Visual Abstract
Keywords: end-stage kidney disease, pediatric nephrology, hemodialysis, peritoneal dialysis, kidney transplantation, Israel
Abstract
Background
Childhood kidney failure is a rare condition with worldwide clinical variability. We used a nationwide multicenter analysis to study the pretransplant course of the entire Israeli pediatric kidney failure population over 30 years.
Methods
In this nationwide, population-based, historical cohort study, we analyzed medical and demographic data of all children treated with KRT and reported to the Israeli kidney failure registry in 1990–2020. Statistical analysis was performed with incidence rate corrected for age, ethnicity, and calendar year, using the appropriate age-related general population as denominator.
Results
During the last 30 years, childhood incidence of kidney failure decreased. Average incidence in 2015–2019 was 9.1 cases per million age-related population (pmarp). Arab and Druze children exhibited higher kidney failure incidence rates than Jewish children (18.4 versus 7.0 cases pmarp for minorities versus Jews). The most common kidney failure etiologies among Arab and Jewish children were congenital anomalies of the kidney and urinary tract (approximately 27%), followed by cystic kidney diseases among Arab children (13%) and glomerulonephritis among Jewish children (16%). The most common etiology among Druze children was primary hyperoxaluria type 1 (33%). Israel's national health insurance provides access to primary health care to all citizens. Accordingly, waiting time for deceased-donor transplantation was equal between all ethnicities. Living-donor kidney transplantation rates among minority populations remained low in comparison with Jews over the entire study period. Although all patient groups demonstrated improvement in survival, overall survival rates were mainly etiology dependent.
Conclusions
In Israel, Arab and Druze children had a higher incidence of kidney failure, a unique etiological distribution, and a lower rate of living-donor kidney transplantations compared with Jewish children.
Introduction
Childhood kidney failure is rare, with etiologies and clinical characteristics that may vary between countries and populations, as those are affected by genetics, consanguinity, age distribution, and availability of medical treatment.1–3 Similarly, treatment modalities, kidney transplantation, and especially access to living-donor kidney transplantation vary between countries and populations. Recent studies demonstrated specifically the adverse effect of low socioeconomic status and immigration on the likelihood to undergo living-donor kidney transplantation.4–7
In Israel, national health insurance has existed since 1994 and provides access to primary health care, including dialysis and kidney transplantation, for all Israeli citizens, with center-based pediatric hemodialysis taking place in one of five pediatric dialysis units. Kidney transplantation in Israel is monitored and supervised by the National Transplant and Organ Donation Center of the Ministry of Health. Patients are listed for deceased-donor kidney transplantation after initiating dialysis, and allocation is preformed according to objective criteria.8 Only patients with available living donors are candidates for preemptive kidney transplantations.
Variability in kidney failure among ethnic groups in Israel has been suggested before. Specifically, previous studies have reported a few rare genetic diseases that presented predominantly among children from Arab or Druze ethnicities, as well as a disproportionally high prevalence of kidney failure compared with the general population.9–14 Nevertheless, because the previous studies were single centered and reported findings regarding a single disease or treatment modality, a national comprehensive study was needed to evaluate the full spectrum and variability of Israeli childhood kidney failure disease. Using a nationwide, multicenter analysis of all Israeli children treated with KRT over a period of 30 years (the Israeli kidney failure registry), we investigated the clinical characteristics, treatment modalities, and outcomes of pediatric patients with kidney failure from different ethnicities during the pretransplant period.
Methods
We conducted a historical cohort study of all children with kidney failure who initiated KRT (i.e., hemodialysis, peritoneal dialysis, or kidney transplantation) between January 1, 1990, and April 1, 2020, and were registered in the Israeli kidney failure registry. Children were eligible if they were up to 18 years of age at the date of KRT initiation and held an Israeli citizenship. We excluded children who were treated for less than 3 consecutive months with KRT. Date of first KRT modality initiation was defined as kidney failure onset, and data per case were collected from that moment until death or April 2020, whichever came first. Data extraction occurred between June and August 2020.
