Influence of CYP3A4*22 and CYP3A5*3 combined genotypes on tacrolimus dose requirements in Egyptian renal transplant patients.

BACKGROUND: Tacrolimus is a widely prescribed immunosuppressant agent for kidney transplantation. However, optimal dosing is challenging due to its narrow therapeutic index, potentially serious adverse effects, and wide inter-individual variability in pharmacokinetics. Cytochrome P450 3A (CPY3A) enzymes metabolize tacrolimus, so allelic variants such as CYP3A4*22 and CYP3A5*3 may contribute to individual differences in pharmacokinetics and therapeutic efficacy of tacrolimus. This study assessed the frequency and influences of CYP3A4*22 and CYP3A5*3 genotypes, alone and combined, on tacrolimus pharmacokinetics and dose requirements in Egyptian kidney transplant patients. METHODS: This is a prospective multicenter observational cohort study. Patients were genotyped for the CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746). Tacrolimus dose (mg), through blood level (ng/ml), and dose-adjusted trough concentration (C0/D) (ng/ml per mg/kg) were recorded during the first and third months post-transplantation and compared among genotype groups. RESULTS: The CYP3A4*22 allele was rare (3.2% of subjects) while the CYP3A5*3 allele was widespread (90.38%) in this cohort. At the third month post-transplantation, median C0/D was significantly higher among CYP3A4*22 carriers than CYP3A4*1/*1 (146.25 [100-380] versus 85.57 [27-370] ng/ml per mg/kg, p = 0.028). Patients harbouring the one copy of the CYP3A4*22 allele and the CYP3A5*3/*3 genotype (n = 5) were classified as poor tacrolimus metabolizers, the CYP3A5*3/*3 plus CYP3A4*1/*1 genotype as intermediate metabolizers (n = 60), and the CYP3A4*1/*1 plus CYP3A5*1/*1 genotype as normal metabolizers (n = 13). During the first month post-transplantation, C0/D was significantly greater in poor metabolizers (113.07 ng/ml per mg/kg) than intermediate and normal metabolizers (90.380 and 49.09 ng/ml per mg/kg) (p < 0.0005). This rank order was also observed during the third month. Acute rejection rate and renal function at discharge did not differ among genotypes. CONCLUSION: Pharmacogenetics testing for CYP3A4*22 and CYP3A5*3 before renal transplantation may help in the adjustment of tacrolimus starting dose and identify patients at risk of tacrolimus overexposure or underexposure.

Clinical value of adding Dapagliflozin in patients with nephrotic syndrome.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors in nephrotic patients on immunosuppression are underexplored. We evaluated dapagliflozin's impact in non-diabetic primary nephrotic syndrome. METHODS: Randomized controlled clinical trial was conducted on 60 non-diabetic primary nephrotic syndrome patients, equally assigned to dapagliflozin and control groups. All patients received the standard of care medication and the Dapagliflozin group received 10 mg dapagliflozin in addition. Demographic data, nephrotic syndrome etiology, proteinuria levels, eGFR, and immunosuppression doses, were well-matched. After 6 months of follow up primary outcomes included changes in and eGFR. RESULTS: Both groups exhibited significant reductions in proteinuria after 6 months, with the dapagliflozin group achieving a mean UPCR reduction of - 94.7%, and the control group - 86.7% (p < 0.001). However, the comparative change in proteinuria between both groups did not reach statistical significance (p = 0.158). Dapagliflozin initially led to a transient eGFR decline. Dapagliflozin also resulted in a significant mean body weight reduction (p < 0.001) and notable improvements in triglyceride levels compared to the control group (p = 0.045). CONCLUSION: In primary nephrotic syndrome patients, adjunct dapagliflozin may enhance the standard of care. While notable, the reduction in proteinuria was comparable to that of the control group by the study's end. Furthermore, after 6 months, eGFR remained stable in both groups. However, significant weight loss and serum triglyceride reduction were particularly pronounced in the dapagliflozin group. Further long-term investigations are necessary to address potential immunosuppression-related confounding effects in patients with primary glomerular disease.

The burden of HCV among prevalent hemodialysis patients after the National Egyptian HCV Eradication program.

