Risk Factors and Rate of Progression of CKD in Children

The prevalence of pediatric chronic kidney disease (CKD) ranges from 15 to 74.7 cases per 1 million children.1Harambat J. Van Stralen K.J. Kim J.J. Tizard E.J. Epidemiology of chronic kidney disease in children.Pediatr Nephrol. 2012; 27: 363-373Crossref PubMed Scopus (571) Google Scholar Mortality among children who progress to end-stage kidney disease (ESKD) is 30 to 50 times higher compared to that in the general population.1Harambat J. Van Stralen K.J. Kim J.J. Tizard E.J. Epidemiology of chronic kidney disease in children.Pediatr Nephrol. 2012; 27: 363-373Crossref PubMed Scopus (571) Google Scholar, 2Mitsnefes M.M. Laskin B.L. Dahhou M. et al.Mortality risk among children initially treated with dialysis for end-stage kidney disease, 1990–2010.JAMA. 2013; 309: 1921-1929Crossref PubMed Scopus (141) Google Scholar Most of the data on pediatric CKD comes from the developed world. The North American Pediatric Renal Collaborative Trials (NAPRTCS) data (n = 4133) show a progression rate from CKD stages II to IV to ESKD of 17% at 1 year and 39% at 3 years, with the median time to ESKD being 4.5 years.3Staples A.O. Greenbaum L.A. Smith J.M. et al.Association between clinical risk factors and progression of chronic kidney disease in children.Clin J Am Soc Nephrol. 2010; 5: 2172-2179Crossref PubMed Scopus (90) Google Scholar The NAPRTCS registry and the Chronic Kidney Disease in Children (CKiD) study identified several modifiable (proteinuria, hypertension, anemia, dyslipidemia) and nonmodifiable (age, primary disease, stage of CKD) risk factors for progression of CKD in children.3Staples A.O. Greenbaum L.A. Smith J.M. et al.Association between clinical risk factors and progression of chronic kidney disease in children.Clin J Am Soc Nephrol. 2010; 5: 2172-2179Crossref PubMed Scopus (90) Google Scholar, 4Mitsnefes M. Hypertension and progression of chronic renal insufficiency in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).J Am Soc Nephrol. 2003; 14: 2618-2622Crossref PubMed Scopus (145) Google Scholar, 5Warady B.A. Abraham A.G. Schwartz G.J. et al.Predictors of rapid progression of glomerular and nonglomerular kidney disease in children and adolescents: the Chronic Kidney Disease in Children (CKiD) cohort.Am J Kidney Dis. 2015; 65: 878-888Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 6Wong C.S. Pierce C.B. Cole S.R. et al.Association of proteinuria with race, cause of chronic kidney disease, and glomerular filtration rate in the Chronic Kidney Disease in Children study.Clin J Am Soc Nephrol. 2009; 4: 812-819Crossref PubMed Scopus (99) Google Scholar The Effect of Strict Blood Pressure Control and Angiotensin Converting Enzyme Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial showed that reduction of blood pressure in children with CKD to below the 50th centile significantly reduced the rate of progression.7Wühl E. Trivelli A. Picca S. et al.Strict blood-pressure control and progression of renal failure in children.N Engl J Med. 2009; 17361: 1639-1650Google Scholar There is scant literature on the etiology, rate of progression, risk factors for progression, comorbidities, and outcomes in children with CKD from low- to middle-income countries (LMIC). Common problems in LMIC include delay in diagnosis, increased burden of comorbidities, poor access to health care, high financial burden of treatment, and lack of social support.8Kamath N. Iyengar A.A. Chronic Kidney Disease (CKD): An observational study of etiology, severity and burden of comorbidities.Indian J Pediatr. 2017; 84: 822-825Crossref PubMed Scopus (20) Google Scholar, 9Jha V. Current status of chronic kidney disease care in Southeast Asia.Semin Nephrol. 