Publications by authors named "Salim Caliskan"

74 Publications

Strong mesangial IgA staining-does it always refer to IgA nephropathy in a patient with proteinuria and hematuria? Answers.

Pediatr Nephrol 2021 Jan 18. Epub 2021 Jan 18.

Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-020-04899-4DOI Listing
January 2021

Strong mesangial IgA staining-does it always refer to IgA nephropathy in a patient with proteinuria and hematuria? Questions.

Pediatr Nephrol 2021 Jan 18. Epub 2021 Jan 18.

Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-020-04886-9DOI Listing
January 2021

Efficacy of tolterodine in children with overactive bladder.

Turk Pediatri Ars 2020 23;55(3):284-289. Epub 2020 Sep 23.

Department of Pediatric Nephrology, İstanbul University Cerrahpaşa Faculty of Medicine, İstanbul, Turkey.

Aim: Tolterodine is an anticholinergic drug used for the treatment of overactive bladder. We evaluated the effects of tolterodine on clinical symptoms and compared its efficacy with that of oxybutynin in terms of bladder capacity, bladder wall thickness, and post-void residual volume in children with overactive bladder.

Material And Methods: Twenty-six patients who were treated with tolterodine for overactive bladder (20 girls, mean age 8.0±2.2 years) were evaluated retrospectively. Twenty patients with overactive bladder who had undergone oxybutynin treatment (15 girls, mean age 7.6±1.8 years) served as the control group. Dysfunctional voiding symptom scoring was used to evaluate the clinical response to tolterodine. To investigate the effect of treatment on the bladder, ultrasonographic data at baseline and the third month were compared with the oxybutynin group.

Results: The dysfunctional voiding symptom scores significantly decreased after the third month of tolterodine treatment (p<0.001). Bladder capacity significantly increased (p<0.001), and filled bladder wall thickness decreased (p=0.007); however, post-void residual volumes significantly increased (p<0.001) at the third month. No serious adverse effects were recorded during tolterodine treatment. The increase in bladder capacity at the third month in the tolterodine group was similar to that in the oxybutynin group (p=0.77), but the decrease in filled bladder wall thickness was significantly greater in the tolterodine group (p=0.019).

Conclusion: Tolterodine remarkably ameliorates the clinical symptoms of overactive bladder in a short time, and seems to be as effective as oxybutynin for the treatment of overactive bladder in children. Its effect on reduction of bladder wall thickness appears to be superior to that of oxybutynin.
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http://dx.doi.org/10.14744/TurkPediatriArs.2020.98215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536450PMC
September 2020

Natural history of patients with infantile nephrolithiasis: what are the predictors of surgical intervention?

Pediatr Nephrol 2021 Apr 2;36(4):939-944. Epub 2020 Oct 2.

Department of Urology, Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, 34098, Istanbul, Turkey.

Background: We evaluated the risk factors for the requirement of surgical intervention in infants with nephrolithiasis.

Methods: The medical records of 122 (156 kidney units (KU)) infants were reviewed. The clinical features, stone characteristics, changes in stone status, and treatment protocols were noted. The stone status of the KU was categorized into 3 groups according to the change in size between the first and last ultrasound: resolution, unchanged, and growth.

Results: The median age was 8 months (r: 2-12). The median length of follow-up was 16 months (r: 10-36). Resolution was detected in 94 KUs (60%). Stone growth was detected in 39 KUs (25%), and stone size was unchanged in 23 KUs (15%). Surgical intervention was required in 26 patients (17%). A history of intensive care unit (ICU) follow-up and a stone size > 5 mm at time of diagnosis were defined as independent risk factors for stone growth (p = 0.005, < 0.001, respectively). The surgical intervention rate was higher in stones > 5 mm and stones with pelvic localization (p = 0.018, 0.021, respectively). Stone resolution was higher in patients with stone size ≤ 5 mm (p = 0.018).

Conclusion: A stone size > 5 mm at the time of diagnosis and a history of ICU follow-up are independent risk factors for stone growth. Pelvic localization of stones and stones > 5 mm are associated with an increased risk of surgical intervention.
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http://dx.doi.org/10.1007/s00467-020-04781-3DOI Listing
April 2021

Anemia after kidney transplantation: Does its basis differ from anemia in chronic kidney disease?

Pediatr Transplant 2020 12 14;24(8):e13818. Epub 2020 Aug 14.

Department of Pediatric Nephrology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.

Background: Although similar factors play a role in both PTA and anemia in patients with CKD, additional risk factors exist in the pathogenesis of PTA. The present study aimed at comparing anemia and inflammation-related parameters between RTx recipients and CKD patients and elucidating the risk factors of PTA.

Methods: This single-centered, cross-sectional study consisted of 68 participants: 48 were in the RTx group and 20 were in the CKD group. The CKD patients were comparable to the RTx recipients in terms of age, gender, and eGFR. Serum levels of EPO, hepcidin, and IL-6 were measured by enzyme-linked immunosorbent assays. The ratio of EPO/Hb was calculated to estimate endogenous EPO resistance.