The Israeli Kidney Failure Registry
The Israeli kidney failure database is a national administrative registry maintained by the Israeli Ministry of Health. It contains information on all patients receiving any form of KRT in Israel. All nephrology and dialysis units in Israel are mandated to report annually to the Ministry of Health on all new and prevalent patients receiving KRT and changes in treatment modality, while the National Transplant Center reports preemptive transplantations. For detailed information regarding data reporting, validation, and extraction, see the Supplemental Material. As opposed to modality type and treatment dates, reporting the primary diagnosis is not mandatory and thus 15% of cases in our database, including almost all preemptive transplantations, have no reported diagnosis (those are henceforth referred to as “missing”). In addition, 9% of cases received a diagnosis of “unknown/uncertain etiology” by the nephrologist in charge. Cases of preemptive transplantations before 2011 were incompletely documented in the registry and were therefore not included in our research, resulting in an estimated maximal 2% missing data for those years. The institutional review boards of both the Israeli Ministry of Health and the Sheba Medical Center approved the study and waived the requirement for informed consent on the basis of preserving participants' anonymity.
Data Analysis
Summary statistics were expressed as absolute numbers and percentages. Crude age- and disease-specific incidence rates were calculated as the number of patients starting KRT during a specified year, divided by the corresponding age- and ethnicity-adjusted mid-year population of Israel recorded at the Israeli Central Bureau of Statistics.15 Annual kidney failure incidence was expressed as cases per million age-related population (pmarp), while disease-specific incidence rates were expressed as cases per 10 million age-related population. Incidence trends over time were presented using a 5-year moving average and least squares regression line.
The reported underlying diagnoses were coded and classified according to Supplemental Table 1. The distributions of the different etiologies were presented according to age (up to 1 year, 2–5 years, 6–12 years, 13–18 years), ethnicity (Jews, Arabs, Druze, or others, with Arabs and Druze grouped together for the analysis as “minorities”), year of KRT initiation, and district of residence. Time of follow-up was calculated from KRT initiation until kidney transplantation or death and from kidney transplantation to return to dialysis or death and served as a denominator for the corresponding survival rates. Outcomes of time to kidney transplantation and survival were evaluated for different demographic predictors, and corresponding relative risks were calculated. The results were stratified according to age and year of KRT initiation. Statistical analysis was performed using Microsoft Excel and SPSS statistical package for social sciences version 24.0 (IBM Corp.). Median survival times were compared using Mann-Whitney tests, using WinPepi software.
Results
Patients' Characteristics
The characteristics of the study population are described in Table 1. Altogether, 759 children in Israel were diagnosed with kidney failure requiring maintenance dialysis or preemptive kidney transplantation between 1990 and 2020, yielding an average annual incidence of 10.4 cases pmarp. Children were diagnosed at a median age of 12 years, with 46% of the cohort being diagnosed at 13–18 years. Overall, we observed a male predominance (57%), which was consistent across all age groups. Forty-eight percent of the participants were of Jewish ethnicity, 45% of Arab ethnicity, and 4% of Druze ethnicity—compared with Arab and Druze children comprising only 25% and 1% of the general age-related population in Israel, respectively.15 The proportion of Arab children was the highest among the youngest age groups (53%–55% of children up to 5 years).
Table 1.
Baseline characteristics of the study population
| Characteristic | 0–1 yr, N (%) | 2–5 yr, N (%) | 6–12 yr, N (%) | 13–18 yr, N (%) | All Ages, N (%) |
|---|---|---|---|---|---|
| 105 (14)a | 103 (14)a | 205 (27)a | 346 (46)a | 759 (100)a | |
