Clinical predictors of neurocognitive deficits in children with chronic kidney disease The purpose of the study was to explore associations between neurocognitive function and chronic kidney disease -LRB- CKD -RRB- - related clinical characteristics . Twenty-nine children , ages 7 to 19 years , with an estimated creatinine clearance -LRB- eCrCl -RRB- of 4 -- 89 ml/min per 1.73 m2 body surface area were enrolled . Intellectual function -LRB- IQ -RRB- , memory , and attention were measured and expressed as age-based standard scores . Clinical data were obtained by physical examination , laboratory testing , parental questionnaires and medical chart review . Pearson correlations and standard Student 's t-tests were used to identify significant -LRB- P < 0.05 -RRB- relationships between targeted clinical variables and neurocognitive scores . Increased CKD severity correlated with lower IQ -LRB- P = 0.001 -RRB- and memory function -LRB- P = 0.02 -RRB- . Memory function was lower in children with longer duration of disease -LRB- P = 0.03 -RRB- . Similarly , IQ scores were lowest when kidney disease had started at a younger age -LRB- P = 0.03 -RRB- and with a greater percent of life with CKD -LRB- P = 0.04 -RRB- . Our findings provide preliminary evidence that increased disease severity , longer duration of disease , and younger age of onset of kidney disease potentially place children with CKD at increased risk of neurocognitive deficits . Additional investigation is required to better quantify these risk factors , particularly regarding how much variability is accounted for by these specific risk factors . Introduction Neurocognitive difficulties have long been observed in the chronic kidney disease -LRB- CKD -RRB- population -LSB- 1 -RSB- . While identification and treatment of specific comorbidities of CKD -LRB- e.g. , anemia -RRB- have yielded improvement in the overall functioning of this population , reports of neurocognitive deficits in children with CKD continue to appear . These neurocognitive deficits undoubtedly will have significant lifelong implications for the CKD population as they move into adulthood . A recent review by Groothoff -LSB- 2 -RSB- examined the long-term outcomes of children diagnosed with CKD and identified persistent difficulties with a limited knowledge base , memory , and concentration into adulthood , as well as lower educational attainment . A better understanding of potential risk factors for cognitive impairment and decline in the pediatric CKD population could allow for earlier intervention and , possibly , less morbidity , particularly for certain cognitive deficiencies . Studies aimed at investigating neurocognitive impairment in children with CKD have identified a wide range of delays in motor and cognitive development . Measures of general intelligence , memory and attention have been used most frequently to look at cognitive function in the pediatric CKD population . Most studies have demonstrated lower IQ scores among children with end stage renal disease -LRB- ESRD -RRB- than in unaffected siblings -LSB- 3 -RSB- or the general population -LSB- 4 , 5 -RSB- and also when pre - and post-transplantation performances are compared -LSB- 6 -RSB- . Memory deficits also have been identified in children with mild CKD as well as ESRD -LSB- 7 -RSB- . Fennell et al. -LSB- 7 -RSB- also reported in this same study that there was no significant decline in measures of attention among these children ; however , improved attention performance has been demonstrated in children with ESRD after transplantation -LSB- 6 -RSB- . Observations of hyperactivity at school also have been noted in 50 % of a study population assessing cognitive outcomes following dialysis during infancy -LSB- 4 -RSB- . The measures of cognitive performance in each of these studies varied widely but , when viewed collectively , suggest that children with CKD are vulnerable to cognitive deficiencies in IQ , memory and attention . One thing to note , however , is that most studies to date have focused primarily on children with ESRD , leaving unanswered whether children with mild to moderate CKD also suffer this same vulnerability . Cognitive deficiencies in children with CKD could arise through a gradual process , proportional to the level of kidney dysfunction , or may develop once a filtration threshold has been passed . It seems logical that the severity of CKD might be proportional to the degree of cognitive impairment , but the data are not yet available to support this . The stage of neurologic development at the time of disease onset or the cumulative time children spend with CKD may also impact on the degree or type of cognitive impairment experienced . To our knowledge , no published study has yet focused specifically on isolating risk factors to identify which children with CKD are most at risk for cognitive decline . The primary goal of this study was to explore associations between clinical aspects describing CKD and selected neurocognitive test scores in a sample of children and adolescents with CKD . In addition , this study should provide the foundation for identifying specific clinical risk factors for subsequent neurodevelopmental dysfunction . Methods Participants Study participants were recruited from a university-based pediatric nephrology practice . The participants included children between 7 and 19 years of age , with an estimated creatinine clearance -LRB- eCrCl -RRB- by Schwartz formula -LSB- 8 -RSB- of less than 90 ml/min per 1.73 m2 body surface area for at least 3 months duration . Renal transplant recipients and children with profound developmental delays were excluded . Following parental consent and patient assent , 29 children meeting these criteria underwent neurocognitive testing at a single point in time . A standardized physical examination and laboratory sample collection were also performed within 2 weeks of cognitive testing . A questionnaire providing demographic and historic information was completed by a parent or legal guardian . The study was reviewed and approved by the University of North Carolina Institutional Review Board . Included among the study sample were 17 children with obstructive uropathy or structural congenital renal anomalies , seven with glomerulonephritis , one with calcineurin inhibitor toxicity , one who had sustained ischemic injury , one with renal insufficiency of undetermined etiology , one child with Alport 's syndrome , and one with cystinosis . Participants were evenly divided with respect to gender and disease severity . Approximately half the study sample had mild to moderate CKD with eCrCl ranging from 31 -- 89 ml/min per 1.73 m2 body surface area . Kidney disease onset was documented from birth in 59 % . The majority -LRB- 59 % -RRB- were hypertensive , and , among these children , 70 % were on antihypertensive therapy , and 65 % had measured blood pressure above the 95th percentile at the time of examination . The mean hemoglobin level was 12.7 mg/dl , with only three -LRB- 10 % -RRB- below 11 mg/dl , with values of 10.8 mg/dl , 10.7 mg/dl and 10.1 mg/dl . The general characteristics of our study sample are described in Table 1 . All the participants attended school in a regular classroom setting , and two reported having an individualized education plan -LRB- IEP -RRB- at the time of participation . Table 1Demographic characteristics and medical variables of the study sample -LRB- PD peritoneal dialysis , HD hemodialysis -RRB- Study sample characteristicsNumber -LRB- n = 29 -RRB- aRangeAge -LRB- years -RRB- 12.5 -LRB- 3.2 -RRB- 7 -- 19Male -LRB- % -RRB- 52Caucasian -LRB- % -RRB- 52eCrCl -LRB- ml/min per 1.73 m2 body surface area -RRB- 32 -LRB- 29 -RRB- 4 -- 89ESRD -LRB- 13 PD , 1 HD -RRB- -LRB- % -RRB- 48Age at disease onset -LRB- years -RRB- 4.4 -LRB- 5.9 -RRB- 0 -- 16Duration of CKD -LRB- years -RRB- 6.7 -LRB- 4.7 -RRB- 0.2 -- 15Percent of life with CKD69 -LRB- 39 -RRB- 1 -- 100Hypertensive -LRB- % -RRB- 59Hemoglobin -LRB- mg/dl -RRB- 12.7 -LRB- 1.5 -RRB- 10 -- 17aMean -LRB- standard deviation -RRB- or percent Neurocognitive instruments All participants completed a battery of intellectual , attention , and memory tasks as part of a larger neuropsychological evaluation . To gain an estimate of overall intellectual functioning , we administered the Wechsler Abbreviated Scale of Intelligence -LSB- 9 -RSB- . The Gordon Diagnostic System -LSB- 10 -RSB- , a computerized continuous performance test , was also administered to gain an estimate of attention functioning . Within the memory domain , the Wide Range Assessment of Memory and Learning -LSB- 11 -RSB- was employed to assess short-term memory across verbal and visual domains . Age-based standard scores -LRB- mean = 100 , standard deviation = 15 -RRB- were generated for variables from each of these tasks . In all instances , higher scores represented higher function for each cognitive test result . All tasks were administered by trained examiners who were supervised by a child neuropsychologist . The Wechsler Abbreviated Scales of Intelligence -LRB- WASI -RRB- is built on the well-known Wechsler measures of global intellectual functioning -LSB- 9 -RSB- . It was designed for ages 6 years through adulthood , and employs a fluid-crystal model of intelligence . Four subtests comprise the WASI and include vocabulary , block design , similarities , and matrix reasoning . All four subtests were administered to gain a brief full scale IQ score . The Gordon Diagnostic System -LRB- GDS -RRB- is a computerized continuous performance test that measures various aspects of visual attention -LSB- 10 -RSB- . For this study , the vigilance task was administered , which requires the individual to respond to specific visual stimuli -LRB- e.g. , the number 1 followed by the number 9 -RRB- from a series of numbers presented at a rate of approximately one per second . This task yields standard scores for the number correct , correct variability , commissions , and commission variability . For this study , the total correct standard score was employed . The Wide Range Assessment of Memory and Learning -LRB- WRAML -RRB- is a comprehensive memory battery of tests -LSB- 11 -RSB- . It includes nine different subtests that measure short-term verbal memory -LRB- story memory , sentence memory , number/letter -RRB- , short-term visual memory -LRB- picture memory , design memory , finger windows -RRB- , and new learning capabilities -LRB- sound symbol , visual learning , verbal learning -RRB- . A general memory index is also computed from the nine subtests . Normative data are available for ages 6 through 18 years . The WRAML was administered and scored according to standardized procedures , with the general memory index being employed for this study . Clinical measures Disease severity , age of onset , and duration of renal disease , coded as time in years and as percent of life with CKD , as well as the presence of anemia or hypertension were explored as potential risk factors of interest , given their association with detrimental cognitive outcomes in the CKD literature . Clinical data were collected through physical examinations and laboratory tests performed within 2 weeks of cognitive testing . Age of disease onset , as well as duration and percent of life with CKD , were determined through record reviews and were based on the date of primary disease diagnosis . The Schwartz formula -LSB- 8 -RSB- , using creatinine and height measurements , was used to estimate the eCrCl for non-dialysis patients . Creatinine clearance and urea kinetics were calculated for peritoneal dialysis patients from a 24 h fluid collection . All but three of the peritoneal dialysis patients exceeded Kidney Disease Outcomes Quality Initiative -LRB- K/DOQI -RRB- guidelines for maintaining a Kt/V of at least 2.0 , and those not achieving this level ranged from 1.8 to 1.9 -LSB- 12 -RSB- . For our continuous analysis , we represented the eCrCl from the 24 h fluid collection from dialysis patients -LRB- incorporating residual renal function for the six dialysis patients who still produced urine -RRB- on a continuum with the eCrCl from the Schwartz formula that had been calculated for CKD patients . The one hemodialysis participant had a Kt/V of 1.34 and received dialysis four times a week . For analysis , we imputed this participant 's eCrCl , designating the mean creatinine clearance value from anuric peritoneal dialysis participants . For the dichotomous analysis , `` mild to moderate '' disease was categorized as an eCrCl of 30 to 89 ml/min per 1.73 m2 body surface area , representing those patients with stage 2 or 3 CKD as defined by K/DOQI guidelines -LSB- 12 -RSB- . Those with an eCrCl of less than 30 ml/min per 1.73 m2 or those on dialysis , consistent with stage 4 or 5 CKD , were categorized as `` severe CKD/ESRD '' . Anemia was defined as a hemoglobin level of less than 11 mg/dl , reflecting the normative ranges of hemoglobin for children aged 9 years and above and the K/DOQI guidelines that specify a target hemoglobin level of 11 -- 12 mg/dl in CKD -LSB- 13 -RSB- . Hypertension was defined as either the regular use of antihypertensive medications or the presence of a blood pressure greater than the 95th percentile for age , height , and gender -LSB- 14 -RSB- . Data analysis Initial summary statistical analysis was used to describe the total study sample . This included both descriptive analysis and graphical examination of all relevant variables . To address the primary research question for this study , we used bivariate analysis comparing neurocognitive scores and the clinical characteristics of the study sample , using Pearson 's correlations for all continuous variables . Trend analysis based on linear regression was also used when continuous variables were compared graphically . For those variables that , by definition , were dichotomous -LRB- e.g. , hypertension -RRB- , Student 's t-tests were used to compare the mean neurocognitive scores between categories . For those clinical variables for which an argument could be made either to express continuously or to dichotomize on the basis of a normal range -LRB- e.g. , hemoglobin -RRB- , both correlations and t-tests were used . Results An initial inspection of the neurocognitive test scores showed that the sample of children and adolescents with CKD was mildly variable , with most of the participants falling within the low average to average range on most tasks . For the full study sample , the mean IQ score was 91 -LRB- range 61 to 117 , SD 16 -RRB- , and the mean memory score was 88 -LRB- range 65 to 128 , SD 16 -RRB- , both falling within the low average to average range when compared with normative expectations . The mean attention score of 96 fell well within the average range but did show much more variability -LRB- range 37 to 120 , SD 23 -RRB- . Disease severity Disease severity , represented by the eCrCl , yielded the strongest relationship with both IQ -LRB- r = 0.57 , P = 0.001 -RRB- and memory -LRB- r = 0.45 , P = 0.02 -RRB- , demonstrating that higher eCrCl correlated with higher scores in these cognitive domains . Figures 1 and 2 illustrate the linear trend in the relationship between the continuous representation of disease severity and both IQ and memory scores . The correlation between attention and eCrCl was not significant . Additionally , lower IQ measures among severe CKD/ESRD participants in our study were evident when compared dichotomously with those with mild to moderate CKD -LRB- P = 0.0008 -RRB- , and the same relationships held for memory scores -LRB- P = 0.009 -RRB- and attention scores -LRB- P = 0.012 -RRB- , despite the fact that attention was not linearly associated with eCrCl . Figure 3 illustrates the mean cognitive scores for categories of disease severity . While a downward trend with increasing severity is observed across all cognitive domains , statistical analysis confined to only the 15 non-dialysis patients yielded similar but less robust correlations among all areas of cognition , with IQ being the strongest -LRB- r = 0.46 , P = 0.08 -RRB- . Fig. 1Relationship between IQ and estimated renal functionFig . 