Chronic Kidney Disease in Iran: First Report of the National Registry in Children and Adolescences Neamatollah Ataei1*, Abbas Madani1, Seyed Taher Esfahani1, Hasan Otoukesh2, Nakysa Hooman2, Rozita Hoseini2, Mojtaba Fazel3, Ali Derakhshan4, Alaleh Gheissari5, Hadi Sorkhi6, Arash Abbasi1, Daryoosh Fahimi7, Fatemeh Ghane Sharbaf8, Fakhrossadat Mortazavi9, Behnaz Falakaflaki10, Ahmad Ali Nikibakhsh11, Simin Sadeghi Bojd12, Seyyed Mohammad Taghi Hosseini Tabatabaei12, Kambiz Ghasemi13, Ali Ahmadzadeh14, Parsa Yousefichaijan15, Afshin Safaei Asl16, Baranak Safaeian17, Salman Khazaei18, Leila Hejazipour1, Abolhassan Seyed Zadeh19, and Fatemeh Ataei1,20 Purpose: Knowing the epidemiological aspects of chronic kidney disease (CKD) in children is crucial for early recognition, identification of reversible causes, and prognosis. Here, we report the epidemiological characteristics of childhood CKD in Iran. Materials and Methods: This cross-sectional study was conducted during 1991 - 2009. The data were collected using the information in the Iranian Pediatric Registry of Chronic Kidney Disease (IPRCKD) core dataset. Results: A total of 1247 children were registered. The mean age of the children at registration was 0.69 ± 4.72 years (range, 0.25 –18 years), 7.79 ± 3.18 years for hemodialysis (HD), 4.24 ± 1.86 years for continuous ambula- tory peritoneal dialysis (CAPD), and 3.4±1.95 years for the children who underwent the renal transplantation (RT) (P < .001). The mean year of follow-up was 7.19 ± 4.65 years. The mean annual incidence of CKD 2–5 stages was 3.34 per million age-related population (pmarp). The mean prevalence of CKD 2–5 stages was 21.95 (pmarp). The cumulative 1-, 5-, and 10-year patients' survival rates were 98.3%, 90.7%, and 84.8%, respectively. The etiology of the CKD included the congenital anomalies of the kidney and urinary tract (CAKUT) (40.01%), glomerulopathy (19.00%), unknown cause (18.28%), and cystic/hereditary/congenital disease (11.14%). Conclusion: The incidence and prevalence rate of pediatric CKD in Iran is relatively lower than those reported in Europe and other similar studies. CAKUT was the main cause of the CKD. Appropriate management of CAKUT including early urological intervention is required to preserve the renal function. Herein, the long-term survival rate was higher among the children with CKD than the literature. Keywords: chronic kidney disease; children; epidemiology; etiology; end-stage renal disease; Iran INTRODUCTION Chronic Kidney Disease (CKD) is a condition char-acterized by a gradual loss of renal function. It can 1Pediatric Chronic Kidney Disease Research Center, Department of Pediatric Nephrology, Children’s Medical Center, Tehran. Univer- sity of Medical Sciences, Tehran, Iran. 2Ali-Asghar Children’s Hospital, Iran University of Medical Sciences, Tehran, Iran. 3Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. 4Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. 5Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran. 6Non-Communicable Pediatric Diseases Research Center, Department of Pediatric Nephrology, Amirkola Children Hospital, Babol University of Medical Sciences, Babol, Iran. 7Bahrami Children's Hospital, Tehran University of Medical Sciences, Tehran, Iran. 8Sheikh Children’s Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. 9Department of Pediatrics, Tabriz University of Medical Sciences Tabriz, Iran. 10Mousavi Hospital, Zanjan University of Medical Sciences, Zanjan, Iran. 11Urmia University of Medical Sciences, Urmia, Iran. 12Department of Pediatrics, Zahedan University of Medical Sciences, Zahedan, Iran. 13Department of Pediatrics Nephrology, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. 