| Sex | |||||
| Male | 55 (52) | 58 (56) | 117 (57) | 201 (58) | 431 (57) |
| Ethnicity | |||||
| Jewish | 38 (36) | 38 (37) | 109 (53) | 182 (53) | 367 (48) |
| Arab | 56 (53) | 57 (55) | 82 (40) | 144 (42) | 339 (45) |
| Druze | 7 (7) | 6 (6) | 6 (3) | 8 (2) | 27 (4) |
| Other | 4 (4) | 2 (2) | 8 (4) | 12 (3) | 26 (3) |
| Diagnosis | |||||
| Nephrotic syndrome | 4 (4) | 13 (13) | 24 (12) | 25 (7) | 66 (9) |
| Congenital nephrotic syndromeb | 4 (4) | 11 (11) | 18 (9) | 17 (5) | 50 (7) |
| Glomerulonephritis | 3 (3) | 8 (8) | 19 (9) | 77 (22) | 107 (14) |
| IgA nephropathyc | – (0.0) | – (0.0) | 1 (0.5) | 16 (5) | 17 (2) |
| Membranoproliferative GN | – (0.0) | – (0.0) | 5 (2) | 11 (3) | 16 (2) |
| Lupus nephritis | – (0.0) | – (0.0) | 2 (1.0) | 9 (3) | 11 (1.0) |
| Alport syndrome | – (0.0) | – (0.0) | – (0.0) | 13 (4) | 13 (2) |
| Unknown/indeterminate | 3 (3) | 8 (8) | 5 (2) | 22 (6) | 38 (5) |
| CAKUT | 34 (32) | 19 (18) | 56 (27) | 87 (25) | 196 (26) |
| Hypodysplasia | 26 (25) | 17 (16) | 47 (23) | 52 (15) | 142 (19) |
| Reflux nephropathy | – (0.0) | – (0.0) | 4 (2) | 18 (5) | 22 (3) |
| Obstructive uropathy | 8 (8) | 2 (2) | 5 (2) | 17 (5) | 32 (4) |
| Nephrolithiasis | 13 (12) | 6 (6) | 6 (3) | 7 (2) | 32 (4) |
| Primary hyperoxaluria type 1 | 13 (12) | 6 (6) | 6 (3) | 5 (1) | 30 (4) |
| Tubulopathies | – (0.0) | 1 (1.0) | 10 (5) | 10 (3) | 21 (3) |
| Interstitial nephritis | – (0.0) | 1 (1.0) | 1 (0.5) | 5 (1) | 7 (0.9) |
| Other tubulopathiesd | – (0.0) | – (0.0) | 9 (4) | 5 (1) | 14 (2) |
| Diabetic kidney diseasee | 1 (1.0) | – (0.0) | – (0.0) | 3 (0.9) | 4 (0.5) |
| Renovascular diseasef | 3 (3) | 1 (1.0) | – (0.0) | 8 (2) | 12 (2) |
| Hemolytic uremic syndromeg | 6 (6) | 5 (5) | 5 (2) | 3 (0.9) | 19 (2) |
| Cystic kidney disease | 5 (5) | 11 (11) | 12 (6) | 26 (7) | 54 (7) |
| PKDh | 2 (2) | 6 (6) | 2 (1.0) | 3 (0.9) | 13 (2) |
| Medullary cystic kidney disease | 3 (3) | 4 (4) | 8 (4) | 19 (5) | 34 (4) |
| Nephronophthisis | – (0.0) | 1 (1.0) | 2 (1) | 4 (1) | 7 (0.9) |
| Familial nephropathy of unknown origin | 8 (8) | 19 (18) | 9 (4) | 15 (4) | 51 (7) |
| Miscellaneous | 7 (7) | 2 (2) | 4 (2) | 6 (2) | 19 (2) |
| Unknown diagnosis | 14 (13) | 7 (7) | 14 (7) | 31 (9) | 66 (9) |
| Missing diagnosis | 7 (7) | 11 (11) | 46 (22) | 48 (14) | 112 (15) |
CAKUT, congenital anomalies of kidney and urinary tract; PKD, polycystic kidney disease.
Percentages depicted here represent the percentage of each age group within the entire cohort.
Forty-eight of them had focal segmental glomerulosclerosis histology, one patient with nail-patella syndrome and one patient with no histology.
Including two cases of Henoch Schönlein purpura at the ages of 11 and 14 years.
Thirteen cases of cystinosis and one patients with nephrogenic DI at the age of 16 years.
Three cases of type 1 diabetes and one case of type 2 diabetes at the age of 18 years.
Four patients due to hypertension and eight cases due to microvascular/atheroembolic disease.
All 19 patients due to atypical hemolytic uremic syndrome.
Twelve patients with autosomal recessive PKD and one patient with autosomal dominant PKD at the age of 17 years.
Pediatric Kidney Failure Incidence and Trends over the Years
Over the last three decades, incidence of kidney failure among Israeli children decreased from the highest 5-year average incidence of 13.5 cases pmarp measured between 1994 and 1998 to 9.1 in 2015–2019 (Figure 1A). Similar trends were observed after stratification according to age groups. Children from minority groups (Arabs and Druze) had a higher average incidence of kidney failure compared with Jewish children, with incidence rates of 18.3, 19.4 and 7.0 cases pmarp in Arabs, Druze, and Jewish children, respectively. Incidence RRs were 2.6 (95% confidence interval [CI], 2.2 to 3.0) and 2.8 (95% CI, 1.9 to 4.1) comparing Arab and Druze children with Jewish children, respectively. Nonetheless, for both Jewish and minority groups, annual incidence decreased over the years in a similar rate (Figure 1B). Age-specific incidence was the highest for children in the 13–18 age group, with an average incidence of 16.5 cases pmarp, followed by infants (0–1 year) who had an average annual incidence of 12.1 cases pmarp.