2Relationship between memory and estimated renal functionFig . 3Mean cognitive scores by level of renal disease Age at disease onset and CKD duration Increased CKD duration in years was associated with lower memory scores -LRB- r = − 0.40 , P = 0.03 -RRB- . Age at disease onset did not correlate significantly with IQ , memory , or attention scores in our original analysis . However , it was noted that many participants in our study sample had presented with already severe disease , making the date of disease diagnosis less reflective of the actual age at which reduced renal function began . In a secondary exploratory analysis , we repeated our analysis using only those subjects -LRB- n = 10 -RRB- for whom we had a clearly documented date on which the eCrCl dropped below 90 ml/min per 1.73 m2 . Among these patients were six with obstructive uropathy or structural congenital renal anomalies , three with glomerulonephritis , and one with cystinosis . In this secondary analysis we observed that the direction of prior relationships was preserved , with a stronger relationship between IQ and both age at disease onset -LRB- r = 0.69 , P = 0.03 -RRB- and percent of life with CKD -LRB- r = − 0.66 , P = 0.04 -RRB- . This may indicate that younger age at onset of CKD and longer percent of life with CKD correlate with lower IQ scores . Hypertension and anemia Table 2 summarizes the results of our analysis of hypertension and anemia . The dichotomous separation of these two variables did not produce significant group differences . These findings suggest that the presence of anemia or hypertension at the time of testing did not correlate with differences in neurocognitive test results between study participants with or without these clinical features . In a secondary analysis we also explored designation of hypertension , defined initially as either the use of antihypertensive medications or the presence of hypertension at the time of examination , on the basis of the presence of each criterion separately , and we found no differences . Additional examination of anemia revealed that only three patients had a hemoglobin level below the anemia definition of < 11 mg/dl , with values of 10.8 mg/dl , 10.7 mg/dl and 10.1 mg/dl . Consequently , we were unable to assess anemic patients across a wide range of hemoglobin -LRB- Hb -RRB- values . Within our sample of hemoglobin ranging between 10.1 mg/dl and 17.0 mg/dl , no association between our cognitive domains and hemoglobin was observed . Table 2Relationships between hypertension , anemia and cognitive measuresNumber -LRB- n = 29 -RRB- IQaGeneral memoryaAttentionaTotal cohort91 -LRB- 16 -RRB- 88 -LRB- 16 -RRB- 96 -LRB- 23 -RRB- Non-hypertensive90 -LRB- 18 -RRB- 87 -LRB- 16 -RRB- 89 -LRB- 24 -RRB- Hypertensive92 -LRB- 15 -RRB- 89 -LRB- 17 -RRB- 100 -LRB- 21 -RRB- Non-anemic91 -LRB- 16 -RRB- 89 -LRB- 16 -RRB- 98 -LRB- 22 -RRB- Anemic -LRB- < 11 mg/dl -RRB- 92 -LRB- 17 -RRB- 81 -LRB- 23 -RRB- 76 -LRB- 20 -RRB- aFor each represented test among the normal population , the mean is 100 with a standard deviation of 15 . No significant differences on Student 's t-tests for hypertension or anemia . The use of a contemporary blood pressure or hemoglobin value to represent the hypertension or anemia status of our participants evaluated the potential effect of these factors on their cognitive performance on the day of testing . Day-to-day changes in blood pressure could cause changes in cognitive function . Another approach is to use time-averaged hemoglobin and blood pressure values as markers of long-term strain on cognitive skills . Therefore , we also did a retrospective chart review of all blood pressure and hemoglobin values recorded in the 6 months prior to the study visit and generated a mean value for each of these two variables . On the basis of these time-averaged values , we repeated our analysis . In the blood pressure range represented , hypertension remained unrelated to any of the cognitive variables . Hemoglobin levels , however , demonstrated a subtle correlation with memory performance in the continuous analysis -LRB- r = 0.41 , P = 0.03 -RRB- . Dichotomous analysis of anemia yielded a significant difference in cognitive scores only when defined as a time-averaged hemoglobin level less than 10.5 mg/dl -LRB- mean memory score of 67 among anemic patients versus 91 among non-anemic participants , P = 0.01 -RRB- . However , this must be interpreted with caution , since only three participants fulfilled this criterion for anemia . We should also acknowledge that there is a high degree of correlation among the results of the individual cognitive domains tested . Among the children included in our study , 12 -LRB- 41 % -RRB- had no cognitive scores greater than one standard deviation below the normative mean of 100 , eight -LRB- 28 % -RRB- deviated in this fashion in a single cognitive domain , three -LRB- 10 % -RRB- did so in two areas , and six -LRB- 21 % -RRB- did so in all three areas . The level of overlap is , in part , likely due to the nature of cognitive testing , whereby testing in one area is , to some degree , dependent upon function in another area . The fact that there is not complete overlap , however , indicates that cognitive testing can distinguish among these deficits with some level of specificity . Discussion Neurocognitive deficits among children with ESRD have been demonstrated in the literature , with some suggestion that key clinical variables can be associated with the level and , perhaps , the pattern of these deficits . The primary purpose of this study was to examine the relationship between targeted clinical variables , based on the available literature , and selected neurocognitive functions as defined by IQ , memory , and attention . Further , the current study examines these relationships across the full spectrum of CKD , including the mild to moderate stages of CKD . While it is recognized that some of the etiologies leading to CKD in our patients , namely cystinosis , calcineurin inhibitor toxicity , and ischemic injury , could potentially be independently associated with some level of cognitive dysfunction , in all three cases the children did not demonstrate evidence of other neurologic signs that would indicate central nervous system damage from their underlying disorders . Additionally , these children are representative of a typical pediatric CKD population , and any contribution from the presence of their comorbid conditions would not compromise the validity of our findings . In the current study , several key findings were evident . First , disease severity significantly