Clinical and molecular characterization of primary hyperoxaluria in Egypt.

Primary hyperoxaluria (PH) is an autosomal recessive disorder of oxalate metabolism caused by pathogenic variants in either of three genes (AGXT, GRHPR or HOGA1). The study aimed at characterizing the clinical phenotypes as well as the genotypic spectrum of PH in Egypt. We screened 25 Egyptian patients suspected of PH for the three responsible genes by Sanger sequencing. We diagnosed 20 patients from 18 unrelated families, in which the natural history, family history, clinical features and genotypes were evaluated. PH patients were 15 males and 5 females ranging in age from 4 months to 31 years (median 8 years). Fifteen families were consanguineous (83%) and familial clustering was reported in six families (33%). Pathogenic variants in all 40 alleles were in AGXT, with none detected in GRHPR or HOGA1. We detected two novel pathogenic variants c.166-1_172dupGATCATGG (p.Asp58Glyfs*65) and c.766delC (p.Gln256fs*16) and seven previously reported variants in our cohort. This is the first study reporting the genotype of a considerable number of PH1 patients from Egypt. Our detected variants in the AGXT gene could form the basis for future genetic counseling and prenatal diagnosis in Egypt and surrounding populations.

Effect of pre and post-transplant body mass index on pediatric kidney transplant outcomes.

INTRODUCTION: Kidney transplantation (KT) has been established as an efficient treatment of end stage renal disease (ESRD) with the advantage of allowing the patient to live a nearly healthy life. We aimed to determine whether pre-transplant body mass index (BMI) affects renal allograft function and survival in pediatric KT recipients. METHODS: cross sectional cohort study included 50 post KT recipients (more than 3 years) with an age range of 10 to 15 years, regularly following at the Kidney Transplantation Outpatient Clinic, Cairo University Children's Hospital, were subjected to a detailed history and physical examination, laboratory investigation in the form of fasting blood glucose (FBG),oral glucose tolerance test (OGTT), lipid profile, hemoglobin A1c (HbA1c) and microalbuminuria. RESULTS: Pre- post- kidney transplant BMI has significant positive correlation with graft rejection episodes, HbA1c, FBG, BMI post-KT, total cholesterol, triglycerides, and low-density lipoprotein (p < 0.01). There was a statistically significant negative correlation between the mean difference of BMI (post - pre) and graft survival in years (p = 0.036). Obese patients displayed lower survival compared with non-obese subjects at 5 years, but this was statistically not significant (p-value = 0.165). CONCLUSION: obesity is an independent risk factor for graft loss and patient death in kidney transplantation. Careful patient selection with pre-transplantation weight reduction is mandatory to reduce the rate of early post-transplantation complications and to improve long-term outcomes.

Subtle cardiac dysfunction in nephropathic cystinosis: insight from tissue Doppler imaging and 2D speckle tracking echocardiography.

BACKGROUND: Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder that initially affects the kidney progressing to multi-organ failure due to accumulation of cystine in all tissue compartments. OBJECTIVE: The main objective of this study is the evaluation of cardiac function in cystinosis patients using non-conventional echocardiographic modalities like pulsed wave tissue Doppler imaging (PW-TDI) and 2D speckle tracking echocardiography (2D-STE). METHODS: This is a case control study conducted on fifteen patients with cystinosis and 15 normal controls. Echocardiography was done for all participants and PW-TDI was performed for measurement of S', E', A' velocities and myocardial performance index (MPI) at basal parts of septal, left ventricle (LV), and right ventricle (RV) free walls. 2D-STE was done for evaluation of global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) of LV. Mitral E and A velocities and tricuspid annular plane systolic excursion (TAPSE) were also measured. RESULTS: The GLS, GRS, and S' velocity at basal septum and LV lateral wall were significantly lower in patients denoting LV systolic dysfunction (p = 0.005, p < 0.0001, p = 0.001, p = 0.006, respectively), while E/E' were significantly higher in patients group denoting LV diastolic dysfunction (p < 0.001). For RV function, TAPSE, S', and E' velocity were significantly lower in patients group (p 0.013, p < 0.01, p = 0.05, respectively) indicating RV systolic and diastolic dysfunction. The TDI-derived MPI for both LV and RV were significantly higher in patients group (p < 0.0001, p < 0.01, respectively) indicating both ventricular systolic and diastolic dysfunction. For prediction of cardiac dysfunction among patients, the receiver operating characteristic (ROC) curve showed that GRS ≤ 29% had sensitivity 93.3% and specificity 100%, GLS > - 20.1% had sensitivity 66.7% and specificity 93.3%, LV-E/E' >7.87 had sensitivity 73.3% and specificity 93.3%, and MPI-LV > 0.36 had sensitivity 100% and specificity 93.3% while MPI-RV > 0.29 had sensitivity 80% and specificity 93.3% and TAPSE ≤ 19 mm had sensitivity 80% and specificity 73.3%. CONCLUSIONS: Patients with cystinosis have significant both left and right ventricular dysfunction, which can be better evaluated using the non-conventional echocardiographic modalities like TDI and 2D-STE for early detection of subtle cardiac dysfunction.

