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Original Articles Indian Pediatrics 2003; 40:1035-1042 |
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To determine the etiology of chronic renal failure amongst children attending the Pediatric Nephrology services at a tertiary care center. Subjects: We reviewed the records of 305 children, diagnosed to have chronic renal failure (CRF) over a 7-year period. CRF was defined as glomerular filtration rate (GFR) below 50-mL/1.73 m2/min persisting for more than 3 months. Results: The mean age at onset and presentation of CRF in these patients was 5.9 and 8 years respectively. Ninety-six children were below 5 years of age. Mean (SD) levels of blood urea and creatinine at presentation were 150 (89) and 4.6 (3.5) mg/dL respectively. The median GFR at presentation was 18.5 mL/min/1.73m2 while 25.3% patients were already in end stage renal failure indicating that these patients were referred late. The mean (SD) hemoglobin at presentation was 7.6 (2.6) g/dL. The mean height and weight SD scores were –2.9 and –2.4 respectively. Obstructive uropathy was the commonest cause of CRF present in 97 (31.8%) children. Other causes included chronic glomerulonephritis in 84 (27.5%), reflux nephropathy in 51 (16.7%), herediatry nephritis in 20 (6.6%), renal dysplasia in 15 (4.9%) and hemolytic uremic syndrome in 5 children. The mean (SD) duration of follow-up was 11(15) months. Peritoneal or hemodialysis was performed in 63 patients. Fifteen patients underwent a live-related renal transplantation. The rest opted out of dialysis program and were conservatively managed due to financial constraints. Conclusions: The commonest causes of CRF were obstructive and reflux nephropathy. A significant proportion of patients presented late; had severe CRF and were malnourished and stunted. Majority of these were managed conservatively due to lack of financial resources. CHRONIC renal failure (CRD) is an irreversible condition that eventually progresses to end stage renal failure. It is an important cause of morbidity and mortality in children worldwide(1,2). The causes of CRF vary from one geographical area to another due to genetic and environmental factors. Some of these causes are preventable while in others, appro-priate medical treatment and interventions may retard the progression of the disease(3). In the absence of a national registry, there is paucity of information regarding the etiology of CRF in children from our country(4,5). An understanding of the causes of CRF is important as it may guide the distribution of limited resources towards its prevention. The aim of the present study was to examine retrospectively the etiology of CRF in children referred to this hospital. Subjects and Methods We reviewed the medical records of all patients diagnosed to have CRF at AIIMS between July 1995 and June 2002. Clinical features including pallor, edema, oliguria, hematuria, and abnormal urinary stream were noted. Examination findings included weight, record of height and blood pressure and screening for skeletal deformities. Pertinent laboratory data including blood chemistry, urinalysis, radiographic and scintigraphic studies and renal histopathology were recorded. CRF was defined as GFR below 50mL/min/1.73 m2 as estimated by Schwartz formula(6) and presence of any of the following: (i) bilateral small contracted kidneys or single contracted kidney, (ii) radiographic evidence of bony deformities(7), and (iii) persistence of GFR below 50mL/min/1.73 m2 over ensuing 3 months. CRF was classified as Moderate if the clearance was between 25 and 50 mL/min/1.73 m2 and Severe between 10-25 mL/min/1.73 m2. GFR below 10mL/min/1.73 m2 was defined as end stage renal disease (ESRD). The tiological classification of CRF was as follows. Chronic glomerulonephritis (CGN) was defined by presence of nephrotic range proteinuria and gradually deteriorating renal function with or without red blood cells and casts and/or hypertension. If possible, a definitive diagnosis of CGN was established on a renal biopsy(8,9). The underlying cause of CRF was considered to be reflux nephro-pathy in the presence of scarred kidney (irregular renal outline) demonstrated by ultrasonography, intravenous pyelography or radionuclide imaging(10) and either of the following: (i) primary vesiocoureteric reflux (VUR) demonstrated on micturating cystouretherography (MCU) or radionuclide cystography, and (ii) history and laboratory evidence of past urinary tract infections. Obstructive uropathy was diagnosed if urinary tract dilatation was demonstrated by radiography or scintigraphy, in the absence of vesicoureteric reflux and bladder dysfunction. Neurogenic bladder was considered in patients with MCU showing a large capacity bladder without any obstruction, and bladder wall trabeculations. Urodynamic studies including cystometry and electromyography of the pelvic and abdominal musculature were done to confirm the diagnosis of neurogenic bladder dysfunction. Cystometry was performed by instilling saline per urethra into the bladder. The type of neurogenic bladder was determined by urine flow rate, residual urine volume and intravesical pressures. External urethral sphincter, pelvic and abdominal electromyography and urethral pressure profile were recorded simulataneously(11). Alport syndrome was diagnosed on cha-racteristic ultrastructural renal histology(12) with sensorineural deafness. A diagnosis of renal dysplasia was based on renal imaging (small kidney with regular outline with or without cysts) or characteristic renal biopsy. Polycystic kidney disease was diagnosed either on histopathology or ultrasonography (enlarged echogenic kidneys)(13). Juvenile