14Abozar Hospital, Ahvaz Jondishapour University of Medical Sciences, Ahvaz, Iran. 15Amirkabir Hospital, Arak University of Medical Sciences, Arak, Iran. 16Department of Pediatrics, Guilan University of Medical Sciences, Guilan, Iran. 17Taleghani Pediatric Hospital, Golestan University of Medical Sciences, Gorgan, Iran. 18Research Center for Health Sciences, Hamadan University of Medical Sciences, Hamadan, Iran. 19Razi Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran. 20Department of Nuclear Medicine, Valiasr Hospital, Zanjan University of Medical Sciences, Zanjan, Iran. *Correspondence: Pediatric Chronic Kidney Disease Research Center, Department of Pediatric Nephrology, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran. Tel : +98 21 66929234, E-mail: ataiinem@tums.ac.ir. Received November 2019 & Accepted August 2020 be progressive and may ultimately lead to the irreversi- ble nephron loss and scarring(1). Extensive research has focused on the epidemiology of CKD in the adult pop- ulation(2,3). In contrast, there is limited knowledge about Urology Journal/Vol 18 No. 1/ January-February 2021/ pp. 122-130. [DOI: 10.22037/uj.v16i7.5759] UNCLASSIFIED the epidemiology of CKD in the pediatric population(4). Understanding the epidemiology of CKD in children is crucial for early detection and precise diagnosis, as well as identification of preventable causes of progression, prognosis, and treatment decisions including treatment of reversible causes. Etiology, the progression of the disease, and treatment modality in the children with CKD are different from those observed in the adult pa- tients(5,6). In children, CKD not only may progress to end-stage renal disease (ESRD) but also influences on the longi- tudinal bone growth through alterations in the nutrition and mineral metabolism(7). It can also negatively influ- ence the life quality of the patients and family members (8,9). Despite few recent studies on the epidemiological and clinical features of the pediatric CKD(10), there is insuf- ficient knowledge about the risk factors leading to dis- ease progression in the children(11). There is much less information available on the epi- demiological and clinical manifestations of the Irani- an children with CKD because of the lack of a central reporting registry(12,13). Therefore, in 1991, the Iranian Pediatric Nephrology Working Group established the Iranian Pediatric Registry of Chronic Kidney Disease (IPRCKD) aimed at providing a comprehensive nation- al data warehouse for studying various aspects of CKD in the pediatric population. Thus, the present study is conducted to report the ba- sic epidemiological information for analysis of the IP- RCKD activity in which 1247 patients with CKD were registered from January 1991 to December 2009. PATIENTS AND METHODS Study Design, Setting, and Sampling The data were collected using the IPRCKD core data- set including name, date of birth, gender, primary renal diagnosis and associated diseases, residence, height, se- rum creatinine (Cr), treatment modality, changes in the therapy, death and its cause at the time of registration. The inclusion criteria of the study were: (1) estimated Creatinine Clearance (eCCI) of ≤ 75 mL/min/1.73m2 body surface area according to the Schwartz’s formula (14,15,16) for at least 3 months and (2) having less than 19 years of age at the time of registration. There were 31 large and small provinces, at the time of registration in Iran, all of which were covered by 19 pediatric nephrology centers. In other words, all the centers in Iran were potentially involved in the care of children and adolescents with CKD, accounting for a total population base of 21.3 million children, and a general population of 75 million inhabitants(17) was considered to report the index cases. Herein, the chil- dren with CKD were not evaluated in each province separately. On the other hand, some provinces lacked the pediatric nephrology center(s) thus; their patients referred to neighboring or non-adjacent provinces with pediatric nephrology center(s) for follow-up treatment. All the 19 pediatric nephrology centers were asked to