correlated with IQ and memory , while duration of disease significantly correlated with memory in the expected direction . Age at onset and percent of life with CKD did not initially correlate with any of the neurocognitive indices . When the age at onset and percent of life with the disease were examined in a secondary analysis restricted to a group of participants with more precisely defined onset of true decreased renal function , there was a clear trend that suggested that the younger the age at onset and the greater the percent of life with CKD , the lower the IQ score . The finding that younger age at renal insufficiency onset is significantly related to lower IQ complements previous observations in two prior studies of children with ESRD -LSB- 3 , 15 -RSB- . Lawry et al. -LSB- 15 -RSB- found that among 24 children , including both dialysis and transplant patients , younger age at ESRD onset correlated with lower IQ scores . Brouhard et al. -LSB- 3 -RSB- also found that younger age at renal diagnosis was associated with lower achievement scores , although not specifically with lower IQ scores . Also interesting to note is the wide range of IQ and memory scores among the ESRD subset of our study sample , as can be observed in Figs. 1 and 2 . This might reflect the presence of other clinical variables , such as duration on dialysis , dialysis adequacy , or presence of residual renal function , which could also influence cognitive performance . A similar wide range of results among children with ESRD has been observed in other study samples , such as that of Brouhard et al. -LSB- 3 -RSB- , in which children with renal disease had scores that included some in the average range but still had mean IQ and achievement scores significantly lower than their healthy sibling controls . These findings support the hypothesis that disease severity plays a strong role in predicting neurocognitive vulnerability , yet also suggest that there might be additional contributing variables characterizing end stage disease that warrant further investigation . In an effort to explore this issue further , the sub-analysis confined to the relationship between disease severity and cognitive outcomes in the non-dialysis participants demonstrated a more subtle downward trend of scores across all cognitive domains that did not reach statistical significance . This was likely , in part , due to the reduction in power resulting from our limiting the analysis to only 15 participants . It also might suggest that therapy with dialysis itself contributes to cognitive dysfunction . The literature has been more ambiguous with regard to attention , and our findings did not demonstrate a significant deficit in attention . Our sample did , however , demonstrate significantly more variation in the attention measure among children with CKD than one would anticipate in the general population , as exhibited by the large standard deviation in our study sample . This suggests the possibility that there may be a subset of children with CKD who are more vulnerable to attention-related problems . More extensive exploration of the various components of attention may be required to explore this observation further . Hypertension , as a single measure or time-averaged , was not associated with the neurocognitive outcomes evaluated . Hypertension in the general pediatric population has been correlated with decreased performance in tasks requiring memory , attention , and concentration -LSB- 16 -RSB- . Using school-aged children from a population-based US survey who were diagnosed with hypertension on the basis of systolic or diastolic blood pressure above the 90th percentile for age , height and gender , Lande et al. -LSB- 16 -RSB- showed that hypertension was significantly associated with lower neurocognitive scores representative of short-term memory , attention and concentration problems . In our study sample of children with CKD , the majority of our participants were on antihypertensive therapy , so any existing hypertension in our study sample was at least partially treated , thus significantly restricting the range of variance available for correlation analysis . Furthermore , some antihypertensive therapies , for instance clonidine , have the potential to cause sedating effects in children but can actually help concentration in other children . The effects of medications on just a few children could appear amplified in our small study sample , and , thus , a true relationship could be obscured . The hemoglobin level at the time of testing did not predict cognitive function . Time-averaged hemoglobin concentrations less than 10.5 mg/dl were associated with lower memory performance . It has also been well established that anemia is associated with decreased cognitive function in adult patients with renal disease -LSB- 17 , 18 -RSB- . Stivelman 's review on the topic highlights several studies investigating the use of erythropoietin in uremic adult patients . Increasing hematocrit was associated with improved neurocognitive measures -LSB- 17 -RSB- . For example , Marsh et al. -LSB- 18 -RSB- used erythropoietin in 24 adult hemodialysis patients to improve their average hematocrit from 23 % to 36 % , resulting in significantly improved neuropsychological test scores reflecting memory , learning and attention . In our study sample of children with CKD , only three children had a low hemoglobin level , and these were between 10.1 mg/dl and 10.8 mg/dl . The mean scores for memory and attention among those three children were 8 points and 22 points lower , respectively , than those for non-anemic children , suggesting that there could be a relationship that would require a larger sample size to identify . In the normal or near-normal range , detrimental effects of lower hemoglobin levels are likely more subtle and , thus , less likely to be captured in analysis of a small sample . Our time-averaged hemoglobin analysis supported this as well . This is the first study to date that focuses specifically on identifying potential risk factors for neurocognitive decline in children and adolescents with CKD . Its value is further enhanced by the inclusion of children with mild to moderate CKD , thus extending findings to a wider range of pediatric CKD patients . Increased disease severity , duration of CKD , and younger age at CKD onset were identified as potential risk factors for the targeted neuropsychological functions of IQ and memory . Our results further suggest a significant linear relationship with disease severity , with IQ scores continuously declining as disease severity worsens . Not only does this finding argue against a threshold effect , it implicates disease severity as an important risk factor for neuropsychological dysfunction . These findings also suggest the possible utility of these variables in a cumulative risk model to predict neurocognitive dysfunction in CKD and lay the foundation for exploration of such a model . Finally , these findings emphasize the importance of conducting further research in neurocognitive development among children with CKD . This includes research both to more clearly predict which children with CKD are most vulnerable to neuropsychological dysfunction and to identify specific correlates of this dysfunction . While there have been great strides in improving quality and length of life among children with CKD , a better understanding of those processes that interfere with normal neurodevelopment is a critical element of providing optimal care to these children .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