Figure 1.
Five-year moving average of pediatric kidney failure incidence over the study period. (A) Overall 5-year moving average incidence. (B) According to ethnicity, Jews versus minorities (Arabs and Druze). Average incidence displayed on a certain year is composed of the average of the 5 preceding years (e.g., the average displayed on 1994 is the average incidence from 1990 to 1994). Linear trend lines and their equations are shown under the relevant incidence line. pmarp, per million age-related population.
Pediatric Kidney Failure Etiologies
The most common kidney failure etiology in our study cohort, across all age groups, was congenital anomalies of kidneys and urinary tract (CAKUT), which accounted for 26% of cases (Table 1). Other etiologies demonstrated a varying distribution by age groups (Figure 2A and Table 1): Among infants (ages 0–1 years), the second most common etiology was primary hyperoxaluria type 1 (12% of cases), followed by familial nephropathy of unknown origin (8%) and hemolytic uremic syndrome (6%). At ages 2–5 years, the distribution of nephrolithiasis as a kidney failure etiology decreased, with the next most common etiologies being familial nephropathy of unknown origin (18%) and cystic kidney disease (11%). Among the older age groups, the second most common etiologies were glomerular diseases with nephrotic syndrome (exclusively secondary to focal segmental glomerulosclerosis [FSGS]) at ages 6–12 years (12%) and glomerulonephritis at ages 13–18 years (22%).
Figure 2.
Pediatric kidney failure etiological distribution in the entire research population (n=759). (A) According to age group. (B) According to ethnicity. The various etiologies are displayed in further detail in Supplemental Table 1. CAKUT, congenital anomalies of kidney and urinary tract; HUS, hemolytic uremic syndrome.
The underlying etiologies differed among the population groups (Figure 2B). Among the Druze, the most common etiology for kidney failure was primary hyperoxaluria type 1—accounting for 33% of the cases, with CAKUT accounting for only 11% of cases, and no recorded cases of cystic kidney disease. Among the Arab participants, CAKUT was the most common etiology (27%), followed by cystic kidney diseases (13%, mostly medullary cystic kidney disease) and glomerulonephritis accounting for 11% of cases. Among Jewish participants, the most common etiologies were CAKUT (27%), followed by glomerulonephritis (16%) and nephrotic syndrome (9%). Nephrolithiasis and cystic kidney diseases were extremely rare.
It is important to consider the differences in overall incidence between the different ethnic populations. Nevertheless, for all etiologies, Arab and Druze children had higher incidence rates than Jewish children, regardless of their ranking (Table 2).
Table 2.
Number of cases and incidence ratesa (in cases per 10 million age-related population) of different pediatric kidney failure etiologies, according to ethnicity
| Diagnosis | Jews, N (IRb) | Arabs, N (IR) | Druze, N (IR) | IRR of Arabs Compared with Jews (95% CI) | IRR of Druze Compared with Jews (95% CI) |
|---|---|---|---|---|---|
| Nephrotic syndrome | 35 (6.7) | 26 (14.1) | 2 (14.4) | 2.1 (1.3 to 3.5) | 2.1 (0.5 to 8.9) |
| Glomerulonephritis | 59 (11.3) | 36 (19.5) | 5 (35.9) | 1.7 (1.1 to 2.6) | 3.2 (1.3 to 7.9) |
| CAKUT | 100 (19.1) | 91 (49.3) | 3 (21.5) | 2.6 (1.9 to 3.4) | 1.1 (0.4 to 3.5) |
| Nephrolithiasis | 2 (0.4) | 20 (10.8) | 9 (6.5) | 28.3 (6.6 to 121.2) | 168.9 (36.5 to 781.5) |
| Tubulopathies | 9 (1.7) | 11 (6.0) | 1 (7.2) | 3.5 (1.4 to 8.3) | 4.2 (0.5 to 32.9) |
| Diabetic kidney disease | 1 (0.2) | 2 (1.1) | – (0.0) | 5.7 (0.5 to 62.5) | 12.5 (0.5 to 307) |
| Renovascular disease | 5 (1.0) | 7 (3.8) | – (0.0) | 4.0 (1.3 to 12.5) | 3.4 (0.2 to 61.7) |
| Hemolytic uremic syndrome | 8 (1.5) | 10 (5.4) | 1 (7.2) | 3.5 (1.4 to 9.0) | 4.7 (0.6 to 37.5) |
| Cystic kidney disease | 9 (1.7) | 43 (23.3) | – (0.0) | 13.5 (6.6 to 27.8) | 2.0 (0.1 to 33.9) |
| Familial nephropathy of unknown origin | 15 (2.9) | 33 (17.9) | 2 (14.4) | 6.2 (3.4 to 11.5) | 5.0 (1.1 to 21.9) |
| Miscellaneous | 13 (2.5) | 6 (3.3) | – (0.0) | 1.3 (0.5 to 3.4) | 1.4 (0.1 to 23.4) |
| Unknown diagnosis | 30 (5.7) | 27 (14.6) | 4 (28.7) | 2.5 (1.5 to 4.3) | 5.0 (1.8 to 14.2) |
| Missing diagnosis | 81 (15.5) | 27 (14.6) | – (0.0) | 0.9 (0.6 to 1.5) | 0.4 (0.0 to 5.9) |
