The impact of CYP3A4 and CYP3A5 genetic variations on tacrolimus treatment of living-donor Egyptian kidney transplanted patients.

BACKGROUND: Tacrolimus (TAC) is the mainstay of immunosuppressive regimen for kidney transplantations. Its clinical use is complex due to high inter-individual variations which can be partially attributed to genetic variations at the metabolizing enzymes CYP3A4 and CYP3A5. Two single nucleotide polymorphisms (SNPs), CYP3A4*22 and CYP3A5*3, have been reported as important causes of differences in pharmacokinetics that can affect efficacy and/or toxicity of TAC. OBJECTIVE: Investigating the effect of CYP3A4*22 and CYP3A5*3 SNPs individually and in combination on the TAC concentration in Egyptian renal recipients. METHODS: Overall, 72 Egyptian kidney transplant recipients were genotyped for CYP3A4*22 G>A and CYP3A5*3 T>C. According to the functional defect associated with CYP3A variants, patients were clustered into: poor (PM) and non-poor metabolizers (Non-PM). The impact on dose adjusted through TAC concentrations (C0) and daily doses at different time points after transplantation was evaluated. RESULTS: Cyp3A4*1/*22 and PM groups require significantly lower dose of TAC (mg/kg) at different time points with significantly higher concentration/dose (C0/D) ratio at day 10 in comparison to Cyp3A4*1/*1 and Non-PM groups respectively. However, CyP3A5*3 heterozygous individuals did not show any significant difference in comparison to CyP3A5*1/*3 individuals. By comparing between PM and Non-PM, the PM group had a significantly lower rate of recipients not reaching target C0 at day 14. CONCLUSION: This is the first study on Egyptian population to investigate the impact of CYP3A4*22 and CYP3A5*3 SNPs individually and in combination on the TAC concentration. This study and future multicenter studies can contribute to the individualization of TAC dosing in Egyptian patients.

Efficacy and safety of ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with chronic kidney disease.

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) prevalence inchronic kidney disease (CKD) patients is significantly higher than in the general population. This study evaluated the efficacy and safety of combined ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with renal impairment. PATIENTS AND METHODS: Our study included 829 patients with normal kidney functions (group 1) and 829 patients with CKD (group 2),which were subdivided into patients not requiring dialysis (group 2a) and those on hemodialysis (group2b). Patients received regimens of ombitasvir/paritaprevir/ritonavir with or without ribavirin or sofosbuvir/ombitasvir/paritaprevir/ritonavir with or without ribavirin for 12 weeks. Clinical and laboratory assessment was done before treatment, and patients were followed up for12 weeks after treatment. RESULTS: The sustained virological response (SVR) at week 12 was significantly higher in group 1 than in the other three groups/subgroups, being 94.2% vs 90.2%, 90%, and 90.7%, respectively. The regimen with the highest SVR was ombitasvir/paritaprevir/ritonavir with ribavirin. The most common adverse event was anemia, which was more common in group 2. CONCLUSION: Ombitasvir/paritaprevir/ritonavir-based therapy in chronic HCV patients with CKD is highly effective, with minimal side effects despite ribavirin-induced anemia.

Seasonal variation of lupus nephritis in a cohort of Egyptian patients.

INTRODUCTION: Systemic lupus erythematosus is an autoimmune multisystem disease; renal affection is one of its most common manifestations. The effect of environmental factors on lupus nephritis flares is not fully understood. METHODS: This is a retrospective study that included 200 patients with lupus nephritis flares. All patients had confirmed diagnosis of lupus nephritis on histopathological examination. Lupus nephritis flares were defined by either (1) nephritic flare: defined as increased proteinuria or serum creatinine concentration; abnormal urinary sediment or a reduction in creatinine clearance, or (2) proteinuria flare defined as persistent increase in proteinuria > 0.5-1.0 g/day after achieving complete remission; doubling to > 1 g/day after achieving partial remission. The time of renal flare (month of the year) was recorded to determine the effect of seasonal variation on lupus nephritis flares. RESULTS: The median age for the patients was 33 years (IQR = 13); 92% of patients were females. The median duration of lupus was 7 years (IQR = 6). The median serum creatinine was 1.4 mg/dl, median serum urea level was 32, and median UPCR was 2.4 gm/dl. The highest incidence of flares occurred in June (14%) and July (12.5%) (p = 0.003). CONCLUSION: Seasonal pattern of LN flare was observed in our study in Egyptian cohort of patients, with most flares observed during meteorological summertime. Larger studies are needed to confirm this seasonal pattern. Key Points • Flares of lupus nephritis are common in patients with systemic lupus erythromatosus. • A seasonal pattern of flares of lupus nephritis was observed in our study. This seasonal pattern has been observed by previous studies in variable ethnicities and variable climatic circumstances.

