Effect of exercise training on functional capacity, muscle strength, exercise capacity, dialysis efficacy and quality of life in children and adolescents with chronic kidney disease: a systematic review and meta-analysis.

PURPOSE: To synthesize the effect of exercise training on functional capacity, muscle strength, exercise capacity, dialysis efficacy, and quality of life (QOL) in children and adolescents with CKD. METHODS: PubMed/Medline, Scopus, PEDro, Web of Science, CINAHL, Cochrane, and Embase were searched from inception to September 30, 2023. Randomized control trials (RCTs) and clinical trials that assessed the effect of exercise training programs on functional capacity, muscle strength, exercise capacity, dialysis efficacy, and QOL in children and adolescents with CKD were included. Random effect model and meta-regression were used for the meta-analysis. RESULTS: Four clinical trials and three RCTs were included. The results showed that exercise training improves strength, but meta-analysis did not show a significant effect of exercise on functional capacity (WMD: 1.02; 95% CI: - 0.14 to 2.18; p = 0.083) and QOL (WMD: 8.00; 95% CI: - 3.90 to 19.91; p = 0.187). Subgroup analysis revealed that more than 25 sessions and 45 min per session of intervention, a PEDro score of more than 5, and being younger than 12 years of age had a large effect on functional capacity and QOL results. Due to the limited number of studies that reported the effect of exercise on dialysis efficacy and exercise capacity, the findings were inconclusive. CONCLUSION: Exercise training could benefit children and adolescents with CKD by increasing their strength. Longer exercise interventions may be beneficial for improving functional capacity and QOL. Future well-designed RCTs should overcome the existing limitations using adequate sample sizes and longer exercise durations.

A Novel Mutation in the OXCT1 Gene Causing Succinyl-CoA:3-Ketoacid CoA Transferase (SCOT) Deficiency Starting with Neurologic Manifestations.

Succinyl-CoA:3-oxoacid CoA-transferase (SCOT) deficiency is an inborn error of ketone body utilization characterized by intermittent ketoacidosis crises. This study reports the first Iranian patient with SCOT deficiency who presented with seizure and hypotonia at birth. Accordingly, she was consequently re-hospitalized due to hypotonia and respiratory distress. Laboratory tests revealed hyperammonemia, ketonuria, and metabolic acidosis. Besides, the plasma glucose level was normal without any other abnormality. Despite treatment with high-dose bicarbonate, severe acidosis persisted. Poor response to treatment raised a significant diagnostic challenge among specialists until genetic investigation identified a homozygous nonsense mutation (c.79G>T; p.Gly27*) in the OXCT1 gene (NM_000436), causing SCOT deficiency. Genetic studies help clinicians achieve a definite diagnosis of such metabolic disorders. In this case, the accurate and early diagnosis of SCOT deficiency opened new therapeutic possibilities, including frequent carbohydrate-rich meals and low fat and protein diet. Moreover, our findings expand the mutational and clinical spectrum of SCOT deficiency.

A Study on the CLCN5 Gene in Iranian Patients: A Report of Novel and Recurrent Mutations.

INTRODUCTION: Dent's disease is an X-linked inherited renal tubular disorder characterized by proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets, and end-stage renal disease. Almost 60% of patients have causative mutations in the CLCN5 gene (Dent 1), and 15% of affected individuals have mutations in the OCRL1 gene (Dent 2). The aims of this study are to identify CLCN5 mutations in Iranian families with Dent's disease and to characterize the associated clinical syndromes. METHODS: We studied 14 patients from 13 unrelated Iranian families with a clinical diagnosis of Dent's disease. Proteinuria was detected in all patients. Nephrolithiasis was found in 5 patient, and hematuria in 2 patients. Most of the affected individuals had nephrocalcinosis. PCR-sequencing for the CLCN5 gene was performed in all 14 patients. Next-generation sequencing (NGS) has also been performed in one patient who we did not find causative mutation. RESULTS: We identified four different CLCN5 mutations including one missense mutation (c.731C>T), one nonsense mutation (c.100C>T), and two novel mutations, consisting of one frameshift mutation (c.1241_1242dupAA) and one splicing mutation (c.805-2A>G). We also identified one OCRL1 mutation, one splicing mutation (c.1466 + 1G>A), using NGS. CONCLUSION: This is the first report to characterize mutations in the CLCN5 gene in Iranian patients with Dent's disease and expands the spectrum of CLCN5 mutations by reporting two novel mutations, c.1241_1242dupAA and c.805-2A>G.