pediatrics
chronic renal insufficiency
developmental delay
cognitive deficits


Improved

renal

survival

in

Japanese

children

with

IgA

nephropathy

Since

the

beginning

of

the

Japanese

medical

practitioners

have

extensively

prescribed

angiotensin-converting

enzyme

-LRB-

ACE

-RRB-

inhibitors

for

children

with

mild

IgA

nephropathy

-LRB-

IgA-N

-RRB-

and

steriods

for

those

with

severe

IgA-N

We

have

performed

a

retrospective

cohort

study

to

clarify

whether

the

long-term

outcome

has

improved

in

Japanese

children

with

IgA-N

Renal

survival

was

defined

as

the

time

from

onset

to

end-stage

renal

disease

-LRB-

ESRD

-RRB-

We

divided

the

study

period

into

two

time

periods

based

on

the

occurrence

of

the

initial

renal

biopsy

and

Actuarial

survivals

were

calculated

by

Kaplan

Meier

method

and

comparisons

were

made

with

the

logrank

test

The

Cox

proportional

hazard

model

was

used

for

multivariate

analysis

Between

and

children

were

diagnosed

as

having

IgA-N

in

our

hospitals

The

actuarial

renal

survival

from

the

time

of

apparent

disease

onset

was

at

years

at

years

and

at

years

Renal

survival

in

the

period

was

significantly

better

than

that

in

-LRB-

p

-RRB-

and

a

marked

improvement

in

renal

survival

in

patients

with

severe

IgA-N

was

also

observed

-LRB-

p

-RRB-

Multivariate

analysis

indicated

that

diagnosis

year

was

a

significant

factor

for

ESRD-free

survival

independently

of

baseline

characteristics

The

results

of

this

study

show

that

there

has

been

an

improvement

in

terms

of

renal

survival

in

Japanese

children

with

IgA-N

Introduction

IgA

nephropathy

-LRB-

IgA-N

-RRB-

is

the

most

common

primary

glomerulonephritis

worldwide

It

was

initially

considered

to

be

a

benign

disease

with

a

favorable

prognosis

but

data

from

long-term

follow-up

studies

subsequently

revealed

that

the

disease

progressed

to

renal

failure

in

of

adult

patients

-LSB-

-RSB-

Although

there

has

been

a

prevailing

belief

that

the

prognosis

of

IgA-N

is

more

benign

in

children

the

results

of

more

recent

studies

do

not

support

this

-LSB-

-RSB-

At

the

beginning

of

the

a

strict

policy

of

treatment

for

IgA-N

was

adopted

by

the

majority

of

physicians

-LSB-

-RSB-

this

consisted

of

the

extensive

use

of

angiotensin-converting

enzyme

inhibitors

-LRB-

ACEIs

-RRB-

as

an

almost

universally

used

therapy

for

IgA-N

and

other

therapies

including

corticosteroids

for

more

severe

IgA-N

-LSB-

-RSB-

This

approach

has

also

been

adopted

in

Japan

since

the

beginning

of

the

with

ACEIs

generally

prescribed

for

children

with

mild

IgA-N

showing

focal

mesangial

proliferation

and

steroids

prescribed

for

children

with

severe

IgA-N

showing

diffuse

mesangial

proliferation

Combined

therapy

with

prednisolone

azathioprine

heparin

warfarin

and

dipyridamole

for

years

in

patients

with

severe

IgA-N

showing

diffuse

mesangial

proliferation

was

started

at

the

Kobe

University

and

Wakayama

Medical

University

hospitals

in

-LSB-

-RSB-

At

present

the

effect

of

this

therapy

on

long-term

renal

survival

in

children

with

IgA-N

remains

unknown

as

there

have

been

few

studies

on

outcome

in

sufficiently

large

cohorts

of

pediatric

patients

-LSB-

-RSB-

In

the

study

reported

here

we

investigated

data

from

children

with

IgA-N

to

determine

whether

the

long-term

outcome

has

improved

in

Japanese

children

with

IgA-N

Methods

Patients

The

medical

history

of

children

under

the

age

of

years

who

underwent

routine

renal

biopsies

at

Kobe

University

and

Wakayama

Medical

University

hospitals

between

January

and

December

were

analyzed

retrospectively

Clinical

data

and

follow-up

information

were

obtained

from

the

medical

records

and

if

needed

further

complementary

information

was

obtained

by

telephone

contact

with

the

patients

family

members

and

or

physicians

A

diagnosis

of

IgA-N

was

based

on

the

presence

of

IgA

as

the

sole

or

predominant

immunoglobulin

in

the

glomerular

mesangium

in

the

absence

of

systemic

disease

-LSB-

-RSB-

Diffuse

or

focal

mesangial

proliferation

was

defined

on

the

basis

of

World

Health

Organization

criteria

-LSB-

-RSB-

diffuse

mesangial

proliferation

was

defined

as

more

than

of

glomeruli

showing

moderate

or

severe

mesangial

cell

proliferation

i.e.

more

than

three

cells

per

peripheral

mesangial

area

focal

mesangial

proliferation

was

defined

as

less

than

of

glomeruli

showing

moderate

or

severe

mesangial

cell

proliferation

All

children

with

IgA-N

were

diagnosed

by

one

investigator

-LRB-

N.Y.

-RRB-

using

the

same

criteria

during

the

entire

study

period

Renal

biopsies

were

performed

in

children

with

persistent

proteinuria

-LRB-

early

morning

urine

protein/creatinine

ratio

g/g

-RRB-

with

or

without

hematuria

Renal

biopsy

criteria

were

not

changed

during

the

entire

study

period

Renal

survival

was

defined

as

the

period

from

the

time

of

apparent

disease

onset

to

end-stage

renal

disease

-LRB-

ESRD

-RRB-

requiring

renal

replacement

therapy

Given

the

change

of

policy

for

treating

IgA-N

patients

in

the

early

we

divided

the

study

period

when

the

initial

renal

biopsy

had

been

performed

into

two

time

periods

-LRB-

early

period

-RRB-

and

-LRB-

late

period

-RRB-

Treatment

Since

we

started

a

strict

policy

of

treatment

for

IgA-N

at

the

beginning

of

the

we

investigated

the

initial

treatment

profile

of

children

with

IgA-N

After

a

pilot

study

period

we

started

the

first

randomized

controlled

trial

-LRB-

RCT

-RRB-

by

the

Japanese

Pediatric

IgA

Nephropathy

Treatment

Study

Group

-LRB-

JPIGANTS

-RRB-

for

treatment

of

children

with

severe

IgA-N

showing

diffuse

mesangial

proliferation

in

-LSB-

-RSB-

We

started

the

second

RCT

by

the

JPIGANTS

for

treatment

of

children

with

severe

IgA-N

in

-LSB-

-RSB-

We

started

the

third

RCT

by

the

JPIGANTS

for

treatment

of

children

with

severe

IgA-N

in

The

details

of

each

treatment

are

shown

in

Table

Table

in

three

randomized

controlled

trials

for

childhood

IgA

nephropathy

with

diffuse

mesangial

-LRB-

first

RCT

-RRB-

-LRB-

second

RCT

-RRB-

present

-LRB-

third

RCT

-RRB-

Group

-LRB-

as

in

group

in

the

first

period

-RRB-

Prednisolone

mg/kg/day

weeks

mg/kg/day

weeks

days

weeks

days

weeks

days

weeks

days

weeks

days

months

days

months

days

monthsAzathioprineAzathioprine

-LRB-

as

in

group

in

the

first

period

-RRB-

No

azathioprine

mg/kg/day

monthsDipyridamoleDipyridamole

-LRB-

as

in

group

in

the

first

period

-RRB-

Dipyridamole

mg/kg/day

months

mg/kg/day

monthsHeparinNo

heparin

APTT

s

daysWarfarinWarfarinWarfarin

TT

months

TT

months

TT

monthsMizoribine

mg/kg/day

monthsGroup

-LRB-

as

in

group

-RRB-

Prednisolone

-LRB-

as

in

group

-RRB-

Prednisolone

-LRB-

as

in

group

-RRB-

Mizoribine

-LRB-

as

in

group

-RRB-

TT

Thrombotest

APTT

activated

partial

thromboplastin

time

RCT

randomized

controlled

trial

For

the

treatment

of

children

with

mild

IgA-N

showing

focal

mesangial

proliferation

we

started

a

RCT

by

the

JPIGANTS

in

During

this

trial

-LRB-

-RRB-

about

half

of

the

children

with

mild

IgA-N

in

our

hospitals

received

Sairei-to

a

Chinese

herb

for

months

and

the

other

half

received

no

medication

We

began

to

use

ACEIs

for

treatment

of

mild

IgA-N

with

focal

mesangial

proliferation

as

the

first

choice

from

the

beginning

of

Statistical

analyses

The

results

were

analyzed

with

SAS

ver

-LRB-

SAS

Institute

Japan

Ltd.