nephronophthisis was diagnosed on character-istic renal histology with or without a positive family history(14). CRF was considered secondary to hemolytic uremic syndrome in patients with previous history of acute renal failure, microangiopathic anemia and typical renal biopsy(15). Patients in whom the cause of CRF could not be idendified were classified as ‘unknown etiology’. Results Of 2625 patients who attended the pediatric nephrology services of this hospital, 305 (11.6%) children met the inclusion criteria for CRF. There were 225 boys. The median age at presentation of CRF was 8 yr (range 3 months to 18 years). The mean (SD) age at onset of the underlying disease was 5.9 (4.3) yr. There were 96 children below 5 years of age, 105 between 6 to 10 yr and 104 above 11 years. At presentation, the mean (SD) blood urea and creatinine were 150 (89) mg/dL and 4.6 (3.5) mg/dL respectively. The median GFR at presentation was 18.5 mL/min/ 1.73 m2; 37.8% patients had Moderate CRF while 36.9% had Severe and 29.8% were in ESRD. Thirty-five patients presented with sudden onset of oliguria and elevated levels of urea and creatinine with no preceding history of renal disease but subsequently failed to recover. The mean (SD) hemoglobin at presentation was 7.6 (2.6) g/dL. The hemoglobin level ranged between 5-10/g/dL in 61.4% and below 5 g/dL in 17.4% patients. The median blood levels of calcium and phosphate were 8.1 mg/dL and 5.9 mg/dL respectively. Radiological features suggestive of renal osteodystorphy were present in 27.8% patients. Fifty-three patients had lower limb skeletal deformities. The mean height and weight SD scores were 2.9 and –2.4 respectively(16). The frequency of the conditions causing CRF at various ages is given in Table I. TABLE I Causes of CRF at Different Ages (n=305)
Obstructive uropathy Boys were affected more commonly than girls (boys 88, girls 9; M: F :: 9.8:1). The mean (SD) age at presentation was 6.4 (4.1) yr. Failure to thrive was present in 73.8% of cases; the median height for age SD score was –3.3. Renal osteodystrophy was present in 31.5% and hypertension in 32.5%. Causes included posterior urethral valve in 45 (46.4%), pelviureteric junction obstruction or hydronephrosis in 41, nephrolithiasis in 11 cases. Four patients with renal calculi also had nephrocalcinosis. Reflux nephropathy Fifty-one (16.7%) patients (34 boys) had reflux nephropathy. The mean (SD) age at presentation was 8.3 (4.5) yr. Hypertension was present in 45.2% patients. The median height SD score at presentation was –2.1. Twenty per cent patients had asymmetrical renal scarring with history of urinary tract infections in the past. A probable diagnosis of reflux nephropathy was made in these subjects although VUR could not be demonstrated on MCU or radionuclide scan. Chronic glomerulonephritis CGN was diagnosed in 84 patients (58 boys). It was the comonest cause of CRF after the first decade of life (Table II). The mean (SD) age at presentation was 9.5 (3.3) yr. The diagnosis was clinical in 24 patients and established on a renal biopsy in the rest. Crescentic, focal segmental, membranoproli-ferative and mesangioproliferative glomeru-lonephritis was found in 25,20,6 and 3 patients respectively. IgA nephropathy and lupus nephritis were seen in 3 patients each. TABLE II Minimum Monthly Direct Cost of Therapy (for a 20 kg child)
*Pretransplant workup and surgery (one time cost) Rs 60,000/-
Edema and oliguria were present in 97.2% and hypertension in 76.8% patients. Twenty-four presented as acute renal failure, which failed to resolve completely. Of these, 21 had crescentic glomerulonephritis and one each had lupus nephritis, MPGN and IgA nephropathy. There was some improvement in renal function in 8 patients while the remaining had end stage renal failure. Other causes Renal dysplasia presented at mean (SD) age of 3.5 (2.5) yr with hypertension present in 18.3% patients. These children were more stunted than the others, their median height SD score being –4.8. Polycystic kidney disease (n = 12) was the commonest cause of herediatry nephro-pathies. Alport syndrome, nephronophthisis and Laurence Moon Biedl syndrome contributed 2, 5 and 1 case respectively to hereditary nephropathies. Management All patients received standard treatment for CRF, including dietary modulation, calcium carbonate, active vitamin D ana-logues, iron and multivitamin supplements. Hypertension was present in 43.8% patients, which was treated with combination of calcium channel and beta-blockers, prazosin, clonidine and loop diuretics. Eighty (26.2%) patients received subcutaneous injections of erythropoietin. The mean (SD) duration of follow-up was 11 (15) months. Of 91 (29.8%) patients in end stage renal failure, 63 received hemodialysis for variable duration. Fifteen patients underwent live related renal transplantation; the remaining opted out of the dialysis and transplant program due to financial constraints. Discussion The incidence of CRF varies in different parts of the world. In most developed countries the incidence varies between 4-10 per million-children below 18 years of age(17,18). The precise incidence of CRF in our country is not known. The age at presentation in the present study was comparable to that of North American Pediatric Transplant Cooperative Studies (NAPRTCS), which showed that 36% of children registered as chronic renal insufficiency were below 5 years of age(19). The age at presentation with features of CRF was higher as compared to reports from developed countries suggesting delayed detection and referral of patients. The etiology of CRF varies in different parts of the world. Hereditary disorders are more common in regions, where