Left ventricular mass index and subendocardial myocardial function in children with chronic kidney disease, a transmural strain and three-dimensional echocardiographic study.

Introduction: Left ventricular hypertrophy (LVH) is the commonest myocardial response to chronic kidney disease (CKD); this response has been regarded detrimental as it impairs the blood flow to the deepest layers of the myocardium causing progressive myocardial dysfunction. The aim of these series is to assess the determinants of LVH in CKD patients and its impact on subendocardial function in such patients. Methods: This study has been conducted on 40 CKD patients (Group 1) and 40 age-matched controls, both groups were assessed by transmural echocardiography to determine the subepicardial and subendocardial global longitudinal strain (GLS) as an expression of the systolic function of each of those layers. LVH was assessed by calculation of left ventricle mass index (LVMI). Both groups underwent ambulatory blood pressure monitoring. Group 1 was assessed as regards lipid profile and insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR). Results: HOMA-IR proved to be a more important determinant of LV hypertrophy than SBP and DBP with a P of 0.01. Moreover subendocardial GLS was negatively correlated with LVMI with r = 0.69 and P < 0.01 denoting the negative effect. LVH plays on subendocardial function probably by impairing myocardial perfusion. Conclusion: This study points toward the importance of insulin resistance in aggravation of myocardial remodeling in CKD patients; more studies are warranted to examine the role of insulin Sensitizers in reversing such remodeling and restoring subendocardial function in such important systemic disorder.

Visfatin versus Flow-Mediated Dilatation as a Marker of Endothelial Dysfunction in Pediatric Renal Transplant Recipients.

BACKGROUND: Renal transplantation (RTx) is the treatment of choice for paediatric end-stage renal disease (ESRD). A major cause of morbidity and mortality after RTx is cardiovascular disease. Independent predictors of cardiovascular events were shown to constitute an endothelial dysfunction (ED). This study aims to evaluate Visfatin serum level in comparison to brachial artery flow-mediated dilatation (FMD) as a marker of endothelial dysfunction in paediatric RTx recipients. METHODS: Visfatin serum level has been evaluated in 30 patients on regular hemodialysis (HD), 36 patients post-RTx and 30 controls as a measure for ED, and has been compared to brachial artery FMD. RESULTS: Visfatin level in transplant recipients was significantly lower than the hemodialysis group as well as FMD was better in transplant recipients. In spite of marked improvement of FMD and marked reduction of visfatin in post-RTx no direct statistical correlation was found between serum Visfatin level and flow-mediated dilatation. CONCLUSION: Pediatric RTx recipients show lower serum Visfatin level and better FMD than those on regular hemodialysis, reflecting less endothelial dysfunction (ED) and less cardiovascular risk. FMD in kidney transplant recipients tends to be less than normal subjects while visfatin level of the same group is similar to controls. Pediatric RTx appears to have a positive impact on the growth development of children with ESRD.

Clinical spectrum of primary hyperoxaluria type 1: Experience of a tertiary center.

BACKGROUND AND AIM: Primary hyperoxalurias are rare inborn errors of metabolism resulting in increased endogenous production of oxalate that leads to excessive urinary oxalate excretion. Diagnosis of primary hyperoxaluria type 1 (PH1) is a challenging issue and depends on diverse diagnostic tools including biochemical analysis of urine, stone analysis, renal biopsy, genetic studies and in some cases liver biopsy for enzyme assay. We characterized the clinical presentation as well as renal and extrarenal phenotypes in PH1 patients. METHODS: This descriptive cohort study included patients with presumable PH1 presenting with nephrolithiasis and/or nephrocalcinosis (NC). Precise clinical characterization of renal phenotype as well as systemic involvement is reported. AGXT mutational analysis was performed to confirm the diagnosis of PH1. RESULTS: The study cohort included 26 patients with presumable PH1 with male to female ratio of 1.4:1. The median age at time of diagnosis was 6 years, nevertheless the median age at initial symptoms was 3 years. Thirteen patients (50%) were diagnosed before the age of 5 years. Two patients had no symptoms and were diagnosed while screening siblings of index patients. Seventeen patients (65.4%) had reached end-stage renal disease (ESRD): 6/17 (35.3%) during infancy, 4/17 (23.5%) in early childhood and 7/17 (41.29%) in late childhood. Two patients (7.7%) had clinically manifest extra renal (retina, heart, bone, soft tissue) involvement. Mutational analysis of AGXT gene confirmed the diagnosis of PH1 in 15 out of 19 patients (79%) where analysis had been performed. Fifty percent of patients with maintained renal functions had projected 10 years renal survival. CONCLUSION: PH1 is a heterogeneous disease with wide spectrum of clinical, imaging and functional presentation. More than two-thirds of patients presented prior to the age of 5 years; half of them with the stormy course of infantile PH1. ESRD was the commonest presenting manifestation in two-thirds of our cohort.

