Treatment of IgA nephropathy in children: a land without KDIGO guidance

Abstract

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.

Introduction

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) [1]. 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 [2]. 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 [3]. 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 [4]. 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 [5], 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 [6], 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 [7]. 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 [8], 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 [9]. 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 [19].

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 [21], 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 [20].

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 [17], 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 [25]. 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 [26].

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 [6]. 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 [36], 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% [24]. 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 [16] 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 [40]. 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% [41].

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 [24], 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 [16]. In the Chinese [39] and Japanese [38] 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 [24]. Similarly, in the Swedish [37], Japanese [38], and Chinese [39] 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 [42], 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.

References

  1. 1.

    Coppo R (2018) Treatment of IgA nephropathy: Recent advances and prospects. Nephrol Ther. Suppl 1:S13-S21. doi:https://doi.org/10.1016/j.nephro.2018.02.010

  2. 2.

    Coppo R (2019) Pediatric IgA nephropathy in Europe. Kidney Dis (Basel) 5:182–188. https://doi.org/10.1159/000495751

    Article  PubMed Central  Google Scholar 

  3. 3.

    Brunner FP, Fassbinder W, Broyer M, Oulès R, Brynger H, Rizzoni G, Challah S, Selwood NH, Dykes SR, Wing AJ (1988) Survival on renal replacement therapy: data from the EDTA registry. Nephrol Dial Transplant 3:109–122

    CAS  Article  Google Scholar 

  4. 4.

    Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis (2012) Immunoglobulin a nephropathy. Kidney Int Suppl 2:139–274

    Article  Google Scholar 

  5. 5.

    Coppo R, Troyanov S, Camilla R, Hogg RJ, Cattran DC, Cook HT, Feehally J, Roberts IS, Amore A, Alpers CE, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D'Agati V, D'Amico G, Emancipator SN, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo AB, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H (2010) The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults. Kidney Int 77:921–927

    CAS  Article  Google Scholar 

  6. 6.

    Floege J, Barbour SJ, Cattran DC, Hogan JJ, Nachman PH, Tang SCW, Wetzels JF, Cheung M, Wheeler DC, Winkelmayer WC, Rovin BH, Conference Participants (2019) Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 95:268–280. https://doi.org/10.1016/j.kint.2018.10.018

    Article  PubMed  Google Scholar 

  7. 7.

    Chong LSH, Sautenet B, Tong A, Hanson CS, Samuel S, Zappitelli M, Dart A, Furth S, Eddy AA, Groothoff J, Webb NJA, Yap HK, Bockenhauer D, Sinha A, Alexander SI, Goldstein SL, Gipson DS, Raman G, Craig JC (2017) Range and heterogeneity of outcomes in randomized trials of pediatric chronic kidney disease. J Pediatr 186:110–117.e11. https://doi.org/10.1016/j.jpeds.2017.03.034

    Article  PubMed  Google Scholar 

  8. 8.

    Shima Y, Nakanishi K, Hama T, Mukaiyama H, Togawa H, Sako M, Kaito H, Nozu K, Tanaka R, Iijima K, Yoshikawa N (2013) Spontaneous remission in children with IgA nephropathy. Pediatr Nephrol 28:71–76

    Article  Google Scholar 

  9. 9.

    Cai Q, Xie X, Wang J, Shi S, Liu L, Chen Y, Lv J, Zhang H (2017) Severe adverse effects associated with corticosteroid treatment in patients with IgA nephropathy. Kidney Int Rep 2:603–609

    Article  Google Scholar 

  10. 10.

    Waldo FB, Alexander R, Wyatt RJ, Kohaut EC (1989) Alternate-day prednisone therapy in children with IgA-associated nephritis. Am J Kidney Dis 13:55–60

    CAS  Article  Google Scholar 

  11. 11.

    Welch TR, Fryer C, Shely E, Witte DP, Quinlan M (1992) Double-blind, controlled trial of short-term prednisone therapy in immunoglobulin a glomerulonephritis. J Pediatr 121:474–477

    CAS  Article  Google Scholar 

  12. 12.

    Niaudet P, Murcia I, Beaufils H, Broyer M, Habib R (1993) Primary IgA nephropathies in children: prognosis and treatment. Adv Nephrol Necker Hosp 22:121–140

    CAS  PubMed  Google Scholar 

  13. 13.