IR, incidence rate; IRR, incidence relative risk; CI, confidence interval; CAKUT, congenital anomalies of kidney and urinary tract.
IRR is calculated as incidence by Arabs/Druze as compared with incidence by Jews.
IR, per 10 million age-related population.
Treatment Modalities
Hemodialysis was the preferred initial of KRT modality in all age groups older than 2 years. Overall, 61% of all children aged 0–18 years were treated with hemodialysis, while infants (younger than 2 years) were treated predominantly with peritoneal dialysis (61%) (Supplemental Figure 1A). Treatment with hemodialysis as the primary modality increased from 44% in 1990–1994 to approximately 70% in the 2000s and subsequently decreased again after 2010, given an increase in preemptive transplantations from 9% in 2010–2014 to 23% in 2015–2020 among children with kidney failure.
Overall, 84% of the children in our cohort eventually underwent a kidney transplantation, of which 6% were preemptive. Transplantation rates were higher with older age, with 60% among infants and 89% and 88% among children aged 6–12 years and 13–18 years, respectively. Infants also had the lowest living-donor transplantation rate (12% of infants, compared with 35–40% among children aged 6–18 years). Over the years, there has been increased usage of living-donor transplantations and preemptive transplantations among the Jewish population. This trend was not shared by the minority populations (Figure 3).
Figure 3.
Transplantation proportions and graft types. (A) According to age group and ethnicity (Jews versus minorities). (B) According to year of kidney replacement treatment initiation and ethnicity.
Israel's national health insurance provides access to primary health care including kidney transplantations to all Israeli citizens. Accordingly, we found that waiting time for deceased-donor transplantation was equal between all ethnic groups, with a median waiting time of 17.5 and 18.5 months for Jews and minority populations, respectively (P=0.09).
The fact that children from minoritized populations had a relatively lower rate of living-donor transplantations9 was demonstrated across all age groups (Figure 3) and resulted in practice in a longer absolute waiting time for transplantation from any donor (median absolute waiting time of 10.5 versus 17.4 months for Jews and minority populations, respectively, P<0.001).
Patient Survival Outcomes
Overall survival improved over the last 30 years (from 2- and 5-year survival rates of 90.6% and 82.8% in 1990–1999 to 96.1% and 89.8% in 2010–2014, respectively), mostly due to improved survival of infants. While the worst survival was seen in infants (Figure 4, A–C for the association of survival with age), this age group demonstrated the most substantial improvement in survival with 2- and 5-year survival rates improving from 54.2% to 45.8% in 1990–1999 to 100.0% and 73.3% in 2010–2014, respectively. A survival improvement trend was noted across all ethnicities. However, survival rates of minority groups during the entire follow-up period from 1990 to 2014 were significantly lower compared with Jewish children (Figure 4, D–F), with a 2-year survival of 89.3% versus 95.2%, respectively (mortality RR: 2.2, 95% CI, 1.2 to 4.0), and a 5-year survival of 82.0% versus 90.4%, respectively (mortality RR: 1.9, 95% CI, 1.2 to 2.8). However, when analyzing survival per diagnosis and ethnicity (Table 3), we did not observe a significant difference in the survival rates for the most common kidney failure etiologies (CAKUT), which together encompass the end-stage kidney disease etiology for 46% of the study population (Table 1). Seemingly worse survival rates for minorities were demonstrated, although not statistically significant, predominantly in rare genetic diseases (primary hyperoxaluria type 1 and hemolytic uremic syndrome), which were also more common among minorities. These apparent differences could possibly be explained by the higher rate of infants with the two diagnoses in the minority compared with the Jewish groups. However, owing to the small number of cases of these diseases, especially among the Jewish groups, we could not draw any firm conclusions from the comparison between the subgroups. Nonetheless, the higher proportion of diseases with a poor prognosis among minorities may explain the difference in overall survival rates that we observed between minorities and Jews.