Advanced glycation end products and soluble receptor as markers of oxidative stress in children on hemodialysis.

BACKGROUND: Advanced glycation end products (AGEs) have biological properties that may contribute to the mortality of children on hemodialysis (HD). This study examines the relationship of LMW fluorescence AGEs, oxidized LDL (ox-LDL), soluble receptor AGE (sRAGE) as markers of oxidative stress in children with end stage renal disease (ESRD) undergoing HD. METHOD: Thirty children with ESRD undergoing HD, and 30 healthy, age- and sex-matched children were included. Serum levels of LMW fluorescence AGEs, sRAGE, oxidized LDL (ox-LDL), pre- and post-dialysis urea, high-sensitivity C-reactive protein (hs-CRP), hemoglobin (Hb) and serum albumin (ALB), were measured. RESULTS: Abnormal serum inflammatory changes: elevated levels of LMW AGEs, sRAGE, oxLDL, CRP and urea were exhibited in HD children compared with healthy controls; more so in anemic when compared to non-anemic patients. Significant positive correlation was found between serum levels of AGEs and sRAGE. CONCLUSION: The low molecular weight form of AGEs is associated with oxidative stress in children receiving chronic HD, and may be important in the mechanisms leading to atherosclerosis and inflammation in such patients. LMW AGEs levels showed a negative correlation with sRAGE and both exhibit a significant negative relation to seum urea.

Clinical utility of chitotriosidase enzyme activity in nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis is an inherited autosomal recessive lysosomal storage disorder characterized by the pathological accumulation and crystallization of cystine inside different cell types. WBC cystine determination forms the basis for the diagnosis and therapeutic monitoring with the cystine depleting drug (cysteamine). The chitotriosidase enzyme is a human chitinase, produced by activated macrophages. Its elevation is documented in several lysosomal storage disorders. Although, about 6% of Caucasians have enzyme deficiency due to homozygosity of 24-bp duplication mutation in the chitotriosidase gene, it is currently established as a screening marker and therapeutic monitor for Gaucher's disease. METHODS: Plasma chitotriosidase activity was measured in 45 cystinotic patients, and compared with 87 healthy controls and 54 renal disease patients with different degrees of renal failure (CKD1-5). Chitotriosidase levels were also correlated with WBC cystine in 32 treated patients. Furthermore, we incubated control human macrophages in-vitro with different concentrations of cystine crystals and monitored the response of tumor necrosis factor-alpha (TNF-α) and chitotriosidase activity. We also compared plasma chitotriosidase activity in cystinotic knocked-out (n = 10) versus wild-type mice (n = 10). RESULTS: Plasma chitotriosidase activity in cystinotic patients (0-3880, median 163 nmol/ml/h) was significantly elevated compared to healthy controls (0-90, median 18 nmol/ml/h) and to CKD patients (0-321, median 52 nmol/ml/h), P < 0.001 for both groups. Controls with decreased renal function had mild to moderate chitotriosidase elevations; however, their levels were significantly lower than in cystinotic patients with comparable degree of renal insufficiency. Chitotriosidase activity positively correlated with WBC cystine content for patients on cysteamine therapy (r = 0.8), P < 0.001. In culture, human control macrophages engulfed cystine crystals and released TNF-α into culture supernatant in a crystal concentration dependent manner. Chitotriosidase activity was also significantly increased in macrophage supernatant and cell-lysate. Furthermore, chitotriosidase activity was significantly higher in cystinotic knocked-out than in the wild-type mice, P = 0.003. CONCLUSIONS: This study indicates that cystine crystals are potent activators of human macrophages and that chitotriosidase activity is a useful marker for this activation and a promising clinical biomarker and therapeutic monitor for nephropathic cystinosis.