Early Postoperative Kidney Transplant Complications Related to Immunomodulator Regimen in Pediatric Recipients.

OBJECTIVES: Calcineurin inhibitors (cyclosporine and tacrolimus) are widely used in kidney transplant to prevent acute transplantrejection; however,the effects of these medications on graft sequelae after transplant remain unclear. We aimed to compare early complications, including graftrejectionandinfectionrates after kidney transplant, in childrenbetween the cyclosporine and tacrolimus immunomodulator regimens. MATERIALS AND METHODS: In this prospective cohort study, 105 pediatric patients who were candidates to receive kidney transplant in the age range of 4 to 18 years were included. There were 28 patients who received cyclosporine, and 77 patients who received tacrolimus. Participants were routinely tested for cytomegalovirus, BK virus, and bacterial infection on a monthly basis for the first 3 months and once every 3 months thereafter for the first year. The graft rejection rate was also assessed and compared between the 2 treatment regimens. RESULTS: There were no significant differences between the 2 groups receiving cyclosporine or tacrolimus in graft rejection rate (P = .719), cytomegalovirus viremia (P = .112), BK viremia (P = .278), and bacterial infection (P = .897). Graftfailure was significantly more frequent in male than in female patients (30.9% vs 8.2%; P = .004). The rates of graft failure in study patients with and without previous history of graftfailure were found to be statistically similar (16.7% vs 20.4%; P = .825). History of infection in donors did not affect the graft complications posttransplant in recipients. CONCLUSIONS: The use of either tacrolimus or cyclosporine leads to similar consequences in terms of graft rejection or posttransplant viral and bacterial infection, so either drug may be exchanged for the other if needed for tolerability.

Gender determination in adults using calcaneal diameters from lateral foot X-ray images in the Iranian population.

Background: Using morphologic features of the bones is the basis of gender determination in anthropology and forensic medicine. In this study, we evaluated the calcaneus diameters for gender determination in the Iranian population. Methods: This cross-sectional study was conducted on Iranians referring to Hazrat-e Rasool Hospital's radiology ward for plain lateral X-ray of the foot. Lateral foot X-rays from 100 men and 100 women were gathered and evaluated for calcaneal indexes. These patients aged between 18 and 80 years old who did not suffer major trauma to the calcaneus bone were recruited. Using a picture archiving and communication system (PACS), four variables were calculated for each X-ray graph: Maximum anterior-posterior length of the calcaneus (MAXL), Maximum height of the bone (MAXH), Height of the cuboid facet (CFH) and Height the calcaneal body (BH). Cut off points for each index were calculated using the area under curve (AUC) in ROC curves. Results: Lateral foot X-rays from 100 men and 100 women were gathered and evaluated for calcaneal indexes. The means of the four indexes were compared between the sexes which showed all four means are significantly different p value <0.001. AUC for MAXL in differentiating the genders was 0.824, which showed 86.8 as the cut off with a sensitivity of 80% and specificity of 69.0%. Cut off point for MAXH was set at 59.8 with sensitivity and specificity of 78.0% and 60.0%, respectively. For BH, 49.5 was set as the cut off point with a sensitivity of 79.0% and specificity of 64.0%. The best cut off point for CFH was 27.8 with 76.0% sensitivity and 63.0% specificity. Conclusion: It can be concluded that the calcaneal diameters are reliable criteria for sex determination. Although the cutoff points are different between various races and populations, it is evident that these diameters can be used for sex determination in general.

