IgA nephropathy (IgAN) in children is no longer considered a rare and benign disease but a nephritis with different presentations and various outcomes. The decision to initiate a treatment and the therapeutic choice depend on the individual risk of progression. The Kidney Disease: Improving Global Outcomes (KDIGO) clinical guidelines in 2012 considered that the risk factors for progression of IgAN were similar in both children and adults and suggested in some conditions to follow the adult schedules. In 2017 a KDIGO Controversies Conference on management and treatment of glomerular diseases decided not to include an update in children with IgAN since the level of evidence of treatments in children was too scarce. Children can follow the indications for adults as far as the disease is similar in the various ages. This review is aimed at discussing why the KDIGO guidelines are poorly suitable to treat children with IgAN, and there is a need to develop new prediction models for progression of IgAN in children to guide selection of the cases to be treated. The identification of different risk levels in children with IgAN may personalize the choice of available drugs and support the use of new targeted therapies.
The dilemma of to treat or not to treat children with IgA nephropathy (IgAN) is nowadays more complex than when this entity was considered rare and benign, since the therapeutic choice varies case by case according to the individual risk of progression to end-stage renal disease (ESRD) . At the present time, we do not have sufficient knowledge to predict individual risk. It is still unknown why 30–60% of subjects with pediatric IgAN will never experience any decline in GFR over a long and healthy life, while about 10% of them will progress to ESRD or severe CKD stages within 10 years after the diagnostic renal biopsy and 20–30% after 20 years . Moreover, several cases reach 40–50 years of age with a silent relentless progression of an undiagnosed IgAN, which is discovered by chance finding after a checkup for hypertension and reduced GFR in subjects without a known personal or familiar history of renal disease. The ERA-EDTA Registry has reported that most subjects with IgAN when entering renal replacement therapy are young adults . Since their functional decline is slow, it is reasonable to suppose that severe progressive IgAN may begin in childhood and that a prompt diagnosis may offer the possibility for early treatment and improvement of the natural history of the disease in adult age.
Kidney Disease: Improving Global Outcomes (KDIGO) guideline approach to treat IgAN in children
The KDIGO clinical guidelines published in 2012 were a milestone document for treatment of glomerular disease in adults and children . KDIGO commented that children with IgAN were less likely to reach ESRD, probably due to an early diagnosis. Since the risk factors for progression had been validated in both children and adults , a generalization of indications across the ages was considered possible. The KDIGO approach was to deliver recommendations on irrefutable publication basis as Level 1 “we recommend” supported by systematic review/meta-analysis and Level 2 “we suggest” supported by at least one randomized controlled trial (RCT). The data available for children with IgAN were so limited that KDIGO just suggested in some conditions to follow the adult guidelines.
The KDIGO 2012 guidelines considered the most frequent presentation in adults with slowly progressive IgAN at risk of ESRD, i.e., patients with proteinuria > 1 g/day (often with hypertension and already slightly reduced GFR), and the first-line treatment recommended was renin-angiotensin system blockers (RASB) valid also in children. A threshold of proteinuria > 0.5 g/day/1.73 m2 was suggested in children. Corticosteroids (CS) were suggested only in patients with persistent proteinuria, despite 3 to 6 months of optimized supportive care with RASB. No additional benefit of adding other immunosuppressive drugs (IS) was reported. In the rare event of crescentic IgAN with > 50% of glomeruli involved, a treatment as for ANCA vasculitis was suggested. In infrequent cases of IgAN associated with minimal change disease, the recommendation was to use the same treatment as for minimal change disease.
In 2017, a KDIGO Controversies Conference on management and treatment of glomerular diseases started the review of the 2012 guidelines. Some results from the panel discussion have already been published , while waiting for new guidelines in 2020. However, an update in children with IgAN will not be included, since there were no new pediatric studies meeting the requirements for “we recommend” or “we suggest.” IgAN was considered similar in children and adults; hence, the final message is once again that children may follow the same treatment indications given for adults.