Results: The prevalence of anemia was 46% in the RTx group and 30% in the CKD group (P = .23). RTx recipients had significantly lower Hb (P = .04), higher EPO (P < .001), and ferritin levels (P = .001), and higher EPO/Hb ratios (P < .001); however, CKD patients showed a higher frequency of absolute iron deficiency (P = .008). Neither hepcidin nor IL-6 levels differed between the two groups. Hb level of RTx recipients was correlated with only eGFR (r = .437, P = .002) but not with any of the transplantation-related factors, while Fe level was the only parameter to be correlated with Hb level of CKD patients (r = .622, P = .01).

Conclusion: In the present study comparing GFR-matched RTx and CKD patients, lower GFR level appears to be the factor most strongly associated with anemia, and endogenous EPO resistance is among the contributing factors to PTA.
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http://dx.doi.org/10.1111/petr.13818DOI Listing
December 2020

Is the burden of late hypertension and cardiovascular target organ damage in children and adolescents with coarctation of the aorta after early successful repair different to healthy controls?

Cardiol Young 2020 Sep 22;30(9):1305-1312. Epub 2020 Jul 22.

Department of Pediatric Cardiology, Istanbul University-Cerrahpasa, Istanbul, Turkey.

Objective: Cardiovascular morbidity is high in patients with coarctation of aorta even after successful repair. This study aimed to assess the frequency of late hypertension and the relationship between ambulatory hypertension and cardiovascular target organ damage in children and adolescents after early and successful repair of coarctation of the aorta.

Methods: Twenty-five children and adolescents (mean age 13.5 ± 3.43 years) with repaired coarctation of the aorta (median age at repair 4 months, arm-leg gradient <20 mmHg) and 16 healthy controls were included. Office and ambulatory blood pressure, pulse wave velocity, and left ventricular mass index were assessed.

Results: Both day- and night-time systolic blood pressure standard deviation score and left ventricular mass index were significantly higher in patients compared to controls (p ≤ 0.001 for all), whereas pulse wave velocity did not differ. The prevalence of masked hypertension, isolated nocturnal hypertension, and left ventricular hypertrophy were 40, 28, and 24%, respectively. Left ventricular mass index was higher in patients with sustained hypertension, masked hypertension, and normotension compared to controls (p < 0.05). In multivariate analysis, higher night-time systolic blood pressure standard deviation score was the only independent predictor of left ventricular mass index.

Conclusion: The present study reveals a high prevalence of masked hypertension, isolated nocturnal hypertension, and left ventricular hypertrophy in children and adolescents with coarctation of the aorta even after early and successful repair. Ambulatory blood pressure monitoring should be considered to diagnose hypertension. All coarctation of aorta patients should be followed up lifelong and encouraged to establish a healthy lifestyle starting from childhood.
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http://dx.doi.org/10.1017/S104795112000205XDOI Listing
September 2020

A homozygous HOXA11 variation as a potential novel cause of autosomal recessive congenital anomalies of the kidney and urinary tract.

Clin Genet 2020 10;98(4):390-395

Nephrogenetics Laboratory, Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of end-stage kidney disease in children. Until now, more than 50 monogenic causes for CAKUT have been described, all of which only explain 10% to 20% of all patients with CAKUT, suggesting the presence of additional genes that cause CAKUT when mutated. Herein, we report two siblings of a consanguineous family with CAKUT, both of which rapidly progressed to chronic kidney disease in early childhood. Whole-exome sequencing followed by homozygosity mapping identified a homozygous variation in HOXA11. We therefore showed for the first time an association between a homozygous HOXA11 variation with CAKUT in humans, expanding the genetic spectrum of the disease.
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http://dx.doi.org/10.1111/cge.13813DOI Listing
October 2020

New guidelines for the diagnosis, evaluation, and treatment of pediatric hypertension.

Turk Pediatri Ars 2020 9;55(1):11-22. Epub 2020 Mar 9.

Division of Pediatric Nephrology, Department of Pediatrics, İstanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, İstanbul, Turkey.

Childhood hypertension has become a significant public health problem due to increased prevalence in recent decades. High blood pressure causes increased mortality and morbidity in childhood, precedes adult hypertension, and causes increased cardiovascular events in adulthood. These concerns have led to an update of guidelines about childhood hypertension by the European Society of Hypertension in 2016 and the American Academy of Hypertension in 2017. This review highlights the important developments in these guidelines and recent literature about childhood hypertension in terms of diagnosis, prevalence, risk factors, diagnostic tools, prevention and management.
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http://dx.doi.org/10.14744/TurkPediatriArs.2020.92679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096568PMC
March 2020

Factors influencing blood pressure and microalbuminuria in children with type 1 diabetes mellitus: salt or sugar?

Pediatr Nephrol 2020 07 24;35(7):1267-1276. Epub 2020 Mar 24.

Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098, Istanbul, Turkey.

Background: The aim of the study is to identify the effect of salt intake and diabetes itself on blood pressure (BP) profile and microalbuminuria in children with type one diabetes mellitus (T1DM). Our hypothesis is that higher amount of salt consumption and/or hyperglycemia may impair blood pressure pattern in children with T1DM.

Methods: This cross-sectional study included 84 children and adolescents with T1DM (62% females, age 13.9 ± 3.2 years, disease duration 7.3 ± 3.1 years, 43% poorly controlled diabetes) and 54 aged- and sex-matched healthy children with an adequately collected 24-h urine samples. Urine sodium, creatinine, and microalbumin were measured and salt intake was assessed on the basis of sodium excretion in 24-h urine. Blood pressure profile of the children with T1DM was evaluated with 24-h ambulatory blood pressure monitoring.