    Yoshikawa N, Ito H, Sakai T, Takekoshi Y, Honda M, Awazu M, Ito K, Iitaka K, Koitabashi Y, Yamaoka K, Nakagawa K, Nakamura H, Matsuyama S, Seino Y, Takeda N, Hattori S, Ninomiya M (1999) A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. The Japanese Pediatric IgA Nephropathy Treatment Study Group. J Am Soc Nephrol 10:101–109

    CAS  PubMed  Google Scholar 

  14. 14.

    Kang Z, Li Z, Duan C, Wu T, Xun M, Ding Y, Zhang Y, Zhang L, Yin Y (2015) Mycophenolate mofetil therapy for steroid-resistant IgA nephropathy with the nephrotic syndrome in children. Pediatr Nephrol 30:1121–1129. https://doi.org/10.1007/s00467-014-3041-y

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Hogg RJ, Bay RC, Jennette JC, Sibley R, Kumar S, Fervenza FC, Appel G, Cattran D, Fischer D, Hurley RM, Cerda J, Carter B, Jung B, Hernandez G, Gipson D, Wyatt RJ (2015) Randomized controlled trial of mycophenolate mofetil in children, adolescents, and adults with IgA nephropathy. Am J Kidney Dis 66:783–791. https://doi.org/10.1053/j.ajkd.2015.06.013

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Cambier A, Rabant M, Peuchmaur M, Hertig A, Deschenes G, Couchoud C, Kolko A, Salomon R, Hogan J, Robert T (2018) Immunosuppressive treatment in children with IgA nephropathy and the clinical value of podocytopathic features. Kidney Int Rep 3:916–925

    Article  Google Scholar 

  17. 17.

    Coppo R (2017) Biomarkers and targeted new therapies for IgA nephropathy. Pediatr Nephrol 32:725–731. https://doi.org/10.1007/s00467-016-3390-9

    Article  PubMed  Google Scholar 

  18. 18.

    Cambier A, Gleeson PJ, Monteiro R (2019) New therapeutic perspectives in IgA nephropathy developed in the young. Pediatr Nephrol. https://doi.org/10.1007/s00467-020-04475-w

  19. 19.

    Coppo R (2018) Towards a personalized treatment for IgA nephropathy considering pathology and pathogenesis. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfy338

  20. 20.

    Thompson A, Carroll K, A Inker L, Floege J, Perkovic V, Boyer-Suavet S, W Major R, I Schimpf J, Barratt J, Cattran DC, S Gillespie B, Kausz A, W Mercer A, Reich HN, H Rovin B, West M, Nachman PH (2019) Proteinuria reduction as a surrogate end point in trials of IgA nephropathy. Clin J Am Soc Nephrol 14:469–481. https://doi.org/10.2215/CJN.08600718

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Yamagata K, Takahashi H, Tomida C, Yamagata Y, Koyama A (2002) Prognosis of asymptomatic hematuria and/or proteinuria in men. High prevalence of IgA nephropathy among proteinuric patients found in mass screening. Nephron 91:34–42

    Article  Google Scholar 

  22. 22.

    Coppo R, Gianoglio B, Porcellini MG, Maringhini S (1998) Frequency of renal diseases and clinical indications for renal biopsy in children (report of the Italian National Registry of Renal Biopsies in Children of the Italian Society of Nephrology). Nephrol Dial Transplant 13:293–307

    CAS  Article  Google Scholar 

  23. 23.

    Mizerska-Wasiak M, Turczyn A, Such A, Cichoń-Kawa K, Małdyk J, Miklaszewska M, Pietrzyk J, Rybi-Szumińska A, Wasilewska A, Firszt-Adamczyk A, Stankiewicz R, Szczepańska M, Bieniaś B, Zajączkowska M, Pukajło-Marczyk A, Zwolińska D, Siniewicz-Luzeńczyk K, Tkaczyk M, Gadomska-Prokop K, Grenda R, Demkow U, Pańczyk-Tomaszewska M (2016) IgA nephropathy in children: a multicenter study in Poland. Adv Exp Med Biol 952:75–84

    CAS  Article  Google Scholar 

  24. 24.