Kidney complications of parasitic diseases.

Parasitic agents have been known to cause human disease since ancient times and are endemic in tropical and subtropical regions. Complications of parasitic diseases, including kidney involvement, are associated with worse outcomes. Chagas disease, filariasis, leishmaniasis, malaria and schistosomiasis are important parasitic diseases that can damage the kidney. These diseases affect millions of people worldwide, primarily in Africa, Asia and Latin America, and kidney involvement is associated with increased mortality. The most common kidney complications of parasitic diseases are acute kidney injury, glomerulonephritis and tubular dysfunction. The mechanisms that underlie parasitic disease-associated kidney injury include direct parasite damage; immunological phenomena, including immune complex deposition and inflammation; and systemic manifestations such as haemolysis, haemorrhage and rhabdomyolysis. In addition, use of nephrotoxic drugs to treat parasitic infections is associated with acute kidney injury. Early diagnosis of kidney involvement and adequate management is crucial to prevent progression of kidney disease and optimize patient recovery.

Neglected Tropical Diseases and the Kidneys.

Clinical Background: Neglected tropical diseases (NTDs), a major public health problem, frequently affect the kidneys. In this chapter, we discuss the NTDs which have been most studied in terms of renal involvement and present a summary of current knowledge regarding kidney disease in all NTDs, through a literature review. Epidemiology: There are more than 1 billion people in the world affected by NTDs. These infections can also be one of the etiologies of chronic kidney disease of unknown cause, which is another great public health problem in Latin America, and these diseases are most prevalent in young people, males, in their productive years, which increases its burden on the society. Challenges: Early detection of renal involvement is crucial to decrease the magnitude of the manifestations and hence allow more favorable outcomes, and for this purpose novel kidney injury biomarkers are a promising solution. Unfortunately, specific treatments for NTDs have not changed in the last decades, as novel drugs have not been investigated. Prevention and Treatment: Prevention includes vector control, blood bank tests, periodic serologic surveys, and health surveillance in general in order to decrease oral transmission and to maintain good hygiene conditions. Recently, many potential therapeutic targets have been evidenced in both clinical and experimental studies.

Erratum to: Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases.

[This corrects the article DOI: 10.1186/s40824-016-0068-0.].

Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases.

BACKGROUND: Bio-products from stem/progenitor cells, such as extracellular vesicles, are likely a new promising approach for reprogramming resident cells in both acute and chronic kidney disease. Forty CKD patients stage III and IV (eGFR 15-60 mg/ml) have been divided into two groups; twenty patients as treatment group "A" and twenty patients as a matching placebo group "B". Two doses of MSC-derived extracellular vesicles had been administered to patients of group "A". Blood urea, serum creatinine, urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used to assess kidney functions and TNF-α, TGF-ß1 and IL-10 have been used to assess the amelioration of the inflammatory immune activity. RESULTS: Participants in group A exhibited significant improvement of eGFR, serum creatinine level, blood urea and UACR. Patients of the treatment group "A" also exhibited significant increase in plasma levels of TGF-ß1, and IL-10 and significant decrease in plasma levels of TNF-α. Participants of the control group B did not show significant improvement in any of the previously mentioned parameters at any time point of the study period. CONCLUSION: Administration of cell-free cord-blood mesenchymal stem cells derived extracellular vesicles (CF-CB-MSCs-EVs) is safe and can ameliorate the inflammatory immune reaction and improve the overall kidney function in grade III-IV CKD patients.