Tokyo

Japan

-RRB-

The

associations

between

categorical

variables

were

examined

using

the

Fisher

's

exact

test

Continuous

characteristics

of

the

groups

were

compared

with

the

Mann-Whitney

U-test

Actuarial

survival

curves

were

calculated

according

to

the

Kaplan-Meier

method

-LSB-

-RSB-

and

comparisons

were

made

with

the

logrank

test

-LSB-

-RSB-

Univariate

and

multivariate

analyses

were

performed

to

assess

the

difference

between

the

two

periods

in

terms

of

renal

survival

For

multivariate

analysis

we

used

the

Cox

proportional

hazard

model

-LSB-

-RSB-

A

two-tailed

p

value

of

less

than

was

taken

as

the

level

of

significance

Results

Patients

Between

and

children

underwent

a

first

renal

biopsy

examination

at

the

Kobe

University

and

Wakayama

Medical

University

hospitals

Among

these

Japanese

children

-LRB-

boys

and

girls

-RRB-

were

diagnosed

as

having

IgA-N

in

and

in

There

was

no

evident

change

in

the

number

of

patients

per

year

between

the

early

-LRB-

-RRB-

and

late

-LRB-

-RRB-

periods

The

median

patient

age

at

diagnosis

was

years

-LRB-

range

years

-RRB-

and

the

median

follow-up

period

for

the

patients

overall

was

years

-LRB-

range

years

-RRB-

The

baseline

characteristics

of

children

with

IgA-N

are

shown

in

Table

There

were

significant

differences

in

some

characteristics

between

the

two

periods

Age

at

diagnosis

had

a

tendency

to

be

higher

in

the

late

group

while

the

ratio

of

asymptomatic

proteinuria

and

hematuria

at

initial

presentation

was

significantly

higher

in

the

late

group

The

ratio

of

heavy

proteinuria

-LRB-

per

day

-RRB-

at

diagnosis

was

significantly

higher

in

the

early

period

but

the

ratio

of

patients

showing

diffuse

mesangial

proliferation

was

higher

in

the

late

period

Based

on

these

data

we

concluded

that

there

was

no

evident

difference

in

disease

severity

between

the

two

periods

Table

characteristicsCharacteristicNumber

of

patients

-LRB-

-RRB-

pTotal

-LRB-

n

-RRB-

-LRB-

n

-RRB-

-LRB-

n

-RRB-

Sex

-LRB-

M/F

-RRB-

Age

at

diagnosis

year

median

-LSB-

range

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

Initial

presentationAsymptomatic

proteinuria

and

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Macroscopic

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Proteinuria

at

diagnosis

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Estimate

creatinine

clearance

at

diagnosis

-LRB-

ml/min

per

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Renal

biopsy

at

diagnosis

Diffuse

mesangial

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Focal

mesangial

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Treatment

The

initial

treatment

for

IgA-N

showing

focal

mesangial

proliferation

or

diffuse

mesangial

proliferation

is

given

in

detail

in

Table

There

was

a

clear

change

of

treatment

for

IgA-N

between

the

early

and

late

periods

This

is

particularly

true

in

terms

of

ACEI

use

for

focal

mesangial

proliferation

and

combined

therapies

for

diffuse

mesangial

proliferation

both

of

which

increased

dramatically

during

the

late

period

Table

of

initial

treatment

for

IgA

nephropathy

in

Japanese

childrenTreatmentFocal

mesangial

proliferationDiffuse

mesangial

-LRB-

n

-RRB-

-LRB-

n

-RRB-

-LRB-

n

-RRB-

-LRB-

n

-RRB-

No

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Antiplatelet

and/or

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Prednisolone

-LRB-

antiplatelet

and/or

anticoagulant

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Prednisolone

immunosuppressant

-LRB-

antiplatelet

and/or

anticoagulant

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Chinese

herb

-LRB-

Sairei-to

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

ACEI

and/or

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

ACEI

Angiotensin-converting

enzyme

inhibitor

ARB

angiotensin

II

receptor

blocker

Renal

survival

Among

a

total

of

patients

who

had

IgA-N

therapy

the

actuarial

renal

survival

from

the

time

of

apparent

disease

onset

was

at

years

at

years

and

at

years

-LRB-

Table

-RRB-

As

shown

in

Fig.

and

Table

in

children

diagnosed

as

having

IgA-N

in

the

actuarial

renal

survival

from

the

time

of

apparent

disease

onset

was

at

years

at

years

and

at

years

In

children

diagnosed

as

having

IgA-N

in

the

actuarial

renal

survival

from

the

time

of

apparent

disease

onset

was

at

years

at

years

-LRB-

p

Fig.

Table

-RRB-

Table

renal

survival

analysis

of

children

with

IgA

nephropathy

Initial

renal

biopsy

yearNumber

of

renal

renal

renal

Diffuse

mesangial

b

b

Focal

mesangial

ap

values

on

the

logrank

testbThe

survivalFig

Meier

plot

of

renal

survival

stratified

by

the

initial

biopsy

year

for

children

with

IgA

nephropathy

CI

Confidence

interval

Figures

and

show

the

long-term

outcome

for

children

in

the

two

different

mesangial

proliferation

groups

For

children

with

severe

IgA-N

showing

diffuse

mesangial

proliferation

both

the

and

renal

survivals

were

when

the

diagnosis

was

made

in

the

period

when

the

diagnosis

was

made

in

the

period

renal

survivals

were

and

respectively

-LRB-

p

Fig.

Table

-RRB-

For

children

with

mild

IgA-N

showing

focal

mesangial

proliferation

both

the

and

renal

survivals

were

when

diagnosis

was

made

in

compared

with

and

respectively

in

-LRB-

p

Fig.