voluntarily register the characteristics of their children with CKD in the questionnaire. There was mandatory request to register CKD patients in this database. The children with CKD were detected using a stand- ardized registration form containing a predefined list of diagnoses classified into eight groups: Congenital anomalies of the kidney and urinary tract (CAKUT) in the forms of hypodysplasia ± reflux nephropathy and obstructive uropathy, glomerular diseases, cystic/he- reditary/congenital diseases, vascular nephropathies, neoplasia/tumors, other renal disorders, miscellaneous causes, and unknown causes. After developing a software program at the following website: “http://www.tums.ac.ir” entitled “http://iprcrf. tums.ac.ir” and including identification code for region- al principal investigators (pediatric nephrologists), they were asked to record their own patient’s data electroni- cally in the questionnaires and send them via e-mail to the executive director. This phase of the registry has been completed with the participation of nearly 120 pediatric nephrologists working in 19 pediatric nephrology centers in the coun- try. All pediatric nephrologists followed a single protocol and, considering the comprehensiveness of the registra- tion system that covered the whole country, as well as the full justification of pediatric nephrologist, the valid- ity, and reliability of the results can be confirmed. The data set used and analyzed during the study is available from the corresponding author upon request. In this phase of registry (first phase), we did not invite primary care physician or pediatrician to register and participate in sharing CKD patients. However, we in- tended to include primary care physicians in the upcom- ing second phase of registry. The incidence was calculated using the number of new- ly detected cases in each year, while the point preva- lence rate included all the living children followed in the registry on 31 December 2009. Both incidence and prevalence were expressed as per million age-related population (pmarp). Hypertension was defined as the blood pressure above the 95th percentile with respect to age, gender, and height as reported in the Task Force percentile reference(18). The children were categorized into the patients with CKD stages 2–5 according to the classification de- scribed by the Clinical Practice Guidelines of the Na- tional Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI guidelines)(19). Stages 2 - 4 were considered as preterminal chronic CKD in Iran-Ataei et al. Table 1. Distribution of the children with respect to different stages of CKD in the studied patients CKD stage Study No (% ) period CKD 2 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 0 0 2(5.8) 2(8) 2(5.2) 1(2) 2(2.8) 3(4.5) 5(6.3) 2(2.5) 1(1.35) 3(3.75) 2(2.35) 2 (2.2) 1(1.35) 4(4.4) 2(2.3) 3(4.3) 4(6.1) CKD 3 0 0 1(2.9) 1(4) 1(2.6) 1(2) 6(8.3) 6(9) 7(8.8) 7(8.8) 2(2.7) 7(8.75) 6(7) 9(9.8) 9(9.7) 6(6.5) 14(15.9) 2(2.9) 9(13.6) CKD 4 1(3) 1(3.6) 2(5.8) 2(8) 2(5.2) 8(16.3) 4(5.6) 10(14.9) 12(15) 17(21.2) 7(9.5) 7(8.75) 10(11.75) 13(14.1) 12(12.9) 19(20.4) 17(19.3) 17(22.5) 15(27.7) CKD 5 32(97) 27(96.4) 29(85.3) 20(80) 33(86.8) 39(79.6) 60(83.3) 48(71.6) 56(70) 54(67.5) 64(86.5) 63(78.75) 67(78.8) 68(76.1) 71(81.7) 64(68.8) 55(62.5) 48(68.6) 38(57.6) Total 33 28 34 25 38 49 72 67 80 80 74 80 85 92 93 93 88 70 66 Vol 18 No 1 January-February 2021 123 renal failure, while CKD Stage 5 ESRD was defined as either having a Glomerular Filtration Rate (GFR) of <15 mL/min/1.73m2 or being candidate for Renal Replacement Therapy (RRT) through dialysis or trans- plantation. For the children less than two years of age, the percentage of loss of renal function in each stage of the KDOQI guidelines was extrapolated considering the reference values of GFR in the children under than two years old(19). The GFR was assessed according to the Schwartz’s formula(14,15,16). The