Results: Compared to the children with well-controlled diabetes, children with poorly controlled diabetes had significantly higher standard deviation scores (SDS) of nighttime systolic BP (0.22 ± 1.28 vs - 0.87 ± 0.76, p = 0.003) and lower dipping in diastole (13.4 ± 5.9 vs 18.4 ± 8.1, p = 0.046). Among T1DM group, children with the highest quartile of salt intake had higher nighttime systolic and diastolic BP-SDS (0.53 ± 1.25 vs - 0.55 ± 0.73, p = 0.002 and 0.89 ± 1.19 vs 0.25 ± 0.63, p = 0.038, respectively) and lower dipping in systole compared to their counterparts (7.7 ± 5.0 vs 11.5 ± 6.1, p = 0.040). High averaged HbA1c was independently associated with higher both daytime and nighttime systolic BP-SDS (p = 0.010, p < 0.001) and nighttime diastolic BP-SDS (p = 0.001), and lower diastolic dipping (p = 0.001). High salt intake was independently associated with higher nighttime systolic BP-SDS (p = 0.002) and lower systolic dipping (p = 0.019). A 24-h MAP-SDS was the only independent risk factor for microalbuminuria (p = 0.035).

Conclusion: Beside poor diabetic control, high salt consumption appears to be an important modifiable risk factor for impaired BP pattern, which contributes to the development of diabetic kidney disease in children with T1DM.
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http://dx.doi.org/10.1007/s00467-020-04526-2DOI Listing
July 2020

The Frequency of Familial Congenital Anomalies of the Kidney and Urinary Tract: Should We Screen Asymptomatic First-Degree Relatives Using Urinary Tract Ultrasonography?

Nephron 2020 7;144(4):170-175. Epub 2020 Jan 7.

Department of Pediatric Nephrology, Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Istanbul, Turkey.

Introduction: The objectives of this study were to determine the incidence of congenital anomalies of the kidney and urinary tract (CAKUT) in asymptomatic first-degree relatives of patients with a CAKUT diagnosis and to evaluate the benefits of such screening.

Methods: Files of patients who were followed up at Cerrahpaşa Faculty of Medicine, Pediatric Nephrology Outpatient Clinic, Istanbul University-Cerrahpaşa between 1998 and 2016 were examined retrospectively and those with CAKUT were identified. These patients, and their asymptomatic first-degree relatives, were invited to participate in this study. Ultrasonography of the urinary tract was performed in siblings and parents of 145 CAKUT patients (index cases) who could be reached by phone and agreed to participate.

Results: A total of 412 asymptomatic first-degree relatives of 145 index patients were screened by ultrasound. CAKUT was diagnosed in 23 individuals among the family members of 21 index subjects. Anomalies detected in asymptomatic first-degree relatives were renal agenesis (RA) and grade 3 hydronephrosis (n = 1), RA (n = 7), renal hypodysplasia (n = 7), grade 2 hydronephrosis (n = 1), and grade 1 hydronephrosis (n = 7). The frequency of familial CAKUT was 14.4%. Familial RA was found in 3 of the 5 families of index cases with RA.

Conclusion: The ratio of familial CAKUT was 14.4%. The findings of the present study could not support a systematic family screening to all asymptomatic first-degree relatives; however, family screening with ultrasonography can be considered for children with RA.
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http://dx.doi.org/10.1159/000505402DOI Listing
January 2020

Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease.

Pediatr Nephrol 2019 12 19;34(12):2571-2582. Epub 2019 Aug 19.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Children's Hospital Heidelberg, Heidelberg, Germany.

Background: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients.

Methods: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6-17 years with initial eGFR of 10-60 ml/min per 1.73 m.

Results: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 μmol/l (8.7) and 17.0 μmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors.

Conclusions: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort.
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http://dx.doi.org/10.1007/s00467-019-04331-6DOI Listing
December 2019

Determinants of Statural Growth in European Children With Chronic Kidney Disease: Findings From the Cardiovascular Comorbidity in Children With Chronic Kidney Disease (4C) Study.

Front Pediatr 2019 5;7:278. Epub 2019 Jul 5.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.

Failure of statural growth is one of the major long-term sequelae of chronic kidney disease (CKD) in children. In recent years effective therapeutic strategies have become available that lead to evidence based practice recommendations. To assess the current growth performance of European children and adolescents with CKD, we analyzed a cohort of 594 patients from 12 European countries who were followed prospectively for up to 6 years in the 4C Study. While all patients were on conservative treatment with a mean estimated glomerular filtration rate of 28 ml/min/1.73 m at study entry, 130 children commenced dialysis during the observation period. At time of enrolment the mean height standard deviation score (SDS) was -1.57; 36% of patients had a height below the third percentile. The prevalence of growth failure varied between countries from 7 to 44% Whereas patients on conservative treatment showed stable growth, height SDS gradually declined on those on dialysis. Parental height, pubertal status and treatment with recombinant growth hormone (GH) were positively, and the diagnosis of syndromic disease and CKD stage were negatively associated with height SDS during the observation period. Unexpectedly, higher body mass index (BMI) SDS was associated with lower height SDS both at enrolment and during follow up. Renal anemia, metabolic acidosis, and hyperparathyroidism were mostly mild and not predictive of growth rates by multivariable analysis. GH therapy was applied in only 15% of growth retarded patients with large variation between countries. When adjusting for all significant covariates listed above, the country of residence remained a highly significant predictor of overall growth performance. In conclusion, growth failure remains common in European children with CKD, despite improved general management of CKD complications. The widespread underutilization of GH, an approved efficacious therapy for CKD-associated growth failure, deserves further exploration.
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http://dx.doi.org/10.3389/fped.2019.00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625460PMC
July 2019

The Relationship between the Waist Circumference and Increased Carotid Intima Thickness in Obese Children.