Application of KDIGO guidelines to children with IgAN
There is a very moderate enthusiasm from experts in guidelines in dealing with an extremely limited number of RCTs, or a few uncontrolled retrospective cohort studies often reporting recent as well as historical patients enrolled over several decades, despite the change over time of diagnostic and therapeutic approaches. The outcomes analyzed in the RCTs involving children with CKD, including IgAN, are extremely heterogeneous and mostly surrogate . Moreover, the initial course of several mild cases of IgAN in children may present a spontaneous remission of urinary abnormalities, often followed by reappearance of clinical manifestations during the follow-up , indicating phases of activity, recovery, and relapses, which can render difficult a standardization of treatments. However, the pediatric nephrologist has in charge precious cases of children with IgAN of unknown destiny and has to make the choice: not to treat, hoping in a self-limiting evolution and avoiding the trouble of pills and controls and – most of all – dangerous drug side effects, or be worried about a potential progression. The pediatric nephrologist is tempted to offer the most powerful treatment as early as possible to avoid an irreversible decline of GFR, but is it always correct? The benefits of therapy in children with IgAN, particularly in mildly proteinuric cases, take years to be appreciated, and adverse events are uncommon but may be severe . IgAN is not a life-threatening condition, and one cannot disregard the cost-benefit balance in individual cases.
Several reports have published results obtained by various treatments in children with IgAN, mostly CS and IS [10,11,12,13,14,15,16]. It is not the aim of this review to list and re-discuss all of them, which are easily found among the references. However, most of the reports do not meet the criteria required for producing KDIGO guidelines in children. This review is aimed at discussing why the KDIGO guidelines are poorly suitable to treat children with IgAN and the need to develop new prediction models for progression of IgAN in children to guide selection of the cases to be treated. The identification of different risk levels at presentation in children with IgAN will support the choice of available drugs and indicate new targeted therapies [17, 18]. This review aims at offering material for individual decision, more than direct suggestions for treatment of pediatric IgAN, a land unfortunately without KDIGO guidance.
KDIGO 2012 concluded that treatment indications for adults and children may be the same since the risk factors are the same. However, treatment can be shared as far as the disease is similar. It is difficult to generalize the course of IgAN in children even more than in adults; hence, it is hard to propose fixed treatment schedules in pediatric IgAN. Each risk factor which is solid and well established in adults is fragile in children. This renders difficult a generalized schedule to treat children with IgAN. The possibility of a personalized treatment remains a tempting promise for the future when new risk stratification models will be available .
Proteinuria at renal biopsy: Is proteinuria enough to guide treatment in children with IgAN?
The KDIGO guidelines consider proteinuria as the only risk factor to target therapy in IgAN. Indeed in adults with chronic slowly progressive IgAN, when proteinuria develops and increases, the risk of progression greatly increases, and there is the need for establishing a treatment [17, 20]. The value of baseline proteinuria as predictor of progression of IgAN in pediatric age has been challenged by some recent observations. In children with IgAN, the clinical data at renal biopsy, as well as at the pathology features, change according to the variable indications to perform renal biopsy in cases with moderate urinary abnormalities or shortly after an acute episode of macroscopic hematuria with nephritic syndrome or nephrotic range proteinuria. In Japan there is a large prevalence of children diagnosed after school screening programs , which is not the case in nearby China or in other continents. The heterogeneity of features of children with IgAN at renal biopsy is often evident, even in the same geographical area and in different periods of the reports [22, 23].
In Europe a rather unbiased observational approach is offered by the cohort gathered by the international collaborative study to validate the Oxford classification of IgAN VALIGA [2, 24], which enrolled 174 children aged < 18 years from 13 European countries, followed for 4.6 (2.5–7.3) years. Renal biopsy was performed in children with median proteinuria of 0.84 g/day/1.73 m2 (in 25% of the children, proteinuria was < 0.30 g/day/1.73 m2, and in only 1%, it was of nephrotic range) and mostly with normal eGFR. RASBs were adopted in 67% of the cases and CS/IS treatment in 50%. In this cohort, the eGFR decline was in median absent, due to improvement in half of the cases, and the combined outcome of 50% reduction in eGFR or ESRD was attained in only 6.3% of the cases. This suggests a possibility of regression, either spontaneous - in mildly proteinuric cases or in children biopsied shortly after gross hematuria - or induced by the CS-IS treatment given in more than half of children. However, the VALIGA pediatric cohort maintained signs of risk factor persistence over long follow-up, since a stable remission on average proteinuria to values < 0.5 g/day/1.73 m2 was reported in only 7.5% of the cases who had initial proteinuria > 0.5 g/day/1.73 m2. Children with IgAN from the VALIGA study did not show a rapid decline in eGFR, but during the follow-up maintained a median proteinuria of 0.56 (0.27–1.02) g/day/1.73 m2. Any level of persistent proteinuria is a risk factor for progression in patients with IgAN, indicating that in the long-term, progression toward ESRD is possible .