Whole Exome Sequencing Reveals a XPNPEP3 Novel Mutation Causing Nephronophthisis in a Pediatric Patient

Background: Nephronophthisis (NPHP) is a progressive tubulointestinal kidney condition that demonstrates an AR inheritance pattern. Up to now, more than 20 various genes have been detected for NPHP, with NPHP1 as the first one detected. X-prolyl aminopeptidase 3 (XPNPEP3) mutation is related to NPHP-like 1 nephropathy and late onset NPHP. Methods: The proband (index patient) had polyuria, polydipsia and chronic kidney disease and was clinically suspected of NPHP. After the collection of blood sample from proband and her parents, whole exome sequencing (WES) was performed to identify the possible variants in the proband from a consanguineous marriage. The functional importance of variants was estimated by bioinformatic analysis. In the affected proband and her parents, Sanger sequencing was conducted for variants' confirmation and segregation analysis. Results: Clinical and paraclinical investigations of the patient was not informative. Using WES, we could detect a novel homozygous frameshift mutation in XPNPEP3 (NM_022098.2: c.719_720insA; p. Q241Tfs*13), and by Sanger sequencing, we demonstrated an insertion in XPNPEP3. Conclusion: The homozygous genotype of the novel p.Q241Tfs*31 variant in XPNPEP3 may cause NPHP in the early childhood age.

Molecular Genetic Analysis of Steroid Resistant Nephrotic Syndrome, Detection of a Novel Mutation.

INTRODUCTION: Nephrotic syndrome is a heterogeneous disease in children, with nearly 10% categorized as steroid-resistant. In this study we evaluated disease related mutations within NPHS1, NPHS2 and new potential variants in other genes. METHODS: In the first phase of study, 25 patients with SRNS were analyzed by Sanger sequencing for NPHS1 (exon 2, 26) and all exons of NPHS2 genes. In the next step, whole exome sequencing was performed on 10 patients with no mutation in NPHS1 and NPHS2. RESULTS: WES analysis revealed a novel mutation in FAT1 (c.10570C > A; Q3524K). We identified 4 pathogenic mutations, located in exon 4 and 5 of NPHS2 gene in 20% of patients (V180M, P118L, R168C and Leu156Phe). Also our study has contributed to the description of previously known pathogenic mutations across WT1 (R205C) and SMARCAL1 (R764Q) and a novel polymorphism in CRB2. CONCLUSION: It seems that NPHS2, especially exons 4 and 5, should be considered as the first step in genetic evaluation of Iranian patients. We suggest conducting WES after NPHS2 screening to identify the potential genes associated with SRNS, Further studies are required to examine more common genes in the first step and then designing native laboratory panels.

CTNS molecular genetics profile in a Persian nephropathic cystinosis population / Perfil genético molecular del gen CTNS en una población persa con cistinosis nefropática

Purpose: In this report, we document the CTNS gene mutations of 28 Iranian patients with nephropathic cystinosis age 1-17 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. Methods: Cystinosis was primarily diagnosed by a pediatric nephrologist and then referred to the Iran University of Medical Sciences genetics clinic for consultation and molecular analysis, which involved polymerase chain reaction (PCR) amplification to determine the presence or absence of the 57-kb founder deletion in CTNS, followed by direct sequencing of the coding exons of CTNS. Results: The common 57-kb deletion was not observed in any of the 28 Iranian patients. In 14 of 28 patients (50%), mutations were observed in exons 6 and 7. No mutation was detected in exon 5, and only one (3.6%) patient with cystinosis showed a previously reported 4-bp deletion in exon 3 of CTNS. Four patients (14.3%) had a previously reported mutation (c.969C>A; p.N323K) in exon 11, and five (18%) had novel homozygous deletions in exon 6 leading to premature truncation of the protein. These deletions included c.323delA; p.Q108RfsX10 in three individuals and c.257-258delCT; p.S86FfsX37 in two cases. Other frame-shift mutations were all novel homozygous single base pair deletion/insertions including one in CTNSexon 9 (c.661insT; p.V221CfsX6), and four (14.3%) in exon 4, i.e., c.92insG; p.V31GfsX28 in two and c.120delC; p.T40TfsX10 in two. In total, we identified eight previously reported mutations and eight novel mutations in our patients. The only detected splice site mutation (IVS3-2A>C) was associated with the insertion mutation in the exon 9. Conclusion: This study, the first molecular genetic analysis of non-ethnic-specific Iranian nephropathic cystinosis patients, may provide guidance for molecular diagnostics of cystinosis in Iran (AU)