Child Obes 2019 10 27;15(7):468-475. Epub 2019 Jun 27.

Department of Pediatric Nephrology, Faculty of Cerrahpasa Medical, Istanbul University, Istanbul, Turkey.

This study aimed to evaluate the cardiometabolic risk factors in normotensive obese and hypertensive obese (HT-obese) children by comparison of anthropomorphic measurements, fat distribution, carotid artery intima-media thickness (CIMT), and inflammatory markers. Fifty-three obese patients 10-18 years of age with a BMI-for-age/gender >95th percentile and 20 age- and gender-matched healthy volunteers enrolled in the study. Obese patients were divided into two groups according to the presence of hypertension (HT), as follows: HT-obese subgroup ( = 30) and nonhypertensive obese (non-HT-obese) subgroup ( = 23). Weight standard deviation score (SDS), BMI-SDS, waist circumference (WC) SDS, and the fat tissue -score were significantly higher ( < 0.001 for all) in the obese patients than the control groups. Obese patients had higher 24-hour systolic blood pressure (SBP) SDS and leptin, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 levels. Furthermore, CIMT and CIMT-SDS were significantly higher in them. HT-obese patients ( = 30) had significantly higher WC-SDS and lower serum leptin and adiponectin levels than those of non-HT-obese group ( = 23). Finally, an association between increased CIMT-SDS and WC-SDS ( = 0.399,  = 0.002) and 24-hour SBP-SDS ( = 0.272,  = 0.009) was shown. Association between increased WC and HT implies the importance of central obesity in atherosclerosis. We concluded that WC measurement could be used to define risk groups since it is related to cardiometabolic complications.
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http://dx.doi.org/10.1089/chi.2019.0022DOI Listing
October 2019

A rare cause of proteinuria after kidney transplantation: Answers.

Pediatr Nephrol 2019 11 30;34(11):2333-2335. Epub 2019 Apr 30.

Cerrahpaşa Faculty of Medicine, Department of Pediatric Nephrology, Istanbul University-Cerrahpaşa, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04263-1DOI Listing
November 2019

A rare cause of proteinuria after kidney transplantation: Questions.

Pediatr Nephrol 2019 11 30;34(11):2331-2332. Epub 2019 Apr 30.

Cerrahpaşa Faculty of Medicine, Department of Pediatric Nephrology, Istanbul University-Cerrahpaşa, Istanbul, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04262-2DOI Listing
November 2019

Childhood-onset Takayasu arteritis: A 15-year experience from a tertiary referral center.

Int J Rheum Dis 2019 Jan 5;22(1):132-139. Epub 2018 Nov 5.

Department of Pediatric Rheumatology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

Aim: To describe clinical manifestations, angiographic findings, treatment, activity and damage of our Takayasu arteritis patients.

Method: The patients who met European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society classification criteria for childhood-onset Takayasu arteritis were reviewed in a retrospective longitudinal manner from 2002 to 2017. Extent of the disease was assessed by Disease Extent Index for Takayasu Arteritis (DEI.Tak), activity by Pediatric Vasculitis Activity Score and Indian Takayasu's Arteritis Activity Score (ITAS 2010) and damage by Pediatric Vasculitis Damage Index and Takayasu Arteritis Damage Score (TADS).

Results: Sixteen subjects (75% female) with a median disease duration of 3.1 years were enrolled in this study. While the median age at disease onset was 12.1 years, there was only a 2.5 months diagnostic delay. Treatment regime included corticosteroids (100%), which were combined with azathioprine or methotrexate in 93.8% and 37.5% of the subjects, respectively. Severe and refractory cases were treated with cyclophosphamide (62.5%) and subsequently with tocilizumab (37.5%). Seven patients (43.8%) required either percutaneous endovascular intervention or bypass for severe disease refractory to medications. The correlation of the activity and damage scores with each other was fairly good. Damage was found to be associated only with high disease activity and extensive disease at disease onset, but not with other parameters.

Conclusion: Despite high usage rates of aggressive immunosuppressive therapy and biologic agents, almost half of the patients underwent interventional procedures. When medications failed, endovascular and surgical interventions were of great importance to avoid end-organ ischemia. The performance of the new activity (DEI.Tak and ITAS2010) and damage indices (TADS) seems satisfactory.
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http://dx.doi.org/10.1111/1756-185X.13425DOI Listing
January 2019

Infants with congenital nephrotic syndrome have comparable outcomes to infants with other renal diseases.

Pediatr Nephrol 2019 04 29;34(4):649-655. Epub 2018 Oct 29.

Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.