Figure 4.
Survival proportions. Trends over the study period according to age group and ethnicity. (A) Two-, 5-, and 10-year survival rates in the years 1990–1999 according to age group. (B) Two-, 5-, and 10-year survival rates in the years 2000–2009 according to age group. (C) Two- and 5-year survival rates in the years 2010–2014 according to age group. (D) Two-, 5-, and 10-year survival rates in the years 1990–1999, Jews versus minorities. (E) Two-, 5-, and 10-year survival rates in the years 1990–1999, Jews versus minorities. (F) Two- and 5-year survival rates in 2010–2014, Jews versus minorities. Differences between survival of Jews and minorities in different times as are presented in this figure were not statistically significant. Significance was, however, reached when survival was calculated over the entire study period.
Table 3.
Two- and 5-year survival proportions for selected pediatric kidney failure etiologies
| Etiologies | 1990–2014 | Mortality Relative Risks of Minorities Compared with Jews (95% CI)a | P Values | ||
|---|---|---|---|---|---|
| 2-yr Survival | 5-yr Survival | ||||
| CAKUT | Jews n=87 | 98.8 | 95.4 | 1.8 (0.6 to 6.0) | 0.32 |
| Minorities n=83 | 95.2 | 91.6 | |||
| Congenital nephrotic syndrome | Jews n=27 | 96.3 | 88.9 | 0.7 (0.1 to 6.0) | 0.74 |
| Minorities n=13 | 92.3 | 92.3 | |||
| Glomerulonephritis | Jews n=51 | 96.1 | 90.2 | 1.2 (0.3 to 4.5) | 0.81 |
| Minorities n=26 | 88.5 | 88.5 | |||
| Cystic kidney disease | Jews n=8 | 100.0 | 100.0 | 2.5 (0.1 to 42.7) | 0.52 |
| Minorities n=31 | 90.3 | 87.1 | |||
| Primary hyperoxaluria type 1 | Jews n=2 | 100.0 | 100.0 | 3.1 (0.2 to 40.0) | 0.38 |
| Minorities n=27 | 85.2 | 48.1 | |||
| Hemolytic uremic syndrome | Jews n=8 | 100.0 | 100.0 | 12.3 (0.8 to 187.0) | 0.07 |
| Minorities n=10 | 40.0 | 30.0 | |||
CI, confidence interval; CAKUT, congenital anomalies of kidney and urinary tract.
The presented mortality relative risks were calculated for the 5-year survivals.