Table

-RRB-

Although

we

observed

better

renal

survival

in

patients

diagnosed

in

the

period

than

in

the

period

for

children

with

IgA-N

showing

focal

mesangial

proliferation

the

difference

did

not

reach

statistical

significance

The

children

with

IgA-N

showing

diffuse

mesangial

proliferation

in

had

excellent

long-term

renal

survival

Fig.

plot

of

renal

survival

stratified

by

the

initial

biopsy

year

for

children

with

severe

IgA

nephropathy

showing

diffuse

mesangial

proliferationFig

plot

of

renal

survival

stratified

by

the

initial

biopsy

year

for

children

with

mild

IgA

nephropathy

showing

focal

mesangial

proliferation

Table

shows

the

results

of

the

univariate

analysis

using

the

logrank

test

and

the

multivariate

analysis

using

the

Cox

proportional

hazard

model

of

prognostic

factors

for

ESRD-free

survival

Mesangial

proliferation

degree

-LRB-

focal

or

diffuse

-RRB-

proteinuria

at

diagnosis

-LRB-

or

per

day

-RRB-

estimate

of

creatinine

clearance

at

diagnosis

-LRB-

or

ml/min

per

-RRB-

and

initial

renal

biopsy

-LRB-

diagnosis

-RRB-

year

-LRB-

or

-RRB-

were

included

as

factors

for

analyses

Mesangial

proliferation

degree

and

initial

renal

biopsy

year

were

significant

in

both

the

univariate

and

the

multivariate

analysis

For

children

with

IgA-N

the

most

influential

prognostic

variable

was

mesangial

proliferation

degree

Proteinuria

at

diagnosis

was

significant

in

the

univariate

but

not

in

the

multivariate

analysis

These

results

from

the

multivariate

analysis

showed

that

initial

renal

biopsy

year

was

a

significant

factor

for

ESRD-free

survival

independently

of

mesangial

proliferation

degree

proteinuria

at

diagnosis

and

estimate

of

creatinine

clearance

at

diagnosis

-LRB-

hazard

ratio

CI

Table

-RRB-

Table

and

multivariate

analysis

of

the

prognostic

value

of

factors

for

end-stage

renal

disease-free

CIpMesangial

proliferation

focal

Proteinuria

at

diagnosis

-LRB-

-RRB-

CCl

at

diagnosis

-LRB-

ml/min

per

-RRB-

Initial

renal

biopsy

year

CI

Confidence

interval

HR

hazard

ratio

CCl

creatinine

clearance

Discussion

Although

this

was

a

retrospective

study

the

data

seem

to

provide

unique

and

valuable

information

about

IgA-N

in

children

for

several

reasons

First

the

study

subjects

were

a

complete

non-selected

cohort

of

patients

with

IgA-N

from

among

all

children

who

underwent

first

renal

biopsy

examinations

at

Kobe

University

and

Wakayama

Medical

University

hospitals

between

and

Five

hundred

children

with

IgA-N

participated

in

our

study

which

to

our

knowledge

is

the

largest

series

used

to

investigate

the

outcome

of

IgA-N

in

children

to

date

Furthermore

these

patients

were

diagnosed

histologically

by

a

single

investigator

-LRB-

N.Y.