In children with IgAN enrolled in VALIGA, the multiple linear regression analysis failed to prove the value of proteinuria at renal biopsy as a risk factor for progression (as well as median arterial blood pressure (MAP) and eGFR). The only risk factors for progression were proteinuria and MAP over the follow-up. Hence, in this large European cohort, proteinuria at renal biopsy – which is the only risk factor considered by KDIGO to select patients to be treated – was not predictive of outcome. Spontaneous remissions, as well as a positive effect of early CS/IS treatment, did not allow the detection of proteinuria at renal biopsy as a risk for progression in children. The only significant biomarker for chronic progression was the persistence of proteinuria and increased MAP values during the follow-up. Children maintaining proteinuria after management of the acute and active phase of IgAN must be targeted for chronic therapy.
In children with IgAN, proteinuria at renal biopsy per se does not indicate the risk of progression. Also the finding of reduced GFR at renal biopsy, which is a strong risk factor in adults , is not predictive of outcome in children [16, 24]. Some data suggest the association with microscopic hematuria increases the value of proteinuria in assessing the clinical activity of patients with IgAN . No literature data support the use of this biomarker for a therapeutic choice, but it is common opinion that it should enter the panel of data to define children with persistent disease activity .
Renal biopsy features: Should MEST-C score be considered to establish treatment in children with IgAN?
The Oxford clinic pathologic classification and subsequent studies detected the independent value as risk factors for progression of mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C), forming the MEST-C score [27, 28]. Its value was independent of proteinuria, MAP, and eGFR at renal biopsy and during the follow-up. Notably, this was unchanged across all age groups and decades after the renal biopsy [27, 29]. However, the KDIGO Controversies Conference in 2019 commented that MEST-C score was developed to predict renal outcome and not to guide treatment or to predict treatment response . Although observational data in adults suggest that E1 [30, 31] and crescents [32,33,34] may predict outcomes differently in treated versus untreated patients, and the benefits of steroids may differ in patients with M1 [19, 35] or S1 , KDIGO concluded that there is currently insufficient evidence to suggest that immunosuppression decisions should be based on histology parameters. New RCTs designed to enroll patients with similar MEST-C scores have been launched in adults but are still ongoing (e.g., Treatment of IgA Nephropathy According to Renal Lesions (TIGER), ClinicalTrials.gov: NCT03188887).
In pediatric IgAN the attempts to validate the value of MEST-C scores have always faced the problem of too few end points (50% decline in eGFR or ESRD) in cohorts with only a few hundred cases, and median follow-up of 5–10 years, which is insufficient to detect functional decline in cases with early diagnosis, such as pediatric ones [24, 37,38,39]. As expected, T lesions are the strongest risk factor for progression in children as well as in adults, but the support given by this score for selecting a correct treatment may be only caution in aggressive therapy when fibrotic changes are too extensive.
Children with IgAN show less T chronic damage and more active lesions (M1, E1, C1) than adults. The prevalence of the MEST-C scores varies according to the renal biopsy policy. In the multinational European VALIGA study, for the 174 children < 18 years of age enrolled, the distribution of frequency was M1, 22%; E1, 14%; S1, 43%; T1–2, 6%; and C1, 15% . In comparison to the adult VALIGA cohort, children showed lower frequency of S1 and T1 lesions and higher frequency of crescentic lesions. M1 was more frequent in children < 12 years of age. A recent report from the Pediatric Nephrology Centers in Paris  presented a different frequency of MEST-C score distribution in 82 children (M1, 80%; E1, 71%; S1, 61%; C, 46%) with exceptional T1–2 (1%). History of gross hematuria was reported in one third of the cases, 25% presented with acute kidney failure and 7% with nephrotic range proteinuria at the time of biopsy. The high frequency of active and severe lesions was likely due to the short time elapsed between clinical onset and renal biopsy, in median less than 2 months. The prompt indication to perform renal biopsy may favor the detection of acute or active renal lesions. In a Japanese pediatric cohort, the prolongation of waiting time before renal biopsy was associated with reduction in M and E lesions, with increase in T damage . Children with IgAN may have onset acute kidney injury (AKI). In a Chinese cohort, AKI with hematuria and massive proteinuria was detected in 9.7% of 196 children with IgAN: C1 was found in 80%, E1 in 60%, and tubular damage with erythrocyte casts in 70% .