Eight-year outcomes of 'the Cairo Kidney Centre sequential protocol'.

OBJECTIVES: To describe the long-term results of a previously developed a sirolimus-based sequential immunosuppression protocol for kidney transplant comprising 2 phases: sirolimus + cyclosporine + prednisolone for 3 months followed by sirolimus + prednisolone + mycophenolate mofetil with steroid minimization the first year. Two-year outcomes of patients on this protocol (group A) showed equivalent patient and graft survival, yet with significantly better function, compared with those on cyclosporine + mycophenolate mofetil + prednisolone (group B). MATERIALS AND METHODS: We report the 8-year outcomes in the same cohort (76 patients in group A and 37 in group B). RESULTS: 42% switched from group A to B versus 43% switching from B to A. Intent-to-treat patient survivals at 5 and 8 years were 88% and 85.5% for group A, and 78% and 73% for group B. Death-censored graft survivals were 93% for group A and 95% for group B. Graft function was significantly better at 8 years, with 91% of group A patients compared with 50% in group B having estimated glomerular filtration rates > 45 mL/min/1.73 m2, and a significantly lower incidence of chronic allograft nephropathy in the former. Secondary parameters including blood pressure control, new onset diabetes mellitus, proteinuria and other drug-related adverse events showed no significant differences between the groups. CONCLUSIONS: The sirolimus-based sequential immunosuppression protocol was well tolerated in 58% of patients. The intent-to-treat and patients-ontherapy analyses revealed that it was equivalent to the widely used cyclosporine + mycophenolate mofetil + prednisolone protocol regarding patient and graft survival. It is associated with better graft function and lower incidence of chronic allograft nephropathy in 8 years' follow-up. The incidence of drug-related adverse reactions was not statistically different from those in the comparator.

Effect of multiple access tracts during percutaneous nephrolithotomy on renal function: evaluation of risk factors for renal function deterioration.

PURPOSE: To assess the impact of multiple access tracts during percutaneous nephrolithotomy (PCNL) on short- and midterm renal function, and to determine risk factors predicting renal function deterioration and/or recoverability. PATIENTS AND METHODS: Patients undergoing PCNL with multiple punctures were prospectively enrolled. Preoperative evaluation included dimercaptosuccinic acid and diethylenetriaminepentaacetic acid renography. Patients were classified according to baseline renal function into patients with normal (<1.4 mg/dL) serum creatinine (group A) and patients with elevated (≥1.4 mg/dL) serum creatinine (group B). Patients were followed with serial serum creatinine evaluations and a repeated renography at 12 months. Factors evaluated for possible impact on renal function changes included preoperative renal function, number of access tracts, hypertension, and diabetes mellitus. RESULTS: There were 102 patients 21 to 65 (mean 39.9) years who completed the study. Fifty patients (group A) had normal preoperative serum creatinine levels and glomerular filtration rate (GFR), which showed no statistically significant change 12 months after PCNL. Fifty-two patients had baseline renal impairment (group B), and they experienced statistically significant worsening of the serum creatinine level and GFR at 12 months postoperatively (P<0.001). Ten (19.23%) patients in group B had a significant deterioration of GFR more than 25%. Independent risk factors for this poor outcome were elevated (≥1.4 mg/dL) preoperative serum creatinine level, diabetes, and hypertension. CONCLUSION: PCNL with multiple tracts carries a risk of adversely affecting renal function. Preoperative baseline renal impairment, diabetes, and hypertension are risk factors for significant renal function deterioration after the procedure.

The Association between Fibroblast Growth Factor-23 and Vascular Calcification Is Mitigated by Inflammation Markers.