Background: Children with congenital nephrotic syndrome (CNS) commonly develop end stage renal failure in infancy and require dialysis, but little is known about the complications and outcomes of dialysis in these children.

Methods: We conducted a retrospective case note review across members of the European Society for Pediatric Nephrology Dialysis Working Group to evaluate dialysis management, complications of dialysis, and outcomes in children with CNS.

Results: Eighty children (50% male) with CNS were identified form 17 centers over a 6-year period. Chronic dialysis was started in 44 (55%) children at a median age of 8 (interquartile range 4-14) months. Of these, 17 (39%) were on dialysis by the age of 6 months, 30 (68%) by 1 year, and 40 (91%) by 2 years. Peritoneal dialysis (PD) was the modality of choice in 93%, but 34% switched to hemodialysis (HD), largely due to catheter malfunction (n = 5) or peritonitis (n = 4). The peritonitis rate was 0.77 per patient-year. Weight and height SDS remained static after 6 months on dialysis. In the overall cohort, at final follow-up, 29 children were transplanted, 18 were still on dialysis (15 PD, 3 HD), 19 were in pre-dialysis chronic kidney disease (CKD), and there were 14 deaths (8 on dialysis). Median time on chronic dialysis until transplantation was 9 (6-18) months, and the median age at transplantation was 22 (14-28) months.

Conclusions: Infants with CNS on dialysis have a comparable mortality, peritonitis rate, growth, and time to transplantation as infants with other primary renal diseases reported in international registry data.
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http://dx.doi.org/10.1007/s00467-018-4122-0DOI Listing
April 2019

Outbreak of Shiga toxin-producing Escherichia-coli-associated hemolytic uremic syndrome in Istanbul in 2015: outcome and experience with eculizumab.

Pediatr Nephrol 2018 12 29;33(12):2371-2381. Epub 2018 Aug 29.

Pediatric Nephrology, Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background: This study aims to identify epidemiological and clinical characteristics of patients and report our experience with eculizumab treatment during an outbreak of hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) in Istanbul in 2015.

Methods: Thirty-two children (21 females, median age 3.25 years) were included in this study. Demographic, clinical and laboratory data, and treatment details were retrospectively collected. Renal outcomes were assessed at last follow-up visit. To assess the effect of eculizumab on prognosis of STEC-HUS, subgroup analysis was performed on patients who required dialysis.

Results: A high number of cases occurred within a certain region of Istanbul. Stool samples were cultured from 21 patients (65%), and enteroaggregative E. coli (EAEC; n = 7) and enterohemorrhagic E. coli (EHEC; n = 3) strains were detected. Rates of dialysis treatment, neurological manifestations, and death were 59%, 25%, and 3%, respectively. Mean follow-up duration was 8.6 ± 2.6 months (range 3-12 months). None of the patients (n = 25) was on dialysis at the final visit. The complete renal recovery rate was 54%. Nine patients were treated with eculizumab. At final follow-up visit, no differences in estimated glomerular filtration rate, proteinuria level, or hypertension incidence were observed between patients treated with eculizumab and those not treated with eculizumab.

Conclusions: An outbreak of EAEC occurred in a specific region of Istanbul. Livestock markets were suspected as the source. Evidence for beneficial effects of eculizumab on renal outcome was not clear in this cohort.
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http://dx.doi.org/10.1007/s00467-018-4033-0DOI Listing
December 2018

Genetic associations of hemoglobin in children with chronic kidney disease in the PediGFR Consortium.

Pediatr Res 2019 02 15;85(3):324-328. Epub 2018 Aug 15.

Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Genome-wide association studies (GWAS) in healthy populations have identified variants associated with erythrocyte traits, but genetic causes of hemoglobin variation in children with CKD are incompletely understood.

Methods: The Pediatric Investigation of Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE), and Cardiovascular Comorbidity in Children with CKD (4C). We performed cross-sectional and longitudinal association studies of single-nucleotide polymorphisms (SNPs) in 1125 patients.

Results: Children of European (n = 725) or Turkish (n = 400) ancestry (EA or TA) were included. In cross-sectional analysis, two SNPs (rs10758658 and rs12718597) previously associated with RBC traits were significantly associated with hemoglobin levels in children of EA and TA. In longitudinal analysis, SNP rs2540917 was nominally associated with hemoglobin in EA and TA children.

Conclusions: SNPs associated with erythrocyte traits in healthy populations were marginally significant for an association with hemoglobin. Further analyses/replication studies are needed in larger CKD cohorts to investigate SNPs of unknown significance associated with hemoglobin. Functional studies will be required to confirm that the observed associations between SNPs and clinical phenotype are causal.
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http://dx.doi.org/10.1038/s41390-018-0148-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377354PMC
February 2019

Shear Wave Elastography in the Evaluation of the Kidneys in Pediatric Patients with Unilateral Vesicoureteral Reflux.

J Ultrasound Med 2019 Feb 19;38(2):379-385. Epub 2018 Jul 19.

Departments of Radiology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey.

Objectives: To evaluate the ability of shear wave elastography (SWE) to detect renal parenchymal scar formation in patients with vesicoureteral reflux.