The analysis of these data, which are so different at baseline, produced different results for risk factors needing treatment. In the multinational pediatric European cohort, no MEST-C score was predictive of progression. The number of combined events of ESRD and 50% loss of eGFR was so limited (6.3%) and the eGFR decline so mild (median loss 0 ml/min/1.73 m2) as to render impossible the detection of risk factors, either clinical or histological. The prediction value of M1, S1, and T1 was attained including in the observation 216 young subjects aged less than 23 years. Until this age, a correlation between age at renal biopsy and log hazard of the combined end point was found , which then reached a plateau, suggesting some age-related protective effect, which seemed to be lost after the age of 23 years. Also in the French series of rather acute and active cases, the MEST-C scores proved the predictive value of S1 only . In the Chinese  and Japanese  cohorts, only T lesions resulted as significantly associated with outcome upon multivariate analysis.
These data prove the limited predictive value of active lesions per se in children with IgAN, due to the limited number of events, the slow median progression rate, and the regression of clinical features in several cases, mostly associated with the high use of CS/IS drugs.
Association of clinical and pathology features to predict progression of IgAN
Individual risk stratification is the starting point for the choice of treatment, and the lack of suitable risk factors for individual clinical and pathology data at renal biopsy in children does not fulfill the expectation of the pediatric nephrologists. Notably, a significant predictive value on outcome was proved in each large cohort of children with IgAN investigated by the association of clinical features (mostly proteinuria) with MEST-C scores. In the VALIGA pediatric study, a survival tree multivariate analysis found that M1 associated with proteinuria > 0.4 g/day/1.73 m2 provided a stratification of children at higher risk for progression . Similarly, in the Swedish , Japanese , and Chinese  cohorts, the association of proteinuria at renal biopsy with MES and C lesions provided at multivariate analysis the identification of potentially progressive patients.
In adults, an IgAN risk prediction tool valid in a large multiethnic cohort (3297 patients of Caucasian, Chinese, and Japanese ethnicity) was recently developed by the International IgA Nephropathy Network , which allows a risk calculation for individual adult patients, based on clinical data and MEST score. The prediction model was assessed in a derivation cohort of 2781 cases and validated in a cohort of 1146 cases. The two cohorts had a similar risk of reaching a composite end point of ESRD or 50% decline in eGFR (14% and 13% at 5 years from renal biopsy, respectively). Two full models (including age; proteinuria; MAP; eGFR; MEST; prior use of RASB or CS/IS drugs; Caucasian, Chinese, or Japanese race; or the same parameters without race) better predicted the composite end point compared to a model with clinical data only (proteinuria, MAP, eGFR). A mobile app calculator was developed by QxMD and a web-based calculator is available at http://qxmd.com/calculate-by-qxmd. Using this calculator for adult patients, a time for prediction can be selected (up to 7 years after renal biopsy, usually 5 years). Then data are entered, including age, race, blood pressure, eGFR, proteinuria at biopsy, MEST score, and use of RASB and CS/IS before biopsy. The calculator provides the percentage of risk of attaining the composite end point at the follow-up time previously selected. Notably, there is a strict correlation between the percentage of patients reaching the composite end point at 5 years and the eGFR yearly decline. Patients may be stratified according to the mean percentage of subjects reaching the composite end point into low, intermediate, high, and highest risk (respective risks: 1.5%, 4.7%, 13.9%, 46.5%) and corresponding eGFR loss (− 1.24, − 1.76, − 2.35, − 3.45 ml/min/1.73 m2/year). The International IgAN network collaboration has gathered data from 1050 children of various ethnicities, including Caucasians, Chinese, and Japanese, among others, and the validation of this predictive tool for risk stratification in children is in progress.
This prediction tool is designed to assess the risk at renal biopsy and not the response to CS/IS drugs. As an example, patients with T2 lesions will be stratified as at high risk, but no indication will be provided on the response to treatments. Accurate risk stratification using this prediction tool (for children the ongoing pediatric version) will be very useful for future RCTs selecting patients with similar risk for progression.
Risk stratification will allow a personalized approach to treatment of children with IgAN, who present with a scenario much more complex than that defined by KDIGO in adults. Treatment choice should consider the moment of the natural history of the disease, the previous personal history, and the rapidity of progression, while evaluating clinical and pathology features together. The prediction model is a step forward to precision medicine in the treatment of IgAN, and the pediatric community is looking forward to its development in children, with the hope that IgAN in children will no longer be a land without KDIGO guidelines.
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Coppo, R. Treatment of IgA nephropathy in children: a land without KDIGO guidance. Pediatr Nephrol 36, 491–496 (2021). https://doi.org/10.1007/s00467-020-04486-7
- IgA nephropathy in children
- Risk factors
- MEST-C score
- Prediction models