2009; 29: 487-496Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar,S1−S5 There is a large knowledge gap regarding the risk factors for CKD progression under such circumstances.8Kamath N. Iyengar A.A. Chronic Kidney Disease (CKD): An observational study of etiology, severity and burden of comorbidities.Indian J Pediatr. 2017; 84: 822-825Crossref PubMed Scopus (20) Google Scholar,S6 Better understanding of modifiable risk factors and early interventions to delay progression to ESKD in LMIC is urgent, as many children are unlikely to gain access to dialysis or transplantation should their kidneys fail.S7 We conducted a prospective cohort study to determine the rate of progression of CKD stages II to IV, to identify the risk factors associated with progression of CKD, and to assess the impact of CKD on quality of life (QoL) in children attending a pediatric CKD clinic in India. The recruitment and follow-up algorithm is shown in Figure 1. The evaluation at recruitment and follow-up are depicted in Table 1. Demographic details of the cohort (n = 78) at recruitment are described in Table 2. Of the 78 children, 5 were lost to follow-up before their first visit, 3 (4.1%) were lost to follow-up later, and 5 (6.8%) died. A total of 65 children were followed up for 2 to 3 years or until they reached an estimated glomerular filtration rate (eGFR) of <15 ml/min per 1.73 m2. The median GFR, CKD stages, and prevalence of comorbidities at recruitment are described in Table 2.Table 1Evaluation of the patient at recruitment and follow-upEvaluationRecruitment6 mo1-yr follow-up18 mo2-yr follow-upHistorySymptomsaClinical details and eGFR done 6 monthly.bInvestigations repeated at yearly intervals.aClinical details and eGFR done 6 monthly.bInvestigations repeated at yearly intervals.ExaminationHeightWeightBody mass indexTanner stageBlood pressureaClinical details and eGFR done 6 monthly.bInvestigations repeated at yearly intervals.aClinical details and eGFR done 6 monthly.bInvestigations repeated at yearly intervals.eGFRCreatinine (eGFR)aClinical details and eGFR done 6 monthly.bInvestigations repeated at yearly intervals.aClinical details and eGFR done 6 monthly.bInvestigations repeated at yearly intervals.RenalUrine Protein/creatinine ratioMetabolic panelcMetabolic panel: serum electrolytes, serum bicarbonate.bInvestigations repeated at yearly intervals.bInvestigations repeated at yearly intervals.bInvestigations repeated at yearly intervals.bInvestigations repeated at yearly intervals.Mineral bone diseaseCalciumPhosphateAlkaline phosphataseVitamin DParathormoneaClinical details and eGFR done 6 monthly.bInvestigations repeated at yearly intervals.bInvestigations repeated at yearly intervals.bInvestigations repeated at yearly intervals.aClinical details and eGFR done 6 monthly.bInvestigations repeated at yearly intervals.bInvestigations repeated at yearly intervals.bInvestigations repeated at yearly intervals.CardiovascularLipid profileCarotid intima-media thicknessEchocardiographybInvestigations repeated at yearly intervals.bInvestigations repeated at yearly intervals.eGFR, estimated glomerular filtration rate.a Clinical details and eGFR done 6 monthly.b Investigations repeated at yearly intervals.c Metabolic panel: serum electrolytes, serum bicarbonate. Open table in a new tab Table 2Demographic characteristics of the cohortDemographic characteristics (n = 78)NumberAge, mo, median (IQR)108 (69.2, 134.2)Sex (%)Male, 75%Duration of CKD from diagnosis, mo, median (IQR)12 (3−21)Stage of CKD, n (%)Stage II, 21 (27)Stage III, 26 (33) (IIIa, 14; IIIb, 12)Stage IV, 31 (40)eGFR (ml/min per 1.73 m2) at recruitment, median (IQR)34.67 (24.3, 65.4)Incident cases (n = 28, 36%)32 (21.5, 55.6)Prevalent cases37 (27.2, 68.1)Prematurity/low birthweight14 (19)Educational status of parents68% NongraduatesFamily income <250 USD/mo75%Socioeconomic status (Modified Kuppuswamy classification)62% Middle class25.6% Lower classEtiology of