Methods: We prospectively evaluated 49 patients with unilateral grade 2 or higher-degree VUR. All patients underwent dimercaptosuccinic acid (DMSA) scintigraphy for evaluation of the renal parenchymal scar. After the DMSA scan, 2 radiologists, who were blinded to clinical data and each other's measurements, evaluated the kidneys of the patients using SWE. The kidneys were divided into 3 parts: upper pole, middle region, and lower pole, and 3 regions of interest were placed to each part. Shear wave velocity (SWV) values were calculated using meters per second as a unit and recorded for each region. Afterward, SWV values were compared to DMSA results.

Results: There was no significant difference between the observers' mean SWV values of kidneys with VUR without scar formation (mean ± SD, 2.11 ± 0.06 and 2.09 ± 0.05 m/s) and the contralateral normal kidney SVW values (2.11 ± 0.06 and 2.10 ± 0.05 m/s; P = .936 and .724, respectively). We observed a significant difference between the mean SWV values of the kidneys with VUR accompanied by scar formation (2.28 ± 0.10 and 2.27 ± 0.11 m/s) and the mean SWV values of the contralateral normal kidneys (2.09 ± 0.05 and 2.10 ± 0.04 m/s; P < .001 for both observers).

Conclusions: Shear wave elastography could detect scar tissue in kidneys; however, the variability of the stiffness due to the kidney's complex structure, and variations in blood perfusion and the glomerular filtration rate of the kidney might limit the use of SWE in current clinical diagnostic algorithms for VUR.
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http://dx.doi.org/10.1002/jum.14698DOI Listing
February 2019

Leptin and ghrelin in chronic kidney disease: their associations with protein-energy wasting.

Pediatr Nephrol 2018 11 6;33(11):2113-2122. Epub 2018 Jul 6.

Department of Pediatric Nephrology, Istanbul University Cerrahpasa Faculty of Medicine, 34098 Fatih, Istanbul, Turkey.

Background: This study aimed to evaluate plasma concentrations of leptin and total ghrelin in children with chronic kidney disease (CKD) and assess their roles in protein-energy wasting (PEW).

Methods: This study consisted of three different CKD populations [CKD group (20 patients with non-dialysis CKD), dialysis group (39 patients on dialysis), and kidney transplant (KTx) group (35 KTx recipients)] and control group (18 healthy children). Plasma leptin and total ghrelin levels were measured. Multi-frequency bioimpedance analysis was used for the assessment of fat and lean mass. PEW was defined using criteria including body mass, muscle mass, growth, serum albumin level, and protein intake.

Results: While plasma leptin levels did not differ among the study groups, total ghrelin levels were significantly higher in the dialysis group (P < 0.001). Seven dialysis patients (18%) and one CKD patient (5%) but none of the KTx recipients met the criteria of PEW. Dialysis patients with PEW had lower plasma leptin levels compared to their counterparts (P = 0.018); however, total ghrelin levels did not differ between the two groups (P = 0.10). Low leptin level in dialysis patients was independently associated with lower fat mass index (P < 0.001) and lower height-specific SD scores of BMI (P = 0.019).

Conclusions: PEW is prevalent in dialysis patients. Low levels of leptin seem to be associated with PEW. Our result suggests that low leptin levels may be a consequence rather than a cause of PEW. Longitudinal studies are required to investigate this complex relationship between leptin and PEW in pediatric dialysis patients.
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http://dx.doi.org/10.1007/s00467-018-4002-7DOI Listing
November 2018

Persistent hypoglycemic attacks during hemodialysis sessions in an infant with congenital nephrotic syndrome: Answers.

Pediatr Nephrol 2019 01 29;34(1):77-79. Epub 2018 Jun 29.

Nephrogenetics Laboratory, Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara, Turkey.

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http://dx.doi.org/10.1007/s00467-018-3982-7DOI Listing
January 2019

Persistent hypoglycemic attacks during hemodialysis sessions in an infant with congenital nephrotic syndrome: Questions.

Pediatr Nephrol 2019 01 29;34(1):75-76. Epub 2018 Jun 29.

Nephrogenetics Laboratory, Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara, Turkey.

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http://dx.doi.org/10.1007/s00467-018-3980-9DOI Listing
January 2019

Hemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children.

PLoS One 2018 18;13(6):e0198320. Epub 2018 Jun 18.

Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

Randomized trials in adults have shown reduced all-cause and cardiovascular mortality on hemodiafiltration (HDF) compared to high-flux hemodialysis (HD), but the mechanisms leading to improved outcomes are not clear. We studied biomarkers of inflammation, oxidative stress, anti-oxidant capacity and endothelial dysfunction in 22 children (13 female, age 8-15 years). All children received HD for at least 3 months, and were then switched to HDF, keeping all dialysis related parameters and dialysis time constant. All the biomarkers of inflammation (ß2-microglobulin, IL-6, IL-10, high sensitive C-reactive protein [hsCRP]), oxidative stress (nitrotyrosine, advanced glycation end-products [AGEs], oxidized low density lipoprotein [ox-LDL] and anti-oxidant capacity) and endothelial dysfunction (asymmetric dimethyl arginine [ADMA], symmetric dimethyl arginine [SDMA]), were comparable between incident and prevalent patients on HD, suggesting that even a short dialysis vintage of 3 months on HD increases inflammation and endothelial stress. After 3 months of HDF therapy there was a significant reduction in ß2-microglobulin (p<0.001), hCRP, ADMA, SDMA, AGEs, ox-LDL (p<0.01 for all) and an increase in total antioxidant capacity (p<0.001) compared to HD. All children were maintained on the same dialyser, dialysis water quality, dialysis time and blood flow speeds suggesting that improved clearances on HDF led to an improved biomarker profile. Even in children with residual renal function there was a significant reduction in ß2 microglobulin, hsCRP, SDMA, ox-LDL and AGEs on HDF compared to HD. Children with a lower blood flow had higher inflammatory status (higher IL-6/IL-10 ratio; p = 0.04, r = -0.43). Children who achieved a higher convective volume (≥median 12.8L/m2) had lower ox-LDL (p = 0.02). In conclusion, we have shown that a significant improvement in inflammation, antioxidant capacity and endothelial risk profile is achieved even within a short time (3 months) on HDF compared to HD treatment.