-RRB-

based

on

the

same

criteria

during

the

whole

study

period

Renal

biopsy

criteria

were

also

unchanged

during

the

whole

study

period

Therefore

the

cohort

in

the

present

study

is

considered

to

have

been

rigidly

homogeneous

in

terms

of

the

analysis

of

the

disease

outcome

One

of

the

conditions

that

facilitated

our

study

was

the

school

screening

program

which

was

started

by

the

Japanese

government

in

In

Japan

all

children

between

the

ages

of

and

years

are

screened

annually

and

those

found

to

have

urinary

abnormalities

are

referred

for

further

investigation

Thus

in

general

treatment

for

IgA-N

is

started

early

in

the

course

of

disease

because

the

duration

of

disease

before

treatment

is

short

as

a

result

of

this

school

screening

program

-LSB-

-RSB-

Therefore

in

this

study

we

were

able

to

observe

the

disease

courses

of

patients

during

the

initial

renal

biopsy

period

who

underwent

initial

treatments

for

IgA-N

at

a

relatively

homogeneous

stage

of

the

disease

Accumulated

experience

indicates

that

long-term

corticosteroid

and/or

immunosuppressive

treatment

during

the

severely

progressive

stage

of

the

disease

does

not

confer

any

benefit

in

adult

patients

-LSB-

-RSB-

In

contrast

it

is

known

that

centers

in

countries

with

active

urine

screening

programs

are

more

likely

to

diagnose

mild

disease

with

a

good

prognosis

thus

favorably

influencing

the

overall

outcome

of

the

cohort

-LSB-

-RSB-

Another

favorable

parameter

of

this

study

was

the

enforcement

of

consecutive

systemic

nationwide

clinical

trials

of

IgA-N

After

a

pilot

study

period

the

first

RCT

for

treatment

of

children

with

severe

IgA-N

showing

diffuse

mesangial

proliferation

was

started

by

the

JPIGANTS

in

-LSB-

-RSB-

To

date

two

RCTs

of

treatment

for

children

with

severe

IgA-N

showing

diffuse

mesangial

proliferation

by

the

JPIGANTS

have

been

completed

-LSB-

-RSB-

and

the

third

RCT

of

treatment

for

children

with

severe

IgA-N

showing

diffuse

mesangial

proliferation

is

currently

being

conducted

by

the

same

group

For

the

treatment

of

children

with

mild

IgA-N

and

focal

mesangial

proliferation

a

RCT

was

also

started

by

the

JPIGANTS

in

After

completion

of

the

RCT

we

have

conducted

prospective

clinical

trials

of

treatment

for

children

with

mild

IgA-N

and

focal

mesangial

proliferation

These

prospective

trials

have

enabled

for

us

to

clarify

the

optimum

treatment

for

IgA-N

and

to

collect

precise

information

on

patients

with

IgA-N

Because

of

the

variable

rate

of

progression

to

renal

failure

and

the

probable

multifactorial

pathogenesis

of

IgA-N

it

is

desirable

to

evaluate

the

effectiveness

of

any

treatment

by

a

prospective

controlled

trial

However

although

the

ultimate

endpoint

in

any

clinical

trial

of

progressive

IgA-N

is

the

development

of

chronic

renal

insufficiency

most

pediatric

patients

do

not

develop

it

during

the

study

period

-LSB-

-RSB-

Therefore

data

from

a

properly

analyzed

long-term

retrospective

study

may

also

be

important

to

evaluate

disease

outcome

and

treatment

effectiveness

-LSB-

-RSB-

Retrospective

studies

with

accurate

statistical

evaluation

using

life-time

analysis

and

multivariate

survivorship

analysis

according

to

the

Cox

regression

model

are

thought

to

work

effectively

together

with

well-designed

RCTs

The

primary

purpose

of

this

study

was

to

clarify

whether

long-term

outcome

was

improved

in

Japanese

children

with

IgA-N

retrospectively

using

adequate

statistical

methods

Although

it

seemed

that

there

were

no

clinically

significant

differences

in

the

baseline

characteristics

of

the

groups

there

were

some

statistically

significant

differences

in

the

baseline

characteristics

of

the

groups

between

the

two

periods

when

initial

renal

biopsies

were

performed

These

different

baseline

characteristics

may

influence

the

final

outcomes

reported

in

this

study

To

compensate

for

this

limitation

we

used

a

multivariate

survivorship

analysis

according

to

the

Cox

regression

model

Since

we

have

to

adjust

for

differences

of

baseline

characteristics

which

were

thought

to

be

important

prognostic

factors

-LSB-

-RSB-

mesangial

proliferation

degree

proteinuria

at

diagnosis

estimate

of

creatinine

clearance

at

diagnosis

and

the

initial

renal

biopsy

-LRB-

diagnosis

-RRB-

year

were

included

as

factors

for

analyses

This

multivariate

analysis

indicated

that

the

initial

renal

biopsy

year

was

a

significant

factor

for

ESRD-free

survival

after

adjustment

of

these

baseline

characteristics

These

data

support

an

improvement

of

renal

survival

in

Japanese

children

with

IgA-N

There

was

a

notable

lack

of

the

usual

dominance

of

males

over

females

in

our

study

and

in

addition

there

was

a

difference

between

the

and

the

periods

with

more

females

being

recruited

in

the

second

period

Although

this

difference

was

not

statistically

significant

-LRB-

p

-RRB-

we

decided

that

it

be

worthwhile

discussing

possible

reasons

for

the

differences

in

gender

representation

between

the

two

periods

Therefore

we

analyzed

males

and

females

separately

However

there

was

no

gender-based

factor

in

the

results

-LRB-

data

not

shown

-RRB-

At

the

beginning

of

the

a

strict

policy

of

treatment

was

adopted

by

the

majority

of

physicians

in

Japan

It

is

likely

that

therapeutic

intervention

early

after

the

onset

of

clinically

apparent

disease

will

provide

the

best

opportunity

for

improving

the

outcome

of

patients

with

IgA-N

thus

reducing

the

number

of

patients

who

develop

ESRD

-LSB-

-RSB-

This

study

showed

a

clear

change

in

the

treatment

of

IgA-N

between

the

early

and

late

groups

-LRB-

Table

-RRB-

In

particular

the

use

of

ACEIs

for

focal

mesangial

proliferation

and

combination

therapies

for

diffuse

mesangial

proliferation

increased

dramatically

in

the

late

group

Corticosteroids

have

been

widely

used

to

treat

moderate

to

severe

IgA-N

particularly

in

pediatric

patients

Some

evidence

has

been

obtained

recently

pertaining

to

the

role

of

corticosteroids

in

the

treatment

of

IgA-N

-LSB-

-RSB-

With

regard

to

children

and

based

on

the

results

of

two

multicenter

RCTs

we

reported

previously

that

the

treatment

of

childhood

IgA-N

with

diffuse

mesangial

proliferation

using

prednisolone

azathioprine

warfarin

and

dipyridamole

for

years

early

in

the

course

of

disease

reduced

the

severity

of

immunologic

renal

injury

and

prevented

any

increase

in

the

percentage

of

sclerosed

glomeruli

-LSB-

-RSB-

In

contrast

in

the

first

RCT

heparin

warfarin

and

dipyridamole

treatments

for

years

did

not

reduce

urinary

protein

excretion

serum

IgA

concentration

and

mesangial

IgA

deposition

and

they

did

not

prevent

any

increase

of

sclerosed

glomeruli

-LSB-

-RSB-

The

results

of

the

second

RCT

showed

that

the

treatment

of

children

with

severe

IgA-N

using

prednisolone

alone

for

years

reduced

the

severity

of

immunologic

renal

injury

but

did

not

prevent

any

further

increase

of

glomerular

sclerosis

-LSB-

-RSB-

Therefore

treatment

with

the

combination

therapy

using

prednisolone

and

immunosuppressant

such

as

azathioprine

may

be

better

than

the

prednisolone

monotherapy

for

patients

with

severe

IgA-N

We

found

an

improvement

of

long-term

renal

survival

in

Japanese

children

with

IgA-N

-LRB-

Table

Figs.

and

-RRB-

Renal

survival

in

was

significantly

better

than

in

-LRB-

Fig.

-RRB-

and

a

marked

improvement

of

renal

survival

in

IgA-N

showing

diffuse

mesangial

proliferation

was

observed

over

time

-LRB-

Fig.

-RRB-

This

improvement

may

be

related

to

the

therapy

including

corticosteroids

for

all

patients

with

IgA-N

showing

diffuse

mesangial

proliferation

as

a

treatment

policy

although

in

principle

the

effectiveness

of

any

treatment

can

only

be

evaluated

properly

by

a

controlled

trial

It

is

conceivable

that

the

outcome

in

the

period

may

have

reflected

the

natural

course

of

disease

whereas

that

in

may

have

reflected

modification

of

the

disease

course

by

the

treatments

The

median

follow-up

period

of

the

patients

overall

was

years

-LRB-

range

years

-RRB-

Although

this

is

a

considerably

long

period

it

may

not

be

sufficiently

long

for

the

follow-up

of

IgA-N

which

has

a

slow

progressive

course

Since

the

elapsed

time

from

apparent

disease

onset

to

ESRD

was

used

to

evaluate

the

disease

outcome

chronic

renal

insufficiency

before

ESRD

was

not

considered

in

our

study

Thus

we

do

not

know

whether

the

observed

improvement

of

outcome

means

a

complete

cure

of

the

disease

or

merely

a

delay

of

the

disease

course

Further

follow-up

of

the

cohort

for

a

long

period

is

therefore

important

One

aspect

which

we

should

consider

in

our

study

is

the

possibility

that

at

least

some

of

the

differences

in

outcome

between

the

early

and

late

groups

may

be

due

to

general

changes

in

care

that

have

occurred

over

time

Such

changes

are

frequently

not

recognized

such

as

a

gradually

greater

awareness

of

managing

marginally

raised

blood

pressure

among

others

In

conclusion

this

study

has

demonstrated

a

substantial

improvement

of

long-term

renal

survival

in

Japanese

children

with

IgA-N

On

the

basis

of

the

results

of

this

study

we

were

unable

to

provide

the

reason

for

this

improved

outcome

directly

however

it

is

likely

that

adequate

management

using

a

strict

policy

of

treatment

may

have

been

responsible

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

corticosteroid
mesangial proliferation
proteinuria