174 transplant recipients with posttransplant erythrocytosis and another 174 recipients without posttransplant erythrocytosis (control group). All recipients were evaluated retrospectively regarding incidence and risk factors for posttransplant erythrocytosis occurrence, graft function and survival, and patient survival. RESULTS: Both patient groups were comparable regarding age and sex (mean age of 32 years and higher percentage of male recipients in both groups). Degree of HLA class I and class II matching was not significantly different between groups. There were also no significant differences in immunosuppression protocols, although most patients were on steroid and cyclosporine therapy. Prevalence of acute and chronic rejection episodes was comparable between groups. Graft function was better in the posttransplant erythrocytosis group than in the control group, and higher patient survival was noted in patients with posttransplant erythrocytosis (P < .001). CONCLUSIONS: Posttransplant erythrocytosis was correlated with good graft function. In our study patients, those with posttransplant erythrocytosis had better graft and patient survival.

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.

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.

Long term prospective assessment of living kidney donors: single center experience.

Virtually, all studies reporting the outcomes of living kidney donation beyond the first year from donation were retrospective. In this prospective study, the outcome of 81 consecutive living kidney donors was thoroughly evaluated. Clinical, laboratory, and radiological assessments were carried out at predonation (basal), 3, 6, 12, and 24 months after donation. The mean age at time of donation was 37.8 ± 9.8 years and the majority was females (75.3%). The mean BMI increased significantly after donation (P < 0.04). The mean serum creatinine levels (mg/dl) were 0.75 ± 0.14, 1.01 ± 0.22, 0.99 ± 0.21, 0.98 ± 0.20, and 0.94 ± 0.20 (P < 0.0001). Likewise, the mean levels of measured creatinine clearance (mL/min) were 148.8 ± 35.7, 94.7 ± 26.6, 95.5 ± 24.6, 96.7 ± 20.2, and 101.6 ± 26.2 (P < 0.0001). The mean 24 hours urinary protein excretion (gm/dL) were 0.09 ± 0.03, 0.19 ± 0.18, 0.16 ± 0.09, 0.18 ± 0.25, and 0.17 ± 0.12 (P < 0.0001). There were significant increases in the means of the longitudinal and transverse diameters of the remaining kidney over time (P < 0.001). Out of 42 female donors, eleven female donors have got successful postdonation pregnancies. There were no reported surgical complications, either intra- or postoperative. Long-term follow-up is necessary for all living kidney donors through local institutional and world registries. This trial is registered with ClinicalTrials.gov NCT00813579.

Long-term outcome of live donor kidney transplantation for renal amyloidosis.

BACKGROUND: The short-term outcome of kidney transplantation in patients with amyloidosis has been reported. The aim of this study is to investigate long-term results in patients with renal amyloidosis. METHODS: We studied results of renal transplantation in 23 amyloidotic transplant recipients compared with those in a control group of 47 nonamyloidotic patients. Amyloidosis was secondary to familial Mediterranean fever (FMF) in 16 patients, whereas it was primary (idiopathic) in 7 transplant recipients. The 2 groups were homogeneous regarding age, sex, HLA matching, immunosuppression, and duration of transplantation. RESULTS: Five- and 10-year actuarial graft survival rates were similar in both groups (79.35% versus 84.04% and 65.92% versus 56.61%, respectively ). Five- and 10-year actuarial patient survival rates also were similar (80% versus 94% and 68% versus 87%, respectively). Moreover, 72.4% of controls experienced at least 1 rejection episode, whereas only 43.5% of amyloidotic transplant recipients experienced 1 or more such events (P = 0.02). Nonetheless, mean serum creatinine concentrations did not differ between the 2 groups during the observation period. Maintenance colchicine therapy prevented the recurrence of both FMF symptoms and amyloidosis. Recurrence was documented in only 1 amyloidotic transplant recipient (4.3%) 10 years posttransplantation. Significant gastrointestinal (GI) problems were more frequent in amyloidotic patients (65% versus 38%; P = 0.03). Amyloidotic patients with GI problems, except for 2 patients, were administered cyclosporine. Eleven of these patients had FMF, which appeared to reflect the effects of both cyclosporine and colchicine. Infections were similar in the groups; whereas amyloidotic patients had significantly lower blood pressures. CONCLUSION: In our experience, long-term (5 to 10 years) outcome of live related donor kidney transplantation in patients with amyloidosis is similar to that in the general transplant population.