Trial Registration: ClinicalTrials.gov: NCT02063776.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198320PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005477PMC
December 2018

Neutral pH and low-glucose degradation product dialysis fluids induce major early alterations of the peritoneal membrane in children on peritoneal dialysis.

Kidney Int 2018 08;94(2):419-429

Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University of Heidelberg, Germany. Electronic address:

The effect of peritoneal dialysates with low-glucose degradation products on peritoneal membrane morphology is largely unknown, with functional relevancy predominantly derived from experimental studies. To investigate this, we performed automated quantitative histomorphometry and molecular analyses on 256 standardized peritoneal and 172 omental specimens from 56 children with normal renal function, 90 children with end-stage kidney disease at time of catheter insertion, and 82 children undergoing peritoneal dialysis using dialysates with low-glucose degradation products. Follow-up biopsies were obtained from 24 children after a median peritoneal dialysis of 13 months. Prior to dialysis, mild parietal peritoneal inflammation, epithelial-mesenchymal transition and vasculopathy were present. After up to six and 12 months of peritoneal dialysis, blood microvessel density was 110 and 93% higher, endothelial surface area per peritoneal volume 137 and 95% greater, and submesothelial thickness 23 and 58% greater, respectively. Subsequent peritoneal changes were less pronounced. Mesothelial cell coverage was lower and vasculopathy advanced, whereas lymphatic vessel density was unchanged. Morphological changes were accompanied by early fibroblast activation, leukocyte and macrophage infiltration, diffuse podoplanin presence, epithelial mesenchymal transdifferentiation, and by increased proangiogenic and profibrotic cytokine abundance. These transformative changes were confirmed by intraindividual comparisons. Peritoneal microvascular density correlated with peritoneal small-molecular transport function by uni- and multivariate analysis. Thus, in children on peritoneal dialysis neutral pH dialysates containing low-glucose degradation products induce early peritoneal inflammation, fibroblast activation, epithelial-mesenchymal transition and marked angiogenesis, which determines the PD membrane transport function.
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http://dx.doi.org/10.1016/j.kint.2018.02.022DOI Listing
August 2018

Early Effects of Renal Replacement Therapy on Cardiovascular Comorbidity in Children With End-Stage Kidney Disease: Findings From the 4C-T Study.

Transplantation 2018 03;102(3):484-492

Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.

Background: The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective cardiovascular comorbidity in children with chronic kidney disease study and focuses on the early effects of renal replacement therapy (RRT) modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis.

Methods: We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n = 76 transplantation, n = 90 dialysis).

Results: RRT modality had a significant impact on the change in arterial structure and function: compared to dialysis treatment, transplantation was independently associated with decreases in pulse wave velocity (ß = -0.67; P < 0.001) and intima media thickness (ß = -0.40; P = 0.008). Independent of RRT modality, an increase in pulse wave velocity was associated with an increase in diastolic blood pressure (ß = 0.31; P < 0.001). Increasing intima media thickness was associated with a larger increase in body mass index (ß = 0.26; P = 0.003) and the use of antihypertensive agents after RRT (ß = 0.41; P = 0.007). Changes in left ventricular mass index were associated with changes in systolic blood pressure (ß = 1.47; P = 0.01).

Conclusions: In comparison with initiating dialysis, preemptive transplantation prevented further deterioration of the subclinical vascular organ damage early after transplantation. Classic cardiovascular risk factors, such as hypertension and obesity are of major importance for the development of cardiovascular organ damage after renal transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001948DOI Listing
March 2018

Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children.

J Am Soc Nephrol 2017 Oct 31;28(10):3055-3065. Epub 2017 May 31.

Division of Pediatric Nephrology, University Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany;

We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug-resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established.
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http://dx.doi.org/10.1681/ASN.2016101121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619960PMC
October 2017

Brief Report: Deficiency of Complement 1r Subcomponent in Early-Onset Systemic Lupus Erythematosus: The Role of Disease-Modifying Alleles in a Monogenic Disease.

Arthritis Rheumatol 2017 09 10;69(9):1832-1839. Epub 2017 Jul 10.

National Human Genome Research Institute, NIH, Bethesda, Maryland.

Objective: To identify a genetic cause of early-onset systemic lupus erythematosus (SLE) in a large consanguineous family from Turkey and to study the mechanisms of the disease.