    Coppo R, Lofaro D, Camilla RR, Bellur S, Cattran D, Cook HT, Roberts IS, Peruzzi L, Amore A, Emma F, Fuiano L, Berg U, Topaloglu R, Bilginer Y, Gesualdo L, Polci R, Mizerska-Wasiak M, Caliskan Y, Lundberg S, Cancarini G, Geddes C, Wetzels J, Wiecek A, Durlik M, Cusinato S, Rollino C, Maggio M, Praga M, K Smerud H, Tesar V, Maixnerova D, Barratt J, Papalia T, Bonofiglio R, Mazzucco G, Giannakakis C, Soderberg M, Orhan D, Di Palma AM, Maldyk J, Ozluk Y, Sudelin B, Tardanico R, Kipgen D, Steenbergen E, Karkoszka H, Perkowska-Ptasinska A, Ferrario F, Gutierrez E, Honsova E (2017) Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort. Pediatr Nephrol 32:139–150

    Article  Google Scholar 

  25. 25.

    Sevillano AM, Gutiérrez E, Yuste C, Cavero T, Mérida E, Rodríguez P, García A, Morales E, Fernández C, Martínez MA, Moreno JA, Praga M (2017) Remission of hematuria improves renal survival in IgA nephropathy. J Am Soc Nephrol 28:3089–3099. https://doi.org/10.1681/ASN.2017010108

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Coppo R, Fervenza FC (2017) Persistent microscopic hematuria as a risk factor for progression of IgA nephropathy: new floodlight on a nearly forgotten biomarker. J Am Soc Nephrol 28:2831–2834. https://doi.org/10.1681/ASN.2017060639

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D'Agati V, D'Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H (2009) The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 76:534–545

    Article  Google Scholar 

  28. 28.

    Trimarchi H, Barratt J, Cattran DC, Cook HT, Coppo R, Haas M, Liu ZH, Roberts IS, Yuzawa Y, Zhang H, Feehally J, IgAN Classification Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Conference Participants (2017) Oxford classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int 91:1014–1021. https://doi.org/10.1016/j.kint.2017.02.003

    Article  PubMed  Google Scholar 

  29. 29.

    Coppo R, D'Arrigo G, Tripepi G, Russo ML, Roberts ISD, Bellur S, Cattran D, Cook TH, Feehally J, Tesar V, Maixnerova D, Peruzzi L, Amore A, Lundberg S, Di Palma AM, Gesualdo L, Emma F, Rollino C, Praga M, Biancone L, Pani A, Feriozzi S, Polci R, Barratt J, Del Vecchio L, Locatelli F, Pierucci A, Caliskan Y, Perkowska-Ptasinska A, Durlik M, Moggia E, Ballarin JC, Wetzels JFM, Goumenos D, Papasotiriou M, Galesic K, Toric L, Papagianni A, Stangou M, Benozzi L, Cusinato S, Berg U, Topaloglu R, Maggio M, Ots-Rosenberg M, D'Amico M, Geddes C, Balafa O, Quaglia M, Cravero R, Lino Cirami C, Fellstrom B, Floege J, Egido J, Mallamaci F, Zoccali C (2018) Is there long-term value of pathology scoring in immunoglobulin a nephropathy? A validation study of the Oxford classification for IgA nephropathy (VALIGA) update. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfy302

  30. 30.

    Chakera A, MacEwen C, Bellur SS, Chompuk LO, Lunn D, Roberts ISD (2016) Prognostic value of endocapillary hypercellularity in IgA nephropathy patients with no immunosuppression. J Nephrol 29:367–375

    CAS  Article  Google Scholar 

  31. 31.

    Beckwith H, Medjeral-Thomas N, Galliford J, Griffith M, Levy J, Lightstone L, Palmer A, Roufosse C, Pusey C, Cook HT, Cairns T (2017) Mycophenolate mofetil therapy in immunoglobulin a nephropathy: histological changes after treatment. Nephrol Dial Transplant 32:i123–i128

    CAS  Article  Google Scholar 

  32. 32.