Discussion
In this retrospective national cohort study, we aimed to characterize the longitudinal characteristics of the entire Israeli pediatric kidney failure population over the last three decades. Overall, we observed that (1) incidence of kidney failure has been decreasing over the last 30 years. (2) Arab and Druze children exhibited a higher kidney failure incidence and a different underlying etiological distribution compared with Jewish children. Specifically, we noticed higher distribution of suspected genetic kidney diseases, such as congenital nephrotic syndrome (mostly resulting in FSGS kidney histology) and cystic kidney diseases among Arab children, and primary hyperoxaluria type 1 among Druze children. (3) Regarding treatment modality, we observed that over the last three decades, hemodialysis and preemptive transplantations have become more common treatment modalities compared with peritoneal dialysis. Peritoneal dialysis was still more common among infants younger than 1 year. (4) While living-donor transplantations became more common among Jewish children, Arab and Druze children did not demonstrate this trend, resulting in a prolonged absolute waiting time for kidney transplantation. (5) We observed a poorer prognosis among infants on dialysis, although their prognosis improved significantly over the study period. We also observed poorer prognosis among minority groups. This was mainly explained by the different etiological profiles, as minorities presented a higher distribution of poor prognosis etiologies (Table 3). Some of these etiologies were reported in the past as being related to minority groups. For instance, primary hyperoxaluria type 1, which is a relatively severe multisystemic condition leading to kidney failure, has been documented exclusively among minorities in the past.13,14,16 In addition, although we did not find a survival difference among nephrotic syndrome patients when comparing ethnicities, several studies in the past have reported worse prognosis of FSGS among Israeli Arabs and unique genetic mutations leading to steroid-resistant nephrotic syndrome in Arabic families.10,11
Our study has several limitations that should be considered. First, our database includes only a final kidney failure diagnosis and no additional clinical information. Further classification of etiologies according to a genetic diagnosis was thus not possible. In addition, some of the diagnoses in the database were ill-defined or outdated, and it is possible that some were inaccurate in retrospect. Second, 23% of the cases in our database had either missing or unknown diagnoses. While no major differences were found in the rate of missing diagnoses between the dialysis units, practically all cases of preemptive transplantations, reported from the National Transplant Center, had a missing diagnosis (95%). As children with slow-progressing kidney diseases have a higher chance to undergo preemptive transplantations, it is possible that we have an underestimation of those etiologies (primarily CAKUT) in our study, predominantly among the Jewish population where more preemptive transplantations accrued. Third, owing to incomplete data, we had to exclude cases of preemptive transplantations before 2011. Nevertheless, as there were only 13 such reported cases in children and young adults (2% of the pediatric cases in those years), we assume that their influence on the results is insignificant. Finally, our study was limited to Israeli children, so its generalizability may be limited.
The strength of our study includes the use of a large, nationwide cohort with detailed data, covering the entire pediatric kidney failure population in Israel over three decades. Demographic, treatment modality, and survival data were comprehensive and complete. Kidney disease etiologies were reported by board-certified pediatric nephrologists and were mostly comprehensive and complete.
Incidence rates of kidney failure in our study cohort were relatively high compared with rates reported in Europe (an incidence of 7.8 pmarp in children up to 19 years in 2013–2018 according to the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA)17 versus 9.4 pmarp in the same years in our study and 10.2–7.9 pmarp in children up to 16 years in 2012–2017 in the United Kingdom18 versus 9.2 pmarp in the same years in our study) but lower than the overall incidence rate reported in the United States (11 pmarp in children up to 17 years in 2019 versus 9.6 in the same year in our study).19 Regarding ethnical variability, the highest incidence in the United States is reported among Black children and is still lower than the incidence among Israeli minorities (15.7 pmarp in Black children in the United States in 2017–2019 versus 18.6 and 21.1 pmarp among Arab and Druze children in the same years in our study).20 These relatively high rates of pediatric kidney failure correspond with findings in previous studies.2,9,21
CAKUT, followed by glomerulonephritides, were the two most prevalent etiologies found in our study, resembling reports from Europe and the United States, as well as previous studies performed in Israel and other developed countries.1,2,9,17,19 Differences lie in lower rates in Europe and the United States of cystic kidney diseases, nephrolithiasis, and other monogenic disorders (including primary hyperoxaluria type 1) compared with Israel.17–19 The high rates of primary hyperoxaluria type 1 among Northern Israel Druze and Arab populations13,14,16 and of other genetic kidney diseases including tubular and cystic kidney disorders among the Arab-Bedouin population in southern Israel were also observed previously.10,11,22 Overall, these findings suggest that genetic factors play a key role in the development of childhood kidney diseases leading to kidney failure in Israeli minorities. In addition, socioeconomic and cultural factors leading to a negative view on prenatal screening tests and pregnancy terminations23,24 may also, to some degree, help explain the high incidence of kidney failure among minorities.
Treatment modalities in Israeli pediatric patients with kidney failure resemble those demonstrated in other Western countries. The increasing use of living-donor transplantations and preemptive transplantations in Israel has not been equally adopted among its minority citizens. This phenomenon has previously been suggested in other Israeli studies8,9,25 and has similarly been reported in other disadvantaged subpopulations around the world.4–7,26 Low living-donor transplantation rates and the resulting prolonged absolute waiting time for kidney transplantation among children from minority groups composes a major concern because they are associated with a higher risk of dialysis-related complications and death.27,28
Low rates of kidney transplantations among infants could partly be explained by the need to achieve a minimal weight of 9–10 kg by the transplant recipient. A second possible contributing factor could be a higher risk for multiple patients with kidney disease in one family, secondary to the high rate of genetic disease, which further complicates decision making on living kidney donation.