estimated Glomeru- lar Filtration Rate (eGFR) in all the children with CKD was calculated based on the Schwartz's formula modi- fied for the children (Cystatin C-Based GFR Estimat- ing Equation) using the fixed numbers of 48 and 38 for boys and girls, respectively according to the following equation(16). Creatinine was determined by the Jaffe method in all the centers. Descriptive statistics including the frequen- cy tables, charts, and percentages were used for present- ing the categorical variables. The patient’s survival was analyzed using the Kaplan– Meier method. The risk for progression to ESRD was assessed using the multiple Cox proportional hazards regression. P-value of ≤ .05 was considered as statis- tically significant. Statistical analyses were performed using the Stata software, version 12 (Stata Corp, Col- lege Station, TX, USA). Table 2. Primary causes of CKD in all the registered patients Groups of Diseases No % N % Obstructive 190 15.23 Posterior urethral valve 73 5.85 Anterior urethral valve 1 0.08 CAKUT Bilateral ureteral stenosis 5 0.4 Ureteropelvic junction stenosis 22 1.76 Ureterovesical junction stenosis 9 0.72 Other obstructive malformation 9 0.72 Prune belly syndrome 2 0.16 Neurogenic bladder 69 5.53 Hypodysplasia 79 6.33 Renal aplasia / hypo/dysplasia 79 6.33 Interstitial nephritis 14 1.12 Reflux Nephropathy/ 230 18.44 Reflux nephropathy 105 8.42 Pyelonephritis Pyelonephritis 26 2.08 VUR with associated neurogenic bladder 60 4.81 VUR without associated neurogenic bladder 25 2 Glomerulopathies 237 19.00 Focal segmental glomerulosclerosis 82 6.57 GN with advanced diffuse sclerosis 4 0.32 Focal segmental proliferative GN 2 0.16 Post infectious GN 21 1.68 Crescentic GN 38 3.04 Membranous GN 3 0.24 Membranoproliferative GN type1 20 1.6 Membranoproliferative GN type2 4 0.32 Non- classified GN 9 0.72 Idiopathic nephrotic syndrome 20 1.6 SLE nephritis 28 2.24 Henoch-Schonlein nephritis 5 0.4 Other systemic immunologic disease 1 0.08 Cystic / Hereditary /Congenital Diseases 159 12.72 Juvenile nephronophthisis 25 2 Infantile polycystic kidney disease 29 2.32 Adult-type polycystic kidney disease 1 0.08 Undetermined polycystic kidney 7 0.56 Medullary cystic disease 6 0.48 Primary hyperoxaluria 3 0.24 Laurence Moon Biedl syndrome 10 0.8 Congentital nephrotic syndrome 22 1.76 Alport syndrome 21 1.68 Cystinosis 34 2.72 Cystinuria 1 0.08 Vascular Nephropathies 47 3.76 Hemolytic uremic syndrome 40 3.2 Sepsis-induced renal ischemia 4 0.32 Polyarteritis nodosa 2 0.16 Renal artery stenosis 1 0.08 Neoplasia / Tumors 6 0.48 Wagner syndrome 1 0.08 Wilms' tumor 4 0.32 Others 1 0.08 Other Renal Disorders 24 1.92 Sickle cell nephropathy 1 0.08 Diabetic glomerulonephritis 6 0.48 Nephropathy + mental retardation 6 0.48 Fanconi syndrome 10 0.8 Acute tubolar necrosis 1 0.08 Miscellaneous Conditions 47 3.76 Nephrolithiasis 25 2 Hyperoxaluria 11 0.88 Others 11 0.88 Unknown 228 18.28 - 228 18.28 Total - 1247 100 CKD in Iran-Ataei et al. Unclassified 124 RESULTS General Characteristics of the Subjects Totally, 1247 children were registered (662 boys, 585 girls, male/female ratio of 1.1) from January 1991 to December 2009. The mean age of the patients at the time of registration was 7.69 ± 4.72 years (range, 0.3- 18). The mean follow-up duration was 7.19 ± 4.65 years. Concerning the gender of the patients, mean age of the patients at the time of registration was (6.27 ± 3.78) and (6.53 ± 3.82) years for boys and girls, respec- tively (P = 0.22). The mean annual incidence and prev- alence of CKD 2–5 stages was 3.34 (pmarp) and 21.95 (pmarp), respectively. The mean annual incidence of CKD 2–4 and CKD 5 stages was 0.83 (pmarp) (range, 0.06-1.57) and 2.53 (range, 1.11-3.62), respectively. The mean annual prev- alence of CKD 2–4 and CKD 5 stages was 2.98 (pmarp) (range, 0.06-7.14) and 18.98 (range, 1.78-45.86), re- spectively. CKD Classification At the time of registration, 