the frequency of consanguineous marriages is high (20-22). Hereditary disorders including juvenile nephronophthisis, autosomal recessive polycystic kidney disease, congenital nephrotic syndrome and Laurence Moon Biedl syndrome were the commonest cause of CRF in Swedish children (17%) and accounted for 20% of the patients in Iran(20). Preventable causes of CRF like obstructive uropathy and reflux nephropathy together accounted for a majority of cases in our study, which is similar to a previous study from this center and reports from other parts of the world(1,4,5,20,21,23). Reflux nephropathy due to primary VUR was seen in 17% cases of CRF and has remained constant in last two decades at our center(4). However, the proportion of cases of CRF due to reflux nephropathy is much less in North American children, while no case has occurred in Swedish children from 1986-1994(17,19). Posterior urethral valve was the commonest cause of urinary tract obstruction accounting for 14.7% of cases of CRF. Others(5,17) have found a similar frequency of this condition except a study from Qatar in which 40% cases of CRF were due to posterior urethral valve(23). These conditions together contribute to 23-34% cases of CRF in developed countries. However these were twice as common in the present study and those reported from other developing countries(20,23,24). It is proposed that a decline in the proportion of patients with reflux nephropathy is chiefly due to prompt detection and management of urinary tract infections, followed by careful screening for underlying anomalies. Screening for urinary tract anomalies by anternatal ultrasonography is likely to detect significant structural disorders, which can be treated postnatally. Early and appropriate management of these disorders would prevent their progression to chronic renal failure(25). Neurogenic bladder and secondary VUR were seen in 4.5% patients, which is similar to the NAPRTCS data(16). However, Sirin et al.(26) reported that proportion of patient due to neural tube defect and secondary VUR was 15.4% in Turkish children. The proportion of patients presenting with ESRD (GFR <10 mL/min/1.73 m2) was higher in our study as compared to NAPRTCS report but lower than that reported by Gulati et al.(5). This again indicates late diagnosis and referral of patients to tertiary care centers in our country. Majority of our patients were anemic (Hb <10 g/dL), malnourished and stunted indicating an inadequate management CRF. Stunting was more obvious in patients with obstructive uropathy and renal dysplasia than in other conditions. Severe growth retardation in these patients could be attributed to early onset of CRF and distal tubular dysfunction (acidosis) in infancy(27). Significant advances have been made in the understanding of various renal replacement measures, which have enabled provision of better care. Both chronic peritoneal dialysis and hemodialysis along with other supportive measures can ensure longevity and improved quality of life in patients of ESRD. However chronic dialysis is, in the long term not able to achieve homeostasis and growth in children. Renal transplantation is thus considered the standard therapy for children with ESRD. Since prolonged dialysis is expensive and associated with multiple complications, we usually advise children with ESRD to undergo renal transplantation as early as possible. Pre-emptive renal transplantation, without prior dialysis is also encouraged in children. The cost of conservative management, erythropoietin therapy, hemodialysis, renal transplantation and post transplant immuno-suppression for a 20 kg child is presented in Table II along with the expenditure in terms of per capita GNP (28). The average cost of hemodialysis per session at our institution is about Rs 600 (including the cost of dialyzer, blood line and fluid). This is much higher in private institutions. The cost of erythropoietin is almost equal to that of hemodialysis in our country while in a country like USA this cost is only 10% of the total expenditure incurred on dialysis(29). Also the cost of continuous ambulatory periotoneal dialysis (CAPD) is much more than hemodialysis in India due to nonavailability of locally made dialysis fluid. Due to lack of state funded renal replacement program, most patients are unable to afford renal transplantation. The frequency of renal transplantation in children from other centers in our country as well as in some other underdeveloped countries is also low because of similar reason(1,5,30). While the facilities for pediatric renal transplan-tation are available at our center for the last 8 years, only a small proportion of patients could avail of this service. The remaining opted for conservative management and rarely for long-term dialysis. Apart from the financial constraints, often nonavailability of a suitable live related donor becomes a limiting factor for transplantation. An active cadaver organ donation program at present is still in its nascent stages. To conclude, a majority of cases of CRF in our population are due to obstructive uropathy and reflux nephropathy and may be preventable. Renal dysplasia is common in infants and toddlers, while CGN accounts for most cases of CRF in older children and adolescents. Majority of patients are referred late and only a few opt for renal replacement measures due to its high cost. Both these factors eventually lead to a poor outcome of CRF in our population. Contributors: MK, MM, ISK and PH collected the data, PH drafted the manuscript, and AB reviewed the manuscript and will act as its guarantor. Funding: None Competiting interests: None stated
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