Overall patient survival in our study between 2012 and 2016 resembled that of Europe.17 Worst survival among infants, as was seen in Israel, was also reported in the United Kingdom and the United States.18,19
In conclusion, our study demonstrates that the Arab and Druze pediatric kidney failure populations differ from the Jewish population regarding incidence, etiology, treatment modalities, and outcomes. Exceptionally high incidence rate, low rates of living-donor transplantations, and an overall worse prognosis of minorities call for special attention for this group of patients to improve their outcomes. Understanding the factors leading to high incidence of kidney diseases and low living-donor transplantations rates may help develop intervention programs that will address both issues. First of all, increasing awareness among minority groups and health care professionals for the high rate of kidney diseases could facilitate early diagnosis and increase community support for prenatal screenings and kidney donations. Second, high incidence of kidney disease could be reduced by using targeted screening in high-risk populations, such as preconception screening for certain genetic diseases (some of which are already being performed in Israel29) and routine urinalysis screening. Recently, our research group and others launched with the Israeli Ministry of Health a national government–supported pilot for trio whole exome sequencing (Trio-WES) testing for all Israeli pediatric patients with kidney failure. Identifying patients and families with genetic kidney diseases could help tailor treatment, identify further cases in the family, and assist with future family planning.
Finally, intervention programs to increase living-donor transplantation rates have been developed worldwide with promising results. These include home-based group education programs,30–32 individual intervention programs,33 house calls,34 and patient advocates.35 Understanding which modifiable factors play a role in the limited access to living-donor transplantations in our population would enable the development and implementation of the most appropriate program.
Supplementary Material
Acknowledgments
We would like to acknowledge all the physicians who consistently reported their patients' data to the Israeli kidney failure registry. We would also like to acknowledge the Israeli Center for Disease Control and the Israeli national research platform TIMNA for facilitating the access for the registry.
Footnotes
R.C.-M. and A.V. contributed equally to this work.
Published online ahead of print. Publication date available at www.cjasn.org.
Disclosures
R. Calderon-Margalit's husband is an employee of AEYE Health, which has patents pending on the use of ML in ophthalmology. Y. Frishberg reports consultancy agreements with Alnylam Pharmaceuticals and advisory or leadership roles for Alnylam Pharmaceuticals Safety Review Committee. D. Magen reports research funding from Alnylam Pharmaceuticals. L.C. Regev-Epstein reports research funding from Nierstichting Nederland. All remaining authors have nothing to disclose.
Funding
A. Vivante is supported by a StGERC grant (#101040267—GeneCKD).
Author Contributions
R. Calderon-Margalit and A. Vivante conceptualized the study; L.C. Regev-Epstein was responsible for visualization; L. Keinan-Boker, L.C. Regev-Epstein, M. Stern-Zimmer, and A. Vivante were responsible for data curation; R. Calderon-Margalit and L.C. Regev-Epstein were responsible for formal analysis; R. Calderon-Margalit, L. Keinan-Boker, L.C. Regev-Epstein, and A. Vivante were responsible for methodology; L.C. Regev-Epstein was responsible for investigation; L.C. Regev-Epstein and A. Vivante were responsible for project administration; P. Beckerman M. Davidovits, Y. Frishberg, D. Landau, and D. Magen were responsible for validation; R. Calderon-Margalit and A. Vivante provided supervision; L.C. Regev-Epstein wrote the original draft; and P. Beckerman, R. Calderon-Margalit, M. Davidovits, Y. Frishberg, L. Keinan-Boker, D. Landau, D. Magen, A. Vivante, and I. Weismann reviewed and edited the manuscript.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/CJN/B570.
Supplemental Methods. Data reporting, validation, and extraction from the Israeli kidney failure registry.
Supplemental Table 1. Classification and coding of the diagnoses given according to the Israeli kidney failure registry.
Supplemental Figure 1. First kidney replacement therapy modality. Proportions of children in our cohort who received hemodialysis, peritoneal dialysis, or preemptive kidney transplantation as their first kidney replacement therapy. A: according to age group. B: according to ethnicity and time period.
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