41(3.28%) children were in CKD Stage 2, 94 (7.54%) in CKD Stage 3, 176 (14.11%) in CKD Stage 4, and 936 (75.06%) were in CKD Stage 5. A high proportion (75.06%) of the pa- tients was diagnosed with CKD Stage 5 at the first visit. During the study period, the number of the patients with CKD Stage 5 decreased from (97%) in 1991 to (57.6%) in 2009. At the same time, the frequencies of CKD in the early stages increased over the years. Table 1 shows the distribution of the children with respect to CKD stage during the whole registration period. Incidence and Prevalence The annual incidence of CKD was equal to 1.43 (pmarp) in 1991. It decreased to 1.21(pmarp) in 1992, while gradually increased to 4.03 (pmarp) in 2006, thereafter the incidence decreased to 2.86 (pmarp) (mean 2.84; range, 1.08-4.03). The prevalence rate had an increas- ing trend in this period so that, it reached from 1.43 (pmarp) in 1991 to 48.10 (pmarp) in 2009 (mean 19.41; range, 1.43-48.10) (Figure 1). Causes of CKD The etiology of CKD included the CAKUT in 499 cases (40.01%) [hypodysplasia ± reflux nephropathy in 309 cases (24.77%) ,and obstructive uropathy in 190 cases (15.23%)], glomerulopathy in 237 cases (19.00%), un- known cause in 228 cases (18.28%), cystic/hereditary/ congenital diseases in 139 cases (11.14%), miscellane- ous conditions in 47 cases (3.76%), vascular nephrop- athies in 47 cases (3.76%), other renal disorders in 44 cases (3.52%) ,and neoplasia /tumors in 6 cases (0.48%) as shown in (Figure 2). Table 2 shows the primary causes of CKD in all the registered children. A signif- icant decreasing trend was observed in the cases with unknown- etiology from 33% in 1991 to 13.6% in 2009 (P for trend=.01). Renal Replacement Therapy Out of 1247 registered children, 310 (24.86%) of them were on the conservative treatment (188 boys, 122 girls mean age: 6.53 ± 4.77 years (range, 0.24-17.8), 537 (43.06%) of them had ESRD who were on the chron- ic hemodialysis (HD), ( 281boys and 256 girls; mean age: 8.85 ± 4.26 years (range, 0.24-17), 182 (14.6%) of them were on the continuous ambulatory peritoneal dialysis (CAPD) (98 boys, 84 girls mean age: 4.27 ± 4.41 years (range, 0.5-16.4), and 218 (17.48%) of them underwent the renal transplantation (RT) (104 boys,114 girls mean age: 9.41 ± 4.13 years (range, 1-15.2). The death occurred in 138 patients (11.06%), mainly due to the cardiovascular and infectious com- plications. HD was the most commonly used modality of RRT. Among 218 children who underwent the RT, 48 patients (22.01%) lost their first grafts. The majori- ty (73.17%) of the transplanted children received their graft from the deceased donors. According to the re- sults of Kaplan-Meier analysis, the 1-, 5 - and 10-year patients' survival rates were obtained as 98.3%, 90.7%, and 84.8%, respectively (Table 3). As shown in Figure 3, (A) the survival rate was lower in the boys than girls, there were no significant gender differences (HR= 1.14, P = 0.42) and (B) patients with ESRD had lower surviv- al rate compared to those affected with other stages of CKD, but the difference was not statistically significant between the two groups (HR = 1.28, P = 0.26). Mean age of the patients at the time of death was 6.71 ± 4.52 years (range, 0.25-15). The percentage of death in the studied patients ranged from 20.43% in 2005 to 4.55% in 2009. DISCUSSION Currently, CKD is a public health issue due to the rap- id rising trend of its prevalence (20). To the best of our knowledge, this study is the first cross-sectional, na- tionwide report on the epidemiologic characteristics and etiology of the Iranian children and adolescents with CKD. Due to the asymptomatic nature of CKD, especially in the earlier stages, there are no accurate ep- idemiological data on the pediatric patients. According to the annual report by the European Renal Associa- tion – European Dialysis and Transplant Association (ERA-EDTA) registry in 2007, the