BACKGROUND: Fibroblast growth factor-23 (FGF-23) has been linked to vascular calcification, ventricular hypertrophy and mortality in chronic kidney disease (CKD), although these links may not be direct and independent. Similar grave outcomes are associated with inflammation and oxidative stress in CKD. Recently, accumulating evidence has linked components of phosphate homeostasis to inflammation and oxidative stress. The interaction between the triad of inflammation, FGF-23 and cardiovascular outcomes is underinvestigated. METHODS: We studied 65 patients with stage 5 CKD on hemodialysis. Serum levels of FGF-23, high-sensitivity C-reactive protein (hsCRP), endogenous soluble receptor of advanced glycation end products (esRAGE), advanced oxidation protein products (AOPP), parathormone, lipids, calcium and phosphorous were measured. The aortic calcification index (ACI) was determined using non-contrast CT scans of the abdominal aorta. RESULTS: FGF-23 was elevated (mean: 4,681 pg/ml, SD: 3,906) and correlated with hsCRP, esRAGE, AOPP, dialysis vintage and phosphorus in univariate analysis. In multiple regression analysis, hsCRP, AOPP and phosphorus but not esRAGE were all significantly correlated to FGF-23 (R2 = 0.7, p < 0.001). In univariate analysis, ACI correlated with hsCRP, esRAGE, FGF-23, dialysis vintage, systolic blood pressure (BP) and serum cholesterol. In multiple regression analysis not including inflammation markers, ACI was associated with FGF-23. However, inclusion of inflammation markers in another multiple regression analyses showed that ACI correlated with hsCRP, BP, dialysis vintage and esRAGE but not with FGF-23 (R2 = 0.65, p < 0.001). CONCLUSION: FGF-23 is strongly correlated to various markers of inflammation and oxidative stress in hemodialysis patients. The association between FGF-23 and vascular calcification was mitigated when corrected for inflammation markers.

The Cairo kidney center protocol for rapamycin-based sequential immunosuppression in kidney transplant recipients: 2-year outcomes.

OBJECTIVE: This study examines the outcomes of de novo kidney transplants treated by a sequential protocol, designed to target the succession of immunologic events following engraftment. SUBJECTS: A total of 113 sequential live-donor recipients were randomized into 2 arms. Patients in arm A received prednisolone, cyclosporine, and sirolimus for 3 months (phase 1), followed by replacement of cyclosporine with mycophenolate mofetil (phase 2). Those in arm B (controls) received prednisolone/cyclosporine/mycophenolate mofetil throughout the study. The primary endpoints were patient and graft survival rates at 2 years. Secondary endpoints included biopsy-proven acute rejection, early and late graft function, hypertension, and adverse reactions. RESULTS: The 2-year intent-to-treat patient and graft survival rates (95.8% vs 91.4% and 94.6% vs 90.2%) were numerically but not significantly higher in arm A. The overall incidence of biopsy-proven acute rejection was numerically lower (13.5% vs 18.9%), yet it occurred exclusively with cyclosporine C2 levels below 770 ng/mL (P = .28). Mean time for serum creatinine to reach 132 micromol/L was significantly longer in arm A (7.3 vs 2.9 days). Graft function at 2 years (eGFR, 70.2 vs 55.9 mL/min) and number of drugs needed to control blood pressure (mean 1.7 vs 2.25) were significantly more favorable in group A. Significant adverse effects for patients in arm A included proteinuria (36.8% vs 18.6%), hyperlipidemia (peak cholesterol > 7.75 mmol/L in 32.9% vs 23.7% of patients) and thrombocytopenia (platelet count < 100 x 109/L in 32.9% vs 13.5 % of patients). CONCLUSIONS: The described protocol reduced the incidence of biopsy-proven acute rejection in patients after kidney transplant, particularly in those with adequate cyclosporine blood levels. Despite the significantly higher incidence of certain adverse effects (ie, delayed graft function, proteinuria, hyperlipidemia, and transient thrombocytopenia), patient and graft survival rates at 2 years were numerically, though not statistically, improved in patients in arm A. At 2-year analysis, compared with patients in the control arm (arm B), graft function significantly improved in patients in arm A, and the number of drugs needed to control blood pressure was significantly lower.