In the first phase of its treatment program, Egypt aimed to treat 250,000 people annually until 2020, thereby reducing the number of viremic patients and limiting hepatitis C virus (HCV) transmission. Egypt strives to eradicate HCV and HCV-associated morbidity by 2030. This study aimed to determine the prevalence of HCV infection among end-stage renal disease patients and the reasons for non-treatment among those offered free medication. This multi-center cross-sectional study was conducted during the period from November 2022 to April 2023. The study included 500 patients receiving hemodialysis (HD) sessions on a regular basis for more than three months in Dakahlia Governorate. According to patients` medical history, we found that 23.4% of patients had previous HCV infection. Of these, 12.6% received treatment, and 10.8% did not receive treatment due to a variety of reasons. For instance, some patients were unaware of the drug's availability, five patients (1%) feared side effects, 43 patients (8.6%) did not require treatment, and five patients (1%) had other causes as contraindications of drugs, noncompliance and deterioration of health status. In addition, 20.4% of patients were reported to have fully recovered, while 0.8% had a recurrence. After investigations, 1% of patients had positive hepatitis B surface antigen (HbsAg), 23.4% positive HCV Ab, and 4.2% positive HCV by the polymerase chain reaction. In conclusion, the low prevalence of HCV among HD patients confirms that HCV infection is not currently a significant health concern among patients on maintenance HD.

Effect of taurolidine citrate and unfractionated heparin on inflammatory state and dialysis adequacy in hemodialysis patients.

BACKGROUND AND AIM: HD patients using dialysis catheters have been associated with chronic inflammatory state. In Egypt 6.6% of HD patients use catheters, of which short term catheters represent 59.6% and 40.4% with long-term catheters. In this study, we aimed to assess the effect of Taurolidine citrate and unfractionated heparin combination (Taurolock-hep500™) as a lock solution compared to unfractionated heparin alone on inflammatory markers, incidence of catheter related blood stream infections (CRBSI) and dialysis adequacy in HD patients with temporary HD catheters only, for 4 weeks duration. METHODS: Sixty ESRD patients from hemodialysis units in Ain-Shams University hospitals (ASUH) at the time of catheter insertion we enrolled in our study. They were randomized into two groups: Group 1: Thirty patients received Taurolock-hep500™ as a catheter lock solution at the end of each hemodialysis session. Group 2: Thirty patients received unfractionated heparin as a catheter lock solution. hsCRP and IL-6 were measured at baseline and 1 month after using the lock solutions. Blood cultures were done in patients who developed symptoms of catheter related infections. RESULTS: At the end of the study, Inflammatory markers were significantly higher in group 2 (p-value: 0.045, 0.001, and 0.018 for WBCs, hsCRP and IL-6, respectively). Group 1 had better dialysis adequacy assessed by URR (p-value: 0.007 and 0.001, respectively). CRBSI were demonstrated in nine patients in group 2 (30%) in contrast to one patient only in group 1(3.3%) (p-value: 0.006) with pseudomonas being the most common isolated organism (27.7%). CONCLUSION: Use of (Taurolock-hep500™) for temporary hemodialysis catheters was associated with lower levels of inflammation markers and lower incidence of CRBSI and better catheter performance.

The effect of hemodiafiltration vs. high-flux hemodialysis on alpha 1-microglobulin level and dialysate albumin loss using a dialyzer surface area of 2.6 m².

Dialysis therapy has remarkably evolved through the innovation in dialyzers and hemodialysis modalities, enhancing patients' quality of life. The efficacy of dialysis can be determined by measuring the reduction ratio (RR) of middle molecules, such as alpha 1-microglobulin (A1M). In this study, we tested a high-flux dialyzer, BIOPURE (Biorema) 260 HF, with a surface area (SA) of 2.6 m2, in terms of A1M removal and concurrent albumin loss in dialysate while receiving high-flux hemodialysis (HF-HD) and post-dilution online hemodiafiltration (OL-HDF). This crossover study comprised 25 patients who received a session of HF-HD using the BIOPURE (Biorema) 260 H, followed by a session of post-dilution OL-HDF. A washout period of 2 weeks was instilled between the two sessions, during which the patients received HF-HD using high-flux dialyzers (maximum SA 2.0 m2). All patients' hourly dialysate albumin and pre/post dialysis concentrations of A1M were measured. The dialyzer used in this study resulted in significantly higher A1M RR of 41.9±7.93% with HDF than with HF-HD 27.12±7.65% (p < 0.001), and a median cumulative dialysate albumin loss of 2.97g (IQR 1.98 - 3.37), and 0.67g (IQR 0.49 - 1.13) with HDF and HF-HD, respectively. In conclusion, the dialyzer BIOPURE (Biorema) 260 HF (SA 2.6 m2) is efficient in eliminating A1M, especially with OL-HDF compared to HF-HD, with acceptable albumin loss in the dialysate.