overall CKD prev- alence in the USA adult population was equal to 11% (Stage 1, 3.3%; Stage 2, 3.0%; Stage 3, 4.3%; Stage 4, Table 3. Patients' survival for all the registered children with CKD (1991-2009) using the life table Survival time (year) Total Event Censored Survival probability SE 95%CI 1 1247 21 1 0.983 0.004 0.97, 0.989 2 1225 25 68 0.962 0.005 0.95, 0.97 3 1132 18 120 0.946 0.007 0.93, 0.958 4 994 17 107 0.929 0.008 0.91, 0.94 5 870 19 110 0.907 0.009 0.89, 0.92 6 741 8 106 0.897 0.01 0.88, 0.91 7 627 12 114 0.878 0.011 0.84, 0.89 8 501 5 50 0.869 0.011 0.84, 0.88 9 444 3 4 0.863 0.012 0.82, 0.87 10 437 7 60 0.848 0.013 0.82, 0.87 CKD in Iran-Ataei et al. Vol 18 No 1 January-February 2021 125 Unclassified 126 0.2%, and Stage 5, 0.2%)(21). The prevalence rate for the early stages of CKD was about 50 times higher than that of advanced stages. Unfortunately, there is no com- parable information regarding the CKD in a pediatric population, especially for early-stages of the disease. In the present study, the prevalence of CKD stages 2-5 was lower than that reported in the studies conducted in Italy(10) and Serbia(22). The prevalence rate of CKD Stage 5 decreased over the study period. In the same period, an increase occurred in the frequency of the early stages of CKD (Table1) attributing to the routine antenatal ultrasound screening, early detection of renal and urinary tract anomalies, ear- ly urological interventions, and treatment. The mean incidence and prevalence rate of CKD among the Iranian children was relatively lower compared to those reported from the European countries, such as Serbia( 22), Italy(10), as well as Chile(23) and Nigeria(24) (Figure 4). However, it is difficult to make a direct comparison regarding the incidence and prevalence of CKD in different pediatric populations due to the methodo- logical differences in the case definitions and disease classifications both within and between the countries. It has been reported that, pediatric patients with ESRD account for a very small proportion of the total ESRD population(21). There are considerable variations in the incidence and prevalence of ESRD in the pediatric pop- Table 4. Etiology of CKD in Iran compared to other similar studies Registry NAPRTCS[6] Italy[10] Belgium[29] Iran ANZDATA[34] ESPN/ERA- UK [36] Japan [32] [reference] EDTA [37] Inclusion criteria CKD(eGFR <75) CKD(eGFR <75) CKD(eGFR <60) CKD(eGFR <75) ESRD ( RRT ) ESRD ( RRT) ESRD (RRT) ESRD (RRT) Age ( years) 0-20 0-19 0-19 0-19 0-19 0-15 0-15 0-19 Period 1994 - 2007 1990 - 2000 2001-2005 1991-2009 2003-2008 2008 2004-2008 1998 Study sample size 7,037 1,197 143 1247 369 499 428 582 CAKUT 3,361 (48%) 689 (58.0%) 84 (59%) 499 (40%) 127 (34%) 182 (36.0%) 184(43% ) 208 (36%) Hypodyspalasia± 1,907(27% ) 516(43.1%) 66 (46.1% ) 309 (24.7%) 95 (25.7%) - 135(31.5%) 198 (34%) Etiology reflux nephropathy Obstructive uropathy 1,454(20.6%) 173 (14.4%) 18 (12.6% ) 190 (15.2% ) 32 (8.7%) - 49(11.4%) 10 (1.7%) Glomerulopathies 993 (14%) 55 (5%) 10 (7% ) 237 (19.0%) 108 (29%) 76 (15%) 78(18% ) 130 (22% ) HUS 141 (2.0%) 43 (4%) 9 ( 6% ) 40 (3.2%) 9 (2.0%) 29 (6%) - 13 (2%) Hereditary nephropathies 717 (10%) 186 (15%) 27 (19% ) 21 (1.7%) - 112 (22%) - 69 (12%) Congenital NS 75 (1%) 13 (1%) 5 (3.5%) 22 (1.8%) 7 (1.9%) - 15(3.5%) 34 (5.8%) Metabolic disease - - 5 (3.5%) - - 17 (3.4%) 18(4.2% ) - Cystinosis 104 (1.5%) 22 (1.8%) 2 (1.4%) 34 (2.7%) 4 (1%) - - 2 (0.3%) Cystic kidney disease 368 (5.2%) 101 (8.4%) 13 ( 9% ) 43 (3.4%) 25 (6.7%) 59 (11.8%) 49(11.4%) 35 (6%) Ischemic renal failure 158 (2%) 49 (4%) 3 (2% ) 4 (0.3%) 8 (2%) 11 (2%) - 11(1.9%) Miscellaneous conditions 1,485 (21.1%) 122 (10.2%) 10 ( 7% ) 47 (3.8%) 65 (17.6%) 52 (10.4%) 19(4.4%) 83 (14.3%) Missing / unknown 182 (2.6%) 40 (3.3%) - 228 (18.3%) 16 (4.3%) 37 (7.4%) 65 (15.2%) 34 (5.8%) Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal disease; RRT, renal replacement