Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALidation of IGA study cohort.

BACKGROUND: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. RESULTS: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). CONCLUSION: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

Predictors of outcome in paediatric IgA nephropathy with regard to clinical and histopathological variables (Oxford classification).

BACKGROUND: There has been a lack of international consensus on the classification and the predictive value of the histopathology findings in IgA nephropathy (IgAN). Recently, the International IgA Nephropathy Network has developed the Oxford classification in which four histological variables with the most prognostic importance are identified (MEST score). Our objective was to validate these findings and to assess their predictive power in our cohort and to compare them to identified clinical predictors. METHODS: Ninety-nine children with a follow-up time >5 years were included and investigated with clearances of inulin or iohexol for glomerular filtration rate (GFR), proteinuria and blood pressure at biopsy and during follow-up. Biopsies (90/99) were re-evaluated and scored according to the Oxford classification. RESULTS: Eighteen patients progressed to a poor outcome [end-stage renal disease (ESRD) or GFR reduction >50%]. In the univariate analysis, we found that mesangial hypercellullarity score >0.5, presence of endocapillary hypercellularity or tubular atrophy/interstitial fibrosis of >25% were each associated with a poor outcome, and also presence of cellular or fibrocellular crescents and of global glomerulosclerosis, but segmental glomerulosclerosis did not reach statistical significance. The clinical predictors of a poor outcome were a low GFR, a high mean arterial blood pressure and a high amount of albuminuria (log Ualb/c) at time of biopsy and low GFR and a high log Ualb/c during follow-up. CONCLUSION: We found that three of the four histology lesions identified in the Oxford classification, as well as presence of crescents, were valid in predicting a poor outcome in our cohort of patients.

Predictors of outcome in Henoch-Schönlein nephritis.

Factors predictive of renal outcome were studied in 78 children with Henoch-Schönlein nephritis followed up for as long as 17 (mean 5.2) years. Patients with a good outcome (74%) were healthy or had microalbuminuria or mild proteinuria at the final follow-up (FU), and those with poor outcome (26%) had active renal disease or chronic kidney disease at stages IV-V. Patients with mild symptoms at onset (hematuria + or - mild proteinuria) had a poor outcome in 15% of cases versus 41% of those with severe symptoms (nephritic or nephrotic syndrome or nephritic-nephrotic picture) (p = 0.011). However, among patients with mild proteinuria at onset, 18% showed a poor prognosis; non-nephrotic proteinuria with a urine albumin/creatinine ratio at a cut-off value of >144 mg/mmol at the 1-year FU was predictive of a poor outcome. Among 59 biopsied patients, 37% of those with advanced histological findings [International Study of Kidney Disease in Children (ISKDC) stages III-V] had a poor outcome compared to none of those with mild findings (ISKDC stages I-II) (p = 0.0015). Patients with a poor outcome were older at onset, had more proteinuria, and lower glomerular filtration rate at the 1-year FU compared with patients with a good outcome. Multivariate analysis showed that proteinuria at the 1-year FU and the ISKDC grading score of the renal biopsy were the two most discriminant factors of a poor prognosis.

Treatment of severe Henoch-Schönlein and immunoglobulin A nephritis. A single center experience.

Our aim was to report the effect of two treatment regimens in 43 cases of severe Henoch-Schönlein nephritis (HSN) and immunoglobulin A nephritis (IgAN) (24 HSN, 19 IgAN). Group A, 11 HSN and 7 IgAN, 88% with an International Study of Kidney Disease in Children (ISKDC) biopsy grade > or = III and severe clinical features, were treated with corticosteroids, cyclophosphamide (CYC-P) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB). Group B, 12 HSN and 13 IgAN, 72% with biopsy findings as above and 52% with severe clinical features, were treated with ACEi/ARB +/- corticosteroids. The outcome classification was: (a) healthy; (b) mild proteinuria, normal glomerular filtration rate (GFR); (c) active renal disease; (d) chronic renal failure. Twenty-six patients had a good outcome (a + b). The 17 children with poor outcome (c + d) had lower GFR at onset and at follow-up, higher albumin excretion at follow-up, and higher percentage of segmental glomerulosclerosis in the renal biopsy, than those with good outcome. Treatment with corticosteroids, CYC-P and ACEi/ARB was effective in increasing GFR, reducing proteinuria and decreasing the disease activity index. The proteinuria had decreased at follow-up in both groups. In group A, GFR increased and histopathological activity index declined after treatment. The outcome did not differ between groups A and B. The effects of treatment did not differ between HSN and IgAN.

Henoch Schönlein nephritis: clinical findings related to renal function and morphology.

We evaluated the renal hemodynamics and the urine protein excretion rates of 73 children with Henoch-Schonlein nephritis (HSN). In 40 children we also performed a renal biopsy. The glomerular filtration rate (GFR) and effective renal plasma flow were determined by the clearances of inulin and para-aminohippurate during water diuresis. Urine albumin and IgG excretion were assessed in short-term timed samples. The mean GFR at the first examination was reduced in the HSN patients and most reduced in those with nephrotic proteinuria. There was an inverse correlation between the GFR at the first examination and the amount of albuminuria and urinary IgG excretion. Among the 40 patients with some degree of proteinuria who underwent a renal biopsy, 9 of 13 patients with mild to moderate proteinuria had severe morphological changes. GFR correlated inversely and fractional albumin and IgG excretion directly with the severity of the pathological findings on the biopsy, and with segmental and global sclerosis, the grade of mesangial proliferation, and interstitial inflammation. In conclusion, GFR is moderately reduced early in HSN and more reduced in patients with more proteinuria and in those with more advanced morphological changes. Moreover, even mild to moderate proteinuria may indicate severe morphological changes, which increase the indications for early renal biopsy in these patients.