CKD Glomerular disease12 (15) Nonglomerular diseaseRenal hypoplasia/dysplasia20 (25.6)Obstructive uropathy12 (15.3)Neurogenic bladder13 (16.6)Reflux nephropathy5 (6.4)Others14 (18) Unknown2 (2.5)Comorbidities associated with CKD at recruitmentProteinuria (n = 73, 93.5%)UPCr >2, 36 (46)ACEi use, 4 (5)Hypertension (n = 46, 59%)Treated, 21 (45.6)Uncontrolled BP, 14 (66)Anemian = 29 (37.17)Mineral bone diseaseBony deformities, 14 (19)Hypocalcemia, 36 (46.1)Hyperphosphatemia, 25 (32)Vitamin D deficiency, 72 (92.3)Hyperparathyroidism, 44 (56.4)CardiovascularDyslipidemia, 50 (64)LVH, 34 (44.7)CIMT, cm, mean 0.05 ± 0.008 SDGrowthMedian height z score, −2.1 (−3.3, −1.16)Short stature, 51 (65.4)Median BMI z score, −1 (−2, −0.12)Undernourished, 20 (25.6)Delayed puberty, 22 (66)Metabolic acidosis59 (75.7)ACEi, angiotensin-converting enzyme inhibitor; BMI, body mass index; BP, blood pressure; CIMT, carotid intima-media thickness test; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; LVH, left ventricular hypertrophy; IQR, interquartile range; UPCr, urine protein-to-creatinine ratio.Numbers in parentheses are percentages unless otherwise noted. Open table in a new tab eGFR, estimated glomerular filtration rate. ACEi, angiotensin-converting enzyme inhibitor; BMI, body mass index; BP, blood pressure; CIMT, carotid intima-media thickness test; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; LVH, left ventricular hypertrophy; IQR, interquartile range; UPCr, urine protein-to-creatinine ratio. Numbers in parentheses are percentages unless otherwise noted. A total of 25 children (38%) experienced progression of CKD within 2 years of follow-up. In all, 12 children had a >50% decline from baseline glomerular filtration rate (GFR), 8 reached a GFR of <15 ml/min per 1.73 m2, 4 were initiated on dialysis, and 1 child underwent renal transplantation. The median rate of decline in GFR was 3.5 (IQR 1.7, 11.00) ml/yr. The median time to progression of CKD was 22.98 (IQR 20.56, 25.41) months. There was no significant difference in the time to progression between incident and the prevalent cases after recruitment into the study, and therefore further analyses were conducted on pooled data. Age at onset of CKD and sex were not associated with progression. The risk of progression was significantly greater in children with glomerular compared with nonglomerular disease (hazard ratio [HR] 2.59, 95% confidence interval [CI] 1.07, 6.27, P = 0.034). The median decline in GFR was 11.36 (IQR 8.7, 12.6) ml/yr, and the mean time to progression of CKD was 15.45 (IQR 9.64, 21.25) months in children with glomerular disease compared to 2.38 ml/yr (IQR 1.1, 4.2) and 24.43 months (IQR 20.56, 25.41) in those with nonglomerular disease (P = 0.007 and P = 0.021 respectively, Figure 2a). An eGFR of <45 ml/min at recruitment was associated with a hazard ratio of 3.3 (95% CI 1.3, 8.4) for progression (P = 0.009). Proteinuria was present in 73 children (93%) at recruitment (Table 2). Urine protein-to-creatinine ratio (UPCr) of >2 at baseline was associated with risk of progression of CKD (HR 3.1, 95% CI 1.33, 7.23, P = 0.009) (Figure 2b). Proteinuria was also associated with progression of CKD in children with nonglomerular disease (HR 1.5, 95% CI 1.21, 1.9, P = 0.02). Hypertension was present in 46 of 78 children (59%) at recruitment (Table 2). Hypertension or systolic/diastolic z scores at recruitment were not associated with CKD progression. When adjusted for baseline eGFR, the following parameters were associated with an increased risk of progression: anemia, hypocalcemia, hyperphosphatemia, hyperparathyroidism, and height z score (Table 3).Table 3Univariate analysis and multivariate analysis of baseline and follow-up risk factors for progression of chronic kidney disease in childrenUnivariate analysisRisk factorsHazard ratio (95% CI) after adjusting for baseline GFRP valueNonmodifiable risk factors Glomerular disease2.59 (1.07, 6.27)0.034 eGFR at baseline3.3 (1.3, 8.4)0.001Modifiable risk factors0.56 Proteinuria3.1 (1.3, 7.2)0.009 Hypertension1.4 (0.43, 4.9)0.56 Anemia4.08 (1.8, 9.26)0.001 Calcium level0.3 (0.19, 0.487)<0.001 Phosphate level2.09 (1.36, 3.220.001 Parathormone level1.004 (1.002, 1.005)<0.001 Height z score0.75 (0.6, 0.9)0.006 Metabolic acidosis3.05 (0.91, 10.2)0.071Multivariate analysisGlomerular disease2.7 (1.1, 6.3)0.032eGFR at baseline3.39 (1.3, 8.8)0.005Proteinuria (baseline)1.04 (1.01, 1.07)0.009Proteinuria on follow-up1.4 (1.2, 1.52)0.005Uncontrolled hypertension at last follow-upaUncontrolled hypertension is defined as blood pressure above the 95th centile for age and sex despite medications.2.53 (1.01, 6.77)0.04Uncontrolled hypertension at last follow-up + proteinuriaaUncontrolled hypertension is defined as blood pressure above the 95th centile for age and sex despite medications.4.2 (1.85. 9.63)0.001CI, confidence interval; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate.Numbers in bold indicate statistically significant risk factors.a Uncontrolled hypertension is defined as blood pressure above the 95th centile for age and sex despite medications. Open table in a new tab CI, confidence interval; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate. Numbers in bold indicate statistically significant risk factors. Persistent proteinuria (UPCr > 2) was significantly associated with progression of CKD (HR 1.4, 95% CI 1.2, 1.52; P = 0.005). Children with uncontrolled hypertension on follow-up had a higher risk of progression (HR 2.53, 95% CI, 1.01, 6.67) compared to those who had normal blood pressure values or controlled hypertension (P = 0.04). Adherence to antihypertensive medications was documented in 92% of the cohort. The combination of severe proteinuria on follow-up (UPCr > 2) and uncontrolled hypertension at last follow-up was associated with a hazard ratio of 4.2 (95% CI, 1.8, 9.6, P = 0.001) for progression. On multivariate analysis, glomerular disease, baseline GFR <45 ml/min, UPCR >2, and the combination of uncontrolled hypertension and proteinuria at follow-up were independent risk factors for progression of CKD (Table 3). The median QoL scores of the child (n = 45) and parents (n = 47) are shown in Table 4.Table 4Quality of life scores of child and parent proxy in the cohort of children with chronic kidney diseaseScoreChild (n = 45 )Parent (n = 47 )Physical score76.56 (62.37, 82.81)75 (42.18, 89.05)Psychosocial score71.66 (64.16, 78.74)75 (55.8, 86.6)Total score72.26 (60.17, 82.05)70.47 (50.6, 83.36)Data are median (interquartile range). Open table in a new tab Data are median (interquartile range). The total scores of the child and the parent correlated significantly (P = 0.01, r = 0.6). The physical and psychosocial scores were significantly lower in the children with lower socioeconomic status (P = 0.035, r = 0.522). There was no difference in the QOL scores based on etiology or stage of CKD. The parent proxy physical score correlated significantly with the height z score (P = 0.002, r = 0.485), eGFR (P = 0.003, r = 0.475), and parent proxy psychosocial score (P < 0.001, r = 0.796). The parent proxy psychosocial score correlated with the height z score (P = 0.004, r = 0.459), eGFR (P = 0.025, r = 0.367) and psychosocial score of the child (P = 0.001, r = 0.73). The psychosocial score was also significantly lower in patients with lower socioeconomic status (P = 0.032). This prospective longitudinal study from a tertiary care hospital in an LMIC shows that children with CKD present late and have a rapid rate of progression. As in most pediatric CKD studies,S8,S9 hypodysplasia, obstructive uropathy, and reflux nephropathy together accounted for about 50% of cases. Glomerular