therapy; eGFR, estimated glomer- ular filtration rate (mL/min/1.73 m2); CAKUT, congenital anomalies of the kidney and urinary tract; NS, nephrotic syndrome; HUS, hemolytic uremic syndrome; NAPRTCS, North American Pediatric Renal Trials and Collaborative Studies; ANZDATA, Australia and New Zealand Dialysis and Transplant Reg- istry; ESPN/ERA-EDTA Registry, European Registry for Children on Renal Replacement Therapy Figure 1. Incidence and prevalence rate of CKD during the study period CKD in Iran-Ataei et al. ulation across the regions of the world. In the present study, the mean annual incidence and prevalence rates of ESRD for children were equal to 2.53 and 18.98 (pmarp), respectively. The results of the study showed that the annual incidence of childhood CKD in Iran in- creased from 1.21 (pmarp) in 1992 to 4.46 (pmarp) in 2006, while at the end of three years of study, the trend became downward. This increasing trend has been also observed in the USA from 1980 to 2008(25), as well as European coun- tries during the 1980s(26) while, Australia and New Zea- land have experienced a constant trend regarding the incidence of childhood CKD during the past 25 years (27). Consistent with our findings, the above-mentioned studies have also reported an increasing trend for the prevalence of childhood CKD attributing to the im- proved survival rate of the patients. The annual inci- dence of RRT including the chronic HD, CAPD, and RT was less in the Iranian children 2.53 (pmarp) than that of other pediatric studies conducted in the countries such as Serbia 5.7 (pmarp)(22), Netherlands 5.8 (pmarp) (28), Belgium 6.2 (pmarp)(29), and Turkey10.9 (pmarp) (30). The true proportion of CKD is expected to be higher than the value observed in the present study, as it is usu- ally asymptomatic in its earliest stages and is often not diagnosed, and therefore, is not reported. Our results revealed a higher frequency of CKD in the boys than the girls (M/F=1.13), which is in accordance with other pediatric studies worldwide (24,29). The highest report- ed incidence rate for ESRD in the children belonged to the USA, New Zealand, and Austria by 14.8, 13.6, and 12.4 per million populations, respectively(31) while, the lowest rate was reported in Japan(32). In our study, the prevalence of CKD stage 5 was similar to the report from Sweden(33) but lower than that of other Europe- an countries, Australia, and the United States(10,22,31, 34,35) (Figure 4). CAKUT is the most common cause of ESRD in the Figure 2. Primary causes of CKD stages 2–5 in the Iranian children Figure 3. (A) Estimated patient’s survival in the studied children with respect to the gender. (B) Estimated patient’s survival in the studied children with respect to the CKD stage. CKD in Iran-Ataei et al. Vol 18 No 1 January-February 2021 127 Unclassified 128 pediatric patients undergoing the RRT(9,10,23). In this study, CAKUT and glomerulopathies were leading causes of CKD in 40.01% and 19.00% of cases, re- spectively, which is consistent with the results reported by the ANZDATA(34), UK(36) and Japanese Registry(32), but hereditary nephropathies were the second cause of CKD in the ESPN/ERA-EDTA(37), Italian(10), and Bel- gian Registry(29) (Table 4). Higher frequency of CA- KUT including renal hypodysplasia as well as obstruc- tive uropathy in the males can justify more frequency of CKD in the boys than the girls(9). HD was the first modality used for RRT in the majority of children with ESRD. The etiology of CKD remained unknown in 18.3% of the patients similar to the studies by Safouh et al., (20.6%)(38) and Lewis et al., (15.2%)(36) mostly due to late manifestation with small smooth kidneys, where tissue sampling (biopsy) would be of little or no benefit to the patients highlighting the need for further investi- gations in this regard to save many lives. In our study, more than 75% of the children were in the advanced stage of CKD at the time of