Value of Sodium-Glucose Co-Transporter 2 Inhibitor Versus Traditional Medication in Microalbuminuric Diabetic Patients.

BACKGROUND: Sodium glucose co-transporter 2 inhibitor (SGLT2i) is a new arment in the prevention and treatment of diabetic kidney disease with a potential effect on reducing and preventing Chronic Kidney Disease (CKD) progression. OBJECTIVE: To evaluate the effect of SGLT2 inhibitor in comparison to traditional medication in diabetic patients with microalbuminuria. METHODS: A total of 60 diabetic patients with microalbuminuria were divided into group I, where 30 patients were treated by traditional medications (RAAS blockers) and group II where 30 patients were treated by Dapagliflozin added to the traditional medications. All patients were followed up for 6 months and their Urine Albumin/Creatinine Ratio (UACR) and eGFR changes were monitered. RESULTS: UACR significantly declined after 6 months of treatment in group II with a p-value <0.001. There were no significant eGFR changes between both groups. Systolic blood pressure decreases in both groups, but the decrease was highly significant in group II (pvalue<0.001). Diastolic blood pressure decreases significantly in both groups (p-value<0.001). Also, bodyweight reduced significantly in group II with a p-value<0.001. CONCLUSION: Dapagliflozin, when added to traditional medications (RAAS Blockers), leads to a significant reduction in microalbuminuria with no significant eGFR changes.

Incidence of acute kidney injury among COVID-19 patients in Egypt.

BACKGROUND: Despite the fact that the fundamental characteristics of coronavirus disease-2019 (COVID-19) are respiratory manifestations, multi-organ failure including the kidney has been documented. There are no clear comparisons of COVID-19 cases with and without acute kidney injury (AKI) to show whether there are aspects of acute kidney injury progression path or outcome that are unique to this disease. METHODS: In this work, we analyzed the data of 734 COVID-19 cases admitted to the Ahmad Maher Teaching Hospital in Cairo, Egypt, between June 6 and July 25, 2020. Data on demographics, comorbidities, laboratory results, and outcomes were assessed. To assess the incidence rate of AKI in Egyptian COVID-19 patients, comparisons were carried out between home-isolated COVID-19 patients, hospitalized COVID-19 patients, and ICU COVID-19-patients with or without AKI. RESULTS: AKI was more common in hospitalized mild COVID-19 patients than in home-isolated and ICU COVID-19 patients (15.0% versus 10.8% and 14.2%, respectively). The overall occurrence rate of AKI was significantly higher in COVID-19 patients (n=91, 14%). Hemodialysis, on the other hand, was required in 76% of the extreme ICU COVID-19 patients who developed AKI (22/29). The absolute number of patients with AKI COVID-19 who required hemodialysis was 34 (37%). This accounted for 5.2% of all COVID-19 patients and 37% of those with AKI. The mortality rate in COVID-19 patients with or without AKI was 15.4% and 4.8%, respectively. CONCLUSION: AKI in our COVID-19 patients is associated with a high mortality rate in ICU-COVID-19 patients. Our findings suggest that COVID-19 patients, particularly ICU COVID-19 patients, should be closely monitored for the development of AKI. Early identification of AKI, as well as prompt intervention, can improve COVID-19 patient outcomes.

Paraoxonase-1 (PON1) activity as a risk factor for atherosclerosis in chronic renal failure patients.

