Idiopathic nephrotic syndrome in Syrian children: clinicopathological spectrum, treatment, and outcomes.

BACKGROUND: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children. We performed this study to report histopathological findings, the correlation between clinical and histopathological features, and the response to steroids and other immunosuppressive drugs and outcomes in Syrian children with INS. METHODS: A single-center retrospective observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients aged 1-14 years, admitted from January 2013 to December 2022, with INS and who underwent kidney biopsy. RESULTS: The study included 109 patients, with a male/female ratio of 1.13:1, and a median age of 5 years with interquartile range (2.8-10). The main indication of kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) (57.8%). The main histopathological patterns were minimal change disease (MCD) (45%) and focal segmental glomerulosclerosis (FSGS) (37.6%). FSGS was the most common histopathological pattern in SRNS (44.3%). In SRNS, we used calcineurin inhibitors to induce remission. Tacrolimus was used in 49 patients with response rate (complete remission of proteinuria) of 69.4% and cyclosporine in 20 patients with response rate of 50%. In steroid-dependent nephrotic syndrome (SDNS), we used mycophenolate mofetil (MMF) and cyclophosphamide to prevent relapses; MMF was used in 9 patients with response rate (maintaining sustained remission) of 89% and cyclophosphamide in 3 patients with response rate of 66.7%. Rituximab was used in four patients with FSGS, two SRNS patients and two SDNS patients, with sustained remission rate of 100%. Fifteen patients (13.7%) progressed to chronic kidney disease stage 5. Of them, 7 patients had FSGS and 8 patients had focal and global glomerulosclerosis;14 of them were steroid-resistant and one patient was steroid-dependent with persistent relapses. The most common outcome was sustained remission (47%) in MCD and frequent relapses (31.7%) in FSGS. CONCLUSIONS: FSGS was the most common histopathological pattern in idiopathic SRNS and had the worst prognosis. Calcineurin inhibitors could be an effective therapy to induce complete remission in SRNS. Rituximab may be an effective treatment to achieve sustained remission in SDNS and frequently relapsing NS and may have a potential role in SRNS with further studies required.

Primary hyperoxaluria type 1 in children: clinical and laboratory manifestations and outcome.

BACKGROUND: Primary hyperoxaluria (PH) results from genetic mutations in different genes of glyoxylate metabolism, which cause significant increases in production of oxalate by the liver. This study aimed to report clinical and laboratory manifestations and outcome of PH type 1 in children in our center. METHODS: A single-center observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients admitted from 2018 to 2020, with a diagnosis of hyperoxaluria (urinary oxalate excretion > 45 mg/1.73 m2/day, or > 0.5 mmol/1.73 m2/day). PH type 1 (PH1) diagnosis was established by identification of biallelic pathogenic variants (compound heterozygous or homozygous mutations) in AGXT gene on molecular genetic testing. RESULTS: The study included 100 patients with hyperoxaluria, with slight male dominance (57%), and median age 1.75 years (range, 1 month-14 years). Initial complaint was urolithiasis or nephrocalcinosis in 47%, kidney failure manifestations in 29%, and recurrent urinary tract infection in 24%. AGXT mutations were detected in 40 patients, and 72.5% of PH1 patients had kidney failure at presentation. Neither gender, age nor urinary oxalate excretion in 24 h had statistical significance in distinguishing PH1 from other forms of hyperoxaluria (P-Value > 0.05). Parental consanguinity, family history of kidney stones, bilateral nephrocalcinosis, presence of oxalate crystals in random urine sample, kidney failure and mortality were statistically significantly higher in PH1 (P-values < 0.05). Mortality was 32.5% among PH1 patients, with 4 PH1 patients (10%) on hemodialysis awaiting combined liver-kidney transplantation. CONCLUSION: PH1 is still a grave disease with wide variety of clinical presentations which frequent results in delays in diagnosis, thus kidney failure is still a common presentation. In Syria, we face many challenges in diagnosis of PH, especially PH2 and PH3, and in management, with hopes that diagnosis tools and modern therapies will become available in our country. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Urinary stone disease in Syrian children.

BACKGROUND: Pediatric urinary stone disease (USD) is a costly medical problem. This study aims to assess the clinical characteristics and outcomes of common and rare causes of pediatric USD. METHODS: A retrospective descriptive cohort study included all children < 13 years of age with confirmed USD admitted to the Children's University Hospital in Damascus, Syria, from January 2013 to December 2019. The study sample was divided into two groups based on etiologies: common and rare causes groups. RESULTS: We evaluated 235 patients; 147 of them were males, and the male-to-female ratio was 1.7:1. The common causes group consisted of 203 patients (mean age 3.52 ± 3.66 years) and mainly included metabolic disorders (45.5%) and anatomical abnormalities (22.3%), while the rare causes group included 32 cases (mean age 4.93 ± 4.08 years), 12 patients with uric acid stones (37.5%), 7 patients with cystinuria (21.9%), and primary hyperoxaluria in 5 patients (15.6%). In addition, 39.6% of study patients were born to consanguineous marriages. Sixty-two patients developed AKI, and eleven patients had chronic kidney disease (CKD). Patients with rare causes were more likely to have AKI, CKD, bilateral stones, and recurrent stones (P-value < 0.05). Stone analysis was performed on 83 patients, and the main stone types were calcium oxalate (34.9%), uric acid (14.4%), and struvite stones (12%). Surgery was the most performed treatment in 101 patients (56.7%). CONCLUSION: Patients with rare causes of pediatric USD are at a higher risk for severe complications and require early diagnosis and management. The high rate of uric acid stones in our society requires further evaluation for possible underlying causes. A higher resolution version of the Graphical abstract is available as Supplementary information.