presentation. Poor manifes- tation of CKD symptoms, delay in diagnosis, and late referral to the pediatric nephrologist makes it difficult to detect the CKD in early stages. Since 1976, the pedi- atric CKD registries revealed the reduction of unknown cause of etiology from 39% to 1.8% in the recent years (10,22,39,40). However, the etiology of CKD is still un- known in 20 - 27% of the adult patients attributing to the multiple factors in the adults(41). The mortality rate of 11.06% in the population under study was similar to that reported in the study by McDonald and Craig(42). Among them, one patient died in the pre-terminal phase due to primary disease or serious coexisting morbidi- ty; 81(15.08%) patients died during treatment with the Figure 4. Incidence and prevalence rate of childhood CKD in dif- ferent countries HD; 54(29.67%) patients died during CAPD treatment, and 2 patients died after RT (1 died due to the cerebro- vascular accident, the other died due to the sepsis). In our study, cardiovascular events (50%) and infections (11.11%) were the main causes of death as reported by other studies(43). RT is associated with higher patients' survival rates, improving quality of life, and fewer public health costs compared to relying on the dialysis(44). The 10–year patients' survival (84.8%) observed in our study is comparable to that reported in the studies by McDonald and Craig (79%)(42), Peco-Antic et al., (75%) (22) and ANZDATA registry (79%)(34). On the other hand, these results are consistent with the findings re- ported in the studies by Mitsnefes et al.,(45) and Neild (41). The improving trend in the survival rates among the patients in the present study is more likely to be related to RT rather than dialysis. All the pediatric nephrologists followed a single pro- tocol thus, the validity and reliability of the results can be confirmed considering the comprehensiveness of the registration system that covered the whole country, as well as the full justification by the pediatric nephrolo- gists. There were a number of limitations in this study. First- ly, the retrospective nature of the study and the lack of screening programs to identify the children with CKD in the early stages of the disease Secondly, incomplete or missing data within the medical records and finally, inter-laboratory variation in the calibration of serum Cr assay, which might have led to some variability, espe- cially for estimating the GFR were among the limita- tions of this study. Despite these limitations, this study provided a comprehensive data source on the childhood CKD in Iran that can be used for healthcare planning and as a basis for further researches. CONCLUSIONS The IPRCKD provided valuable information about the epidemiological characteristics of the pediatric CKD in Iran. The incidence and prevalence rate of childhood CKD in Iran was found to be relatively lower than those reported from European countries and other sim- ilar studies. Most children had non-glomerular disease and CAKUT was the main cause of CKD similar to the studies reported from the European countries. Howev- er, the etiology of CKD was unknown in a significant number of children (18.3%) highlighting the need for further investigation on the etiologic factors associated with the progression of CKD. The long-term survival rate among the children with CKD in the present study was higher than the similar studies. ACKNOWLEDGEMENT The authors would like to thank Professor Farahnak As- adi for his thoughtful comments. We also thank the staff of pediatric nephrology, dialysis, and transplant centers in all parts of the country for their kind cooperation, as well as the patients and their families who contributed to this study. CONFLICT OF INTEREST The authors declare no conflict of interest. CKD in Iran-Ataei et al. REFERENCES 1. Greenbaum LA, Warady BA, Furth SL. 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