Objetivo: En este informe, documentamos las mutaciones del gen CTNS de 28 pacientes iraníes con cistinosis nefropática y una edad de 1-17 años. En un principio, todos presentaron retraso del desarrollo, poliuria y polidipsia. Métodos: En primer lugar, un nefrólogo pediátrico diagnosticó la cistinosis y luego los pacientes fueron trasladados a la clínica genética de la Universidad de Ciencias Médicas de Irán para consulta y análisis molecular, que incluía la multiplicación por reacción en cadena de la polimerasa (PCR), para determinar la existencia o ausencia de la deleción del fundador del 57kb en el CTNS, seguida por la secuenciación directa de los exones de codificación del CTNS. Resultados: La deleción frecuente del 57kb no se observó en ninguno de los 28 pacientes iraníes. En 14 de los 28 pacientes (50%) se observaron mutaciones en los exones 6 y 7. No se detectó ninguna mutación en el exón 5 y solo un paciente (3,6%) con cistinosis mostró una deleción del 4pb, anteriormente comunicada, en el exón 3 del CTNS. De ellos, 4 pacientes (14,3%) tenían una mutación anteriormente comunicada (c.969C > A; p.N323K) en el exón 11 y 5 (18%) tenían nuevas deleciones homocigóticas en el exón 6 que produjeron el vaciamiento prematuro de la proteína. Entre estas deleciones se puede citar c.323delA; p.Q108RfsX10 en 3 personas y c.257-258delCT; p.S86FfsX37 en 2 casos. Otras mutaciones con desplazamiento del marco de lectura fueron todas nuevas deleciones/inserciones de un par de bases únicas homocigóticas, incluyendo una en el exón 9 del CTNS(c.661insT; p.V221CfsX6) y 4 (14,3%) en el exón 4, es decir, c.92insG; p.V31GfsX28 en 2 y c.120delC; p.T40TfsX10 en 2. En total, en nuestros pacientes se identificaron 8 mutaciones anteriormente comunicadas y 8 mutaciones nuevas. La única mutación del sitio de empalme detectada (IVS3-2A>C) estaba asociada con la mutación de inserción en el exón 9. Conclusión: Este estudio, el primer análisis genético molecular de pacientes iraníes con cistinosis nefropática de carácter no específicamente étnico, puede servir como guía para el diagnóstico molecular de la cistinosis en Irán (AU)

CTNS molecular genetics profile in a Persian nephropathic cystinosis population.

PURPOSE: In this report, we document the CTNS gene mutations of 28 Iranian patients with nephropathic cystinosis age 1-17 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. METHODS: Cystinosis was primarily diagnosed by a pediatric nephrologist and then referred to the Iran University of Medical Sciences genetics clinic for consultation and molecular analysis, which involved polymerase chain reaction (PCR) amplification to determine the presence or absence of the 57-kb founder deletion in CTNS, followed by direct sequencing of the coding exons of CTNS. RESULTS: The common 57-kb deletion was not observed in any of the 28 Iranian patients. In 14 of 28 patients (50%), mutations were observed in exons 6 and 7. No mutation was detected in exon 5, and only one (3.6%) patient with cystinosis showed a previously reported 4-bp deletion in exon 3 of CTNS. Four patients (14.3%) had a previously reported mutation (c.969C>A; p.N323K) in exon 11, and five (18%) had novel homozygous deletions in exon 6 leading to premature truncation of the protein. These deletions included c.323delA; p.Q108RfsX10 in three individuals and c.257-258delCT; p.S86FfsX37 in two cases. Other frame-shift mutations were all novel homozygous single base pair deletion/insertions including one in CTNS exon 9 (c.661insT; p.V221CfsX6), and four (14.3%) in exon 4, i.e., c.92insG; p.V31GfsX28 in two and c.120delC; p.T40TfsX10 in two. In total, we identified eight previously reported mutations and eight novel mutations in our patients. The only detected splice site mutation (IVS3-2A>C) was associated with the insertion mutation in the exon 9. CONCLUSION: This study, the first molecular genetic analysis of non-ethnic-specific Iranian nephropathic cystinosis patients, may provide guidance for molecular diagnostics of cystinosis in Iran.

A novel mutation pattern of kidney anion exchanger 1 gene in patients with distal renal tubular acidosis in Iran.