disease and baseline eGFR were significant nonmodifiable risk factors for progression of CKD. Proteinuria, uncontrolled hypertension, and the combination of these were significant modifiable risk factors for progression. Socioeconomic status, eGFR, and height z scores were significantly associated with lower QoL scores. Very little has been reported on outcomes of children with CKD in LMIC.S6 The median eGFR in our cohort was lower than that observed in CKiD and the Italkid project, 34.7 versus 44 and 41.7 ml/min per 1.73 m2, respectively.S8,S10 It is of concern that one-third of the patients in our cohort were newly diagnosed with CKD (stage IIIb) at the time of recruitment. This reflects the delay in diagnosis of CKD in our population, which is common in practice in LMIC. A similar low baseline eGFR of 33 ml/min per 1.73 m2 was reported from Brazil.S11 The rate of progression of CKD in our cohort was faster than that reported in other studies.4Mitsnefes M. Hypertension and progression of chronic renal insufficiency in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).J Am Soc Nephrol. 2003; 14: 2618-2622Crossref PubMed Scopus (145) Google Scholar,S12 The median rate of decline in GFR was 3.5 ml/yr, almost twice that in the CKiD study (1.8 ml/yr).S12 A comparable rate of decline in GFR of 5.8 ml/yr was reported from the Latin American Registry.S13 The mean time to progression of CKD in our cohort was 1.8 years. The median time to ESKD was 4.5 years in the NAPRTCS M. Hypertension and progression of chronic renal insufficiency in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).J Am Soc Nephrol. 2003; 14: 2618-2622Crossref PubMed Scopus (145) Google Scholar and years in In of children with CKD to ESKD in The higher rate of progression and time to progression of CKD in our cohort the that our children were diagnosed at stages of CKD and have to and to health of in time to CKD progression also The similar progression rate in our incident and prevalent patients is time from diagnosis was not in prevalent and the have been to a The nonmodifiable risk factors for progression in our cohort were glomerular disease as the etiology of CKD and a lower baseline This is with from the CKiD and other E. Trivelli A. Picca S. et al.Strict blood-pressure control and progression of renal failure in children.N Engl J Med. 2009; 17361: 1639-1650Google N. Iyengar A.A. Chronic Kidney Disease (CKD): An observational study of etiology, severity and burden of comorbidities.Indian J Pediatr. 2017; 84: 822-825Crossref PubMed Scopus (20) Google which reported baseline GFR as a significant risk for progression, and the NAPRTCS which showed that primary disease and stage of CKD were significant risk factors for progression of A.O. Greenbaum L.A. Smith J.M. et al.Association between clinical risk factors and progression of chronic kidney disease in children.Clin J Am Soc Nephrol. 2010; 5: 2172-2179Crossref PubMed Scopus (90) Google Scholar Proteinuria was present in children with glomerular and nonglomerular disease, and the of proteinuria was 4 times higher than that reported in the CKiD C.S. Pierce C.B. Cole S.R. et al.Association of proteinuria with race, cause of chronic kidney disease, and glomerular filtration rate in the Chronic Kidney Disease in Children study.Clin J Am Soc Nephrol. 