Even mild cases of paediatric Henoch-Schönlein purpura nephritis show significant long-term proteinuria.

AIM: Henoch-Schonlein purpura (HSP) is a common cause of paediatric renal disease in children, representing 10-15% of paediatric glomerulonephritis. This study examined the long-term outcome of biopsy-proven HSP nephritis to identify correlations between disease development and treatment. METHODS: Patients from three French centres were retrospectively analysed. RESULTS: We followed up 142 patients aged from 2 to 10.5 years with HSP nephritis, graded according to the International Study Group of Kidney Disease in Childhood classification. Mean (±SD) age at presentation was 7.6 ± 2.8 years. Nephrotic range proteinuria was present in 28% of patients with Grade II lesions, 60% with Grade III and 90% with Grade IV. Significant proteinuria (>0.5 g/L) was found in nine of 48 patients 3 years after renal biopsy, eight of 25 patients after 5 years and three of 14 patients after 10 years. There was no correlation between the proteinuria risk at 3, 5 or 10 years and the initial histological lesion or treatment modality. Treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) was linked to lower proteinuria, especially if it was started precociously. CONCLUSION: Even mild forms of HSP nephritis risk significant long-term proteinuria. Very early introduction of ACEi/ARB may improve the long-term outcome independent of histological lesions.

Protocol biopsies in pediatric renal transplant recipients on cyclosporine versus tacrolimus-based immunosuppression.

BACKGROUND: Protocol biopsies can detect subclinical rejection and early signs of calcineurin inhibitor-induced nephrotoxicity. METHODS: In a prospective study, protocol biopsies 3 and 12 months after transplant in transplanted children from two centers were studied. One center used cyclosporine (CsA)-based immunosuppression and the other center used tacrolimus. Patients were on CsA (n = 26, group 1) or on tacrolimus (n = 10, group 2). Patients received basiliximab induction, mycophenolate mofetil, and prednisone. RESULTS: In patients on CsA, 26 kidney biopsies were performed during the 6 months after transplantation. Eighteen protocol biopsies were performed at 3 months post transplant; 13 were normal and five showed rejection (two borderline and three Banff II rejections). Eight biopsies were motivated by an increase of serum creatinine; four were normal and four revealed signs of acute rejection (two borderline and two Banff II). Twelve protocol biopsies were performed after 12 months; all were normal. For patients on tacrolimus (n = 10), ten protocol transplant biopsies were performed at 3 months post-transplant; none showed signs of rejection. No biopsy was performed for an increase of serum creatinine. There were no differences in patient age, number of human leukocyteantigen (HLA) incompatibilities, or other patient characteristics. CONCLUSIONS: Patients on tacrolimus had less acute rejection episodes detected on protocol biopsies 3 months after transplant. Protocol biopsies seem to play an important role in the detection of subclinical rejection in patients on CsA.

Molecular analysis of the AGXT gene in Syrian patients suspected with primary hyperoxaluria type 1.

BACKGROUND: Characterization of the molecular basis of primary hyperoxaluria type 1 (PH-1) in Syria has been accomplished through the analysis of 90 unrelated chromosomes from 45 Syrians patients with PH-1 from different regions. METHODS: Alanine glyoxylate aminotransferase (AGXT) gene mutations have been analyzed by using molecular detection methods based on the direct DNA sequencing for all exons of the AGXT gene. RESULTS: Seventeen pathogenic mutations were detected in our patients. Six mutations were novels. The three most frequent mutations were c.33_34insC (p.Lys12fs) in Exon 1, c.584 T < G; p.Met195Arg in exon 5 and c.1007 T > A (p.Val336Asp) in exon 10, with a frequency of 33.3%, 12.2%, and 11.1%, respectively. CONCLUSION: DNA sequencing used in this study can offer a useful method to investigate the mutations in Syrian PH-1 patients, and could offer an accurate tool for prenatal diagnosis and genetic counseling.

Aortic stiffness in ESRD children before and after renal transplantation.

Cardiovascular complications are the main cause of death in end-stage renal failure in adult patients, but those complications start in childhood. Renal transplantation (RT) seems to reduce or even reverse certain abnormalities seen in dialyzed patients. Since RT seems to correct metabolic abnormalities that play a role in cardiovascular disease, aortic pulse wave velocity (APWV) was used to evaluate aortic stiffness before and after RT. We included 15 children on chronic hemodialysis (HD), aged 11.1 +/- 4.8 years and dialysis duration was 12.9 +/- 7.4 months. APWV was performed every 6 months before RT and 6 months after. There was no significant difference in APWV (6.1 +/- 1.3 m/s vs 6.5 +/- 1.4 m/s) and augmentation index (AI) on HD and 6 months after RT. APWV pre-transplant was not correlated with time on HD, but increased with age (p = 0.016). No correlation between APWV pre-/post-transplant and other HD parameters or calcineurin inhibitor exposure were found. Only graft function was inversely correlated with APWV post-transplant (p = 0.02). In conclusion, aortic stiffness seems to remain stable before and 6 months after pediatric RT. Graft function was inversely correlated with APWV. Differences in vessel structure among children of the same age group and increase in aortic stiffness with age may jeopardize data interpretation.

Atypical hemolytic uremic syndrome with peripheral gangrene and homocysteinemia in a child.

Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, life-threating disease that frequently has a genetic component; it is usually caused by familial, sporadic or idiopathic reasons. We report a case of aHUS in a 21-month-old girl with coexisting of methylenetetrahydrofolate reductase mutations, homocysteinemia and thalassemia minor complicated by peripheral gangrene as extrarenal manifestation.