INTRODUCTION: Mutations of the anion exchanger 1 (AE1) gene encoding the kidney anion exchanger 1 can result in autosomal dominant or autosomal recessive form of distal renal tubular acidosis (DRTA). This study aimed to report deletion mutations of the AE1 and its impact on Iranian children with DRTA. MATERIALS AND METHODS: Twelve children with DRTA referred to Ali Asghar Children Hospital were investigated for all AE1 gene exons through polymerase chain reaction amplification, DNA sequencing, and bioinformatics analysis. RESULTS: Eleven of 12 patients (91.7%) showed an alteration in AE1 gene with a real hot spot in its exons 11 or 15. Homozygote and heterozygote deletions were confirmed in exon 15 in 5 (41.7%) and 3 (25.0%), respectively. Two patients (16.7%) showed homozygote deletions in exon 11 of AE1 gene, and 1 patient (8.3%) showed point mutation in exon 11. The 3-dimensional structures of the native and these mutant kidney AE1 proteins were determined by the multitemplate method using the Phyre and Hidden Markov Model algorithms. CONCLUSIONS: Parents' consanguinity of these patients reveals that cousins are at a high risk for DRTA. This study is considered as a pilot study showing the importance of AE1 mutations in Iranian children with DRTA and further studies is recommended in this geographic region of the world. These models suggest that alteration in the structures leads to alteration in function and change in the current role of AE1.

Kidney transplantation before or after augmentation cystoplasty in children with high-pressure neurogenic bladder.

OBJECTIVE: To compare the outcome and complications of augmentation cystoplasty before or after renal transplantation in children with neurogenic bladders, with those after kidney transplantation in children with normal bladders. PATIENTS AND METHODS: Augmentation cystoplasty preceded transplantation in 21 children (group 1) and after transplantation in 23 (group 2) operated from 1985 to 2006; these two groups were compared with a control group of 45 children with a normal bladder (group 3) who also received a transplant, for kidney function, episodes of urinary tract infection (UTI), surgical and medical complications. RESULTS: The mean age of the three groups was 12.9, 13.2 and 13.6 years, respectively (P = 0.2). Graft survival at 1, 3, 5 and 7 years was 90%, 76%, 65% and 43% in group 1, 94%, 61%, 50% and 40% in group 2, and 94%, 87%, 81% and 75% in group 3, respectively, which was not significantly different between groups 1 and 2, but was higher in group 3 (P = 0.03). Febrile UTI was reported in five (24%), seven (30%) and one (2%) patients in groups 1-3, respectively. UTI was significantly less frequent in group 3 (P = 0.01) but was not different between groups 1 and 2. Acute rejection was reported in nine (43%), nine (39%) and 15 (33%) patients in groups 1-3, respectively (P = 0.2). CONCLUSION: The timing of cystoplasty in relation to transplantation has no apparent significant effect on the outcome of transplantation.

Kidney transplantation in children with augmentation cystoplasty.

PURPOSE: Treatment of children with end stage renal disease, especially those with significant bladder dysfunction, is difficult. A high pressure and low capacity bladder is a major risk factor for a transplanted kidney. Cystoplasty can protect the kidney allograft by reducing the intravesical pressure and creating an appropriate capacity. The aim of this study was to evaluate the outcome of kidney transplantation in children with and without prior cystoplasty. MATERIALS AND METHODS: A total of 43 children with bladder dysfunction in urgent need of cystoplasty were enrolled in the study and were compared to a control group with regard to acute and chronic rejection rates, survival of the transplanted kidney, surgical complications and febrile urinary tract infection. RESULTS: The rates of febrile urinary tract infection and chronic rejection were significantly higher in patients with prior cystoplasty (p<0.001 and p=0.004, respectively). Also, graft loss was much more frequent in these patients (34.9% vs 20.9%), although this difference was not statistically significant. In patients with prior cystoplasty graft survival rates were 92%, 73%, 58% and 45% at postoperative years 1, 3, 5 and 7, respectively. In the control group these rates were 94%, 87%, 81% and 75%, respectively (p=0.007). CONCLUSIONS: Based on our findings, the survival rate of the kidney is significantly lower in children with prior cystoplasty, possibly due to the higher prevalence of chronic rejection and febrile urinary tract infection in this group.