2009; 4: 812-819Crossref PubMed Scopus (99) Google The severity of proteinuria reflects disease delay in diagnosis of CKD, and lower prevalence of angiotensin-converting enzyme in our of our patients angiotensin-converting enzyme compared to 50% in the CKiD and therefore analysis was not Proteinuria at recruitment and follow-up were significant of progression on multivariate analysis and after for baseline GFR, as reported Proteinuria adjusted for GFR was significantly associated with reduced time to ESKD in children with glomerular and nonglomerular disease in the CKiD B.A. Abraham A.G. Schwartz G.J. et al.Predictors of rapid progression of glomerular and nonglomerular kidney disease in children and adolescents: the Chronic Kidney Disease in Children (CKiD) cohort.Am J Kidney Dis. 2015; 65: 878-888Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar The showed that children with a of had a decline of renal and a renal at 5 The prevalence of hypertension in our study was comparable with that reported in the CKiD B.A. Abraham A.G. Schwartz G.J. et al.Predictors of rapid progression of glomerular and nonglomerular kidney disease in children and adolescents: the Chronic Kidney Disease in Children (CKiD) cohort.Am J Kidney Dis. 2015; 65: 878-888Abstract Full Text Full Text PDF PubMed Scopus (153) Google In to the CKiD study, hypertension at recruitment was not a significant risk for progression of CKD in our on children with uncontrolled hypertension had a higher risk of progression of CKD. The trial showed that control of blood pressure was associated with a reduced risk of progression of CKD, the of blood pressure control in pediatric E. Trivelli A. Picca S. et al.Strict blood-pressure control and progression of renal failure in children.N Engl J Med. 2009; 17361: 1639-1650Google Scholar was to a significant of progression on not multivariate analysis in our cohort. In data from the CKiD study that was a significant of progression in children with nonglomerular disease, as the NAPRTCS A.O. Greenbaum L.A. Smith J.M. et al.Association between clinical risk factors and progression of chronic kidney disease in children.Clin J Am Soc Nephrol. 2010; 5: 2172-2179Crossref PubMed Scopus (90) Google Scholar, 5Warady B.A. Abraham A.G. Schwartz G.J. et al.Predictors of rapid progression of glomerular and nonglomerular kidney disease in children and adolescents: the Chronic Kidney Disease in Children (CKiD) cohort.Am J Kidney Dis. 2015; 65: 878-888Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar low high and were significantly associated with progression on not multivariate analysis, with severity of renal This is also in to the NAPRTCS which that of and of were associated with a higher risk of A.O. Greenbaum L.A. Smith J.M. et al.Association between clinical risk factors and progression of chronic kidney disease in children.Clin J Am Soc Nephrol. 2010; 5: 2172-2179Crossref PubMed Scopus (90) Google Scholar The lack of of these parameters in our cohort the of life correlated significantly with stature, eGFR, and socioeconomic The CKiD study showed that children and those with a of CKD had higher scores in the and significantly lower was significantly associated with poor scores in the physical study has and A of study is prospective longitudinal and the study to our of the from an LMIC is a study with a our is large and is of children with CKD in our not the the pooled analyses that the in our late and to follow-up. the analysis of comorbidities associated with CKD and other factors such as low use, and not to not ratio. with a significant between proteinuria and progression, a urine protein-to-creatinine ratio a and for in our cohort. Better data on the burden of hypertension blood pressure have been was not in our The significant with blood pressure as with CKD progression also a for This longitudinal study shows that the of children with CKD stages II to IV in an LMIC is from those in developed The lower median baseline GFR delay in diagnosis of CKD. The rate of progression of CKD was in those with glomerular disease and associated with proteinuria and uncontrolled blood that the risk factors associated with progression of CKD identified early and treated The QoL analysis the impact of CKD on children and the of socioeconomic status, which the to and to There is an to of pediatric CKD in to early diagnosis and