Methods: We performed whole-exome sequencing and single-nucleotide polymorphism array genotyping in family members with and without SLE. Protein and gene expression, cytokine profile, neutrophil extracellular trap (NET) formation, and presence of low-density granulocytes were evaluated in patient primary cells and serum samples.

Results: We identified a novel, homozygous, loss-of-function mutation (p.Pro445Leufs*11) in the C1R gene. Using the Sanger method of DNA sequencing in 14 family members, we confirmed the presence of the mutation in 4 patients with SLE and in an asymptomatic 9-year-old girl. Complement levels were low in sera from patients with truncated C1r protein. Two siblings with SLE who were available for detailed evaluation exhibited strong type I interferon (IFN) inflammatory signatures despite their disease being clinically inactive at the time of sampling. The type I IFN transcriptional signature in the patients' blood correlated with disease expressivity, whereas the neutrophil signature in peripheral blood mononuclear cells was likely associated with disease severity. The female patient with SLE with the most severe phenotype presented with a stronger neutrophil signature, defined by enhanced NET formation and the presence of low-density granulocytes. Analysis of exome data for modifying alleles suggested enrichment of common SLE-associated variants in the more severely affected patients. Lupus-associated HLA alleles or HLA haplotypes were not shared among the 4 affected subjects.

Conclusion: Our findings revealed a novel high-penetrance mutation in C1R as the cause of monogenic SLE. Disease expressivity in this family appears to be influenced by additional common and rare genetic variants.
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http://dx.doi.org/10.1002/art.40158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609811PMC
September 2017

Acoustic radiation force impulse (ARFI) elastography in the evaluation of renal parenchymal stiffness in patients with ureteropelvic junction obstruction.

J Med Ultrason (2001) 2017 Apr 8;44(2):167-172. Epub 2016 Dec 8.

Department of Radiology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey.

Purpose: To investigate the role of acoustic radiation force impulse (ARFI) elastography in the detection of renal parenchymal damage in kidneys with and without ureteropelvic junction obstruction (UPJO).

Methods: Twenty-five pediatric patients with a diagnosis of UPJO who underwent surgery and 15 pediatric patients with conservatively managed UPJO were prospectively evaluated with ARFI elastography. Sixteen healthy volunteers constituted the control group. Shear wave velocity (SWV) measurements in the upper, mid, and lower poles of the affected kidney were performed. SWV values of kidneys based on presence of UPJO and hydronephrosis grade were compared. The correlation of SWV values with residual renal function obtained from diethylenetriaminepentaacetic acid or mercaptoacetyltriglycine-3 renal scan was evaluated.

Results: Significantly, higher SWV values were found in control kidneys compared to kidneys affected by UPJO. The median SWVs were 2.82 (2.51-3.07) m/s for the control kidneys and 2.36 (2.09-2.53) m/s for the kidneys in the UPJO group (p < 0.001). When UPJO patients were grouped according to the grade of hydronephrosis, grade 0 hydronephrotic kidneys [2.35 (2.11-2.50) m/s] and grade 3-4 hydronephrotic kidneys [1.86 (1.96-2.25) m/s] had significantly lower SWV values compared to grade 1-2 hydronephrotic kidneys [2.62 (2.37-2.90) m/s] (p < 0.05).

Conclusions: ARFI as a noninvasive, radiation-free procedure for evaluating parenchymal stiffness may prove useful in the diagnostic work-up and follow-up of children with UPJO-induced renal disease.
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http://dx.doi.org/10.1007/s10396-016-0760-7DOI Listing
April 2017

Molecular analysis of the AGXT gene in patients suspected with hyperoxaluria type 1 and three novel mutations from Turkey.

Mol Genet Metab 2016 12 1;119(4):311-316. Epub 2016 Nov 1.

Department of Pediatric Metabolic Disorders and Pediatric Genetics, Gazi University Medical Faculty, Turkey.

Primary hyperoxaluria type 1 (PH1) is a rare, autosomal recessive disease, caused by the defect of AGXT gene encoding hepatic peroxisomal alanine glyoxylateaminotransferase (AGT). This enzyme is responsible for the conversion of glyoxylate to glycine. The diagnosis of PH1 should be suspected in infants and children with nephrocalcinosis or nephrolithiasis. Early diagnosis and treatment is crucial in preventing disease progression to end stage kidney disease (ESKD). In this study, AGXT gene sequence analyses were performed in 82 patients who were clinically suspected (hyperoxaluria and nephrolithiasis or nephrocalcinosis with or without renal impairment) to have PH1. Disease causing mutations have been found in fifteen patients from thirteen families (18%). Novel mutations have been found (c.458T>A (p.L153X), c.733_734delAA (p.Lys245Valfs*11), c.52 C>T (p.L18F)) in three of 13 families. There were 3-year lag time between initial symptoms and the time of PH1 is suspected; additionally, 5.5-year lag time between initial symptoms and definitive diagnosis. Consanguinity was detected in 77% of the patients with mutation. After genetic diagnosis, one patient received combined kidney and liver transplantation. AGXT gene sequencing is now the choice of diagnosis of PH1 due to its non-invasive nature compared to liver enzyme assay. Early diagnosis and accurate treatment in PH1 is important for better patient outcomes.
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http://dx.doi.org/10.1016/j.ymgme.2016.10.011DOI Listing
December 2016