    Haas M, Verhave JC, Liu ZH, Alpers CE, Barratt J, Becker JU, Cattran D, Cook HT, Coppo R, Feehally J, Pani A, Perkowska-Ptasinska A, Roberts IS, Soares MF, Trimarchi H, Wang S, Yuzawa Y, Zhang H, Troyanov S, Katafuchi R (2017) A multicenter study of the predictive value of crescents in IgA nephropathy. J Am Soc Nephrol 28:691–701

    CAS  Article  Google Scholar 

  33. 33.

    Hou JH, LeWB CN, Wang WM, Liu ZS, Liu D, Chen JH, Tian J, Fu P, Hu ZX, Zeng CH, Liang SS, Zhou ML, Zhang HT, Liu ZH (2017) Mycophenolate mofetil combined with prednisone versus full-dose prednisone in IgA nephropathy with active proliferative lesions: a randomized controlled trial. Am J Kidney Dis 69:788–795

    CAS  Article  Google Scholar 

  34. 34.

    Shen XH, Liang SS, Chen HM, Le WB, Jiang S, Zeng CH, Zhou ML, Zhang HT, Liu ZH (2015) Reversal of active glomerular lesions after immunosuppressive therapy in patients with IgA nephropathy: a repeat biopsy based observation. J Nephrol 28:441–449

    CAS  Article  Google Scholar 

  35. 35.

    Barbour SJ, Espino-Hernandez G, Reich HN, Coppo R, Roberts IS, Feehally J, Herzenberg AM, Cattran DC, Oxford Derivation, North American Validation and VALIGA Consortia; Oxford Derivation North American Validation and VALIGA Consortia (2016) The MEST score provides earlier risk prediction in IgA nephropathy. Kidney Int 89:167–175

    CAS  Article  Google Scholar 

  36. 36.

    Bellur SS, Lepeytre F, Vorobyeva O, Troyanov S, Cook HT, Roberts IS, International IgA Nephropathy Working Group (2017) Evidence from the Oxford classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy. Kidney Int 91:235–243

    Article  Google Scholar 

  37. 37.

    Edström Halling S, Söderberg MP, Berg UB (2012) Predictors of outcome in paediatric IgA nephropathy with regard to clinical and histopathological variables (Oxford classification). Nephrol Dial Transplant 27:715–722

    Article  Google Scholar 

  38. 38.

    Shima Y, Nakanishi K, Hama T, Mukaiyama H, Togawa H, Hashimura Y, Kaito H, Sako M, Iijima K, Yoshikawa N (2012) Validity of the Oxford classification of IgA nephropathy in children. Pediatr Nephrol 27:783–792

    Article  Google Scholar 

  39. 39.

    Le W, Zeng CH, Liu Z, Liu D, Yang Q, Lin RX, Xia ZK, Fan ZM, Zhu G, Wu Y, Xu H, Zhai Y, Ding Y, Yang X, Liang S, Chen H, Xu F, Huang Q, Shen H, Wang J, Fogo AB, Liu ZH (2012) Validation of the Oxford classification of IgA nephropathy for pediatric patients from China. BMC Nephrol 13:158. https://doi.org/10.1186/1471-2369-13-158

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Shima Y, Nakanishi K, Hama T, Sato M, Mukaiyama H, Togawa H, Tanaka R, Kaito H, Nozu K, Iijima K, Yoshikawa N (2015) Biopsy timing and Oxford classification variables in childhood/adolescent IgA nephropathy. Pediatr Nephrol 30:293–299

    Article  Google Scholar 

  41. 41.

    Chen MG, Ye XH, Liang HY, Yang Q (2016) Clinical and pathological analysis of IgA nephropathy with acute kidney injury. Zhonghua Er Ke Za Zhi 54:610–613. https://doi.org/10.3760/cma.j.issn.0578-1310.2016.08.012

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Barbour SJ, Coppo R, Zhang H, Liu ZH, Suzuki Y, Matsuzaki K, Katafuchi R, Er L, Espino-Hernandez G, Kim SJ, Reich HN, Feehally J, Cattran DC, International IgA Nephropathy Network (2019) Evaluating a new international risk-prediction tool in IgA nephropathy. JAMA Intern Med 179:942–952. https://doi.org/10.1001/jamainternmed.2019.0600

    Article  PubMed  PubMed Central  Google Scholar 

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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

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Keywords

  • IgA nephropathy in children
  • Treatment
  • KDIGO
  • Risk factors
  • MEST-C score
  • Prediction models