Paraoxonase is a high-density lipoprotein-associated enzyme and has been shown to reduce the susceptibility to low-density lipoprotein peroxidation. This study aimed to investigate the activity of serum paraoxonase in uremic patients on hemodialysis (HD) and in the predialysis period, and to evaluate the correlations of vascular disease with paraoxonase activity. Thirty patients with chronic renal failure (CRF) undergoing HD (group 1), 30 patients with CRF under conservative treatment (group 2), and 30 healthy controls (group 3) were included. Basal, salt-stimulated, and arylesterase activity were tested by UV spectrophotometry. Serum lipid parameters were determined. B-Mode Doppler ultrasound was used to assess common carotid intima-media thickness (IMT). Basal paraoxonase, salt-stimulated, and arylesterase activity showed no significant difference between group 1 and group 2. However, it was significantly lower in group 1 and in group 2 than controls. Carotid IMT was significantly higher in group 1 than group 2 and both were significantly higher than controls. Basal paraoxonase-1 (PON1), salt-stimulated PON1, and arylesterase activity correlate with BUN, but only basal PON1 and salt-stimulated PON1 correlate with serum albumin. Linear regression showed that the most significant determinant of carotid IMT was PON1 arylesterase activity in group 1 and arylesterase activity and basal PON1 activity in group 2. Patients with CRF, whether under HD or conservative treatment, have reduced basal and stimulated paraoxonase activities, and this could be an important factor causing increased vascular disease in those patients. Modifying this factor can be of great value to protect against this common complication.

Intradialytic changes of serum magnesium and their relation to hypotensive episodes in hemodialysis patients on different dialysates.

Magnesium is a crucial mineral, involved in many important physiological processes. Magnesium plays a role of maintaining myocardial electrical stability in hemodialysis patients. Intradialytic hypotension is a common complication of dialysis and it is more common with acetate dialysate. The significance of the intradialytic changes of magnesium and their relation to parathyroid hormone (PTH) level and calcium changes during dialysis, and their relation to hypotensive episodes during dialysis are interesting. The aim of this work is to investigate the intradialytic changes of serum magnesium in chronic hemodialysis patients with different hemodialysis modalities and the relation to other electrolytes and to PTH, and also the relation to intradialytic hypotension. The present study was conducted on 20 chronic renal failure patients. All patients were on regular hemodialysis thrice weekly 4 hr each using acetate dialysate (group I). To study the effect of an acetate-based dialysate vs. a bicarbonate-based dialysate on acute changes of magnesium, calcium, phosphorus, and PTH during a hemodialysis session, the same patients were shifted to bicarbonate dialysis (group II). All patients were subjected to full history and clinical examination, predialysis laboratory assessment of blood urea nitrogen (BUN), serum creatinine, albumin, and hemoglobin, serial assessment of magnesium, calcium, phosphorus, and parathyroid hormone at the start of the hemodialysis session, 2 hr later, and at the end of the session, blood pH, and electrocardiogram (ECG) presession and postsession. All patients were urged to fix their dry weight, diet, and current medications. None of the patients had diabetes, neoplasia, liver disease, or cachexia, nor had they been recently on magnesium-containing drugs or previously parathyroidectomized. Hemodialysis sessions were performed by volumetric dialysis machines using the same electrolyte composition. Magnesium level significantly increased in the bicarbonate group at the end of dialysis (0 hr: 2.73+/-0.87, 2 hr: 3.21+/-1.1, and at 4 hr: 5.73+/-1.45 mg/dL, p value <0.01), while it significantly decreased in the acetate group (0 hr: 3.00+/-0.58, 2 hr: 2.26+/-0.39, 4 hr: 1.97+/-0.33 mg/dL, p value <0.01). Calcium level significantly increased in the bicarbonate group (p=0.024) but not in the acetate group. Phosphorus level significantly decreased in both acetate and bicarbonate groups. PTH level did not significantly change in either group, p value > or =0.05. Blood pH significantly increased, changing from acidic to alkaline pH, with both modalities of hemodialysis. ECG showed no significant changes during sessions with either type of dialysate. Hypotension was significantly higher in group I compared with group II (p=0.01), and this hypotension was positively correlated with a decrease in serum magnesium level in group I. Intradialytic changes in serum magnesium have no correlation with intradialytic changes in serum calcium or with PTH level. However, it was significantly correlated with hypotension during the dialysis session, especially with acetate dialysate. Further investigations are needed to determine whether or not this is true in patients using bicarbonate dialysis.