Validation of the absolute renal risk of dialysis/death in adults with IgA nephropathy secondary to Henoch-Schönlein purpura: a monocentric cohort study

In IgA nephropathy (IgAN), one difficulty is to predict accurately at time of diagnosis (by renal biopsy) the ultimate prognosis one or two decades later of the individual patient with the probability risk of reaching end-stage renal failure with the need for dialysis or to die before this event.

In primary IgAN, many risk factors predictive of progression have been described [1, 2] and in a previous work [3], we focused on the following three consensual and major risk factors: occurrence of arterial hypertension (HT), amount of daily proteinuria, and severe renal lesions on optical microscopy (appreciated by local pathological scoring [4, 5] or by the new Oxford classification [6]). These risk factors were simplified and dichotomized, before integration in an Absolute Renal Risk (ARR) score, which proved to be an overall accurate predictor of ultimate prognosis. These simplified risk factors, present or not at time of diagnosis, were:-HT (Yes or No); daily proteinuria ≥ 1 g/day (Yes or No);-and a global optical score, GOS ≥ 8 (Yes or No). We have previously defined the ARR score as the number of these risk factors present at diagnosis with four possibilities: 0, 1, 2, and 3. This ARR permitted us in a prospective study [3], including 332 patients with primary IgAN, to predict the cumulative incidence rate at 20 years post clinical onset of the combined final event, dialysis or death: 4% for ARR = 0; 9% for ARR = 1; 18% for ARR = 2; and 64% for ARR = 3. These findings were also validated in a retrospective historical cohort including 250 patients [3].

IgA nephropathies, defined as at least 1+ mesangial IgA deposits by immunofluorescence, are clinically divided in two groups:-primary IgAN, also called Berger’s disease which represent 90% of the cases, and-secondary IgAN observed in different clinical conditions: Henoch-Schönlein Purpura, HSP, alcoholic liver cirrhosis, some cases of Systemic Lupus Erythematosus, SLE, and few other rare conditions.

The goal of this retrospective observational study was to review all our cases of secondary IgAN and to apply our ARR score for an additional validation in another group of patients, and we focused on IGAN 2ary to HSP, which represented the majority of the cases.

The strict application of our ARR score to a moderate-size cohort of adult IgAN secondary to HSP demonstrated that the ARR score was able to predict at time of evaluation (diagnosis) the ultimate prognosis 10 and 20 years post-onset with a good stratification from ARR = 0 to ARR = 3. In this regard, our ARR scoring developed originally in a large prospective cohort of primary IgAN [3] (N = 332) was validated in this external cohort (but from the same group) after being validated in an internal retrospective cohort of 250 cases of primary IgAN. Recently a Norvegian group confirmed the validity of our Absolute Renal Risk in 633 primary IgAN patients and can serve as an external validation of our predictive model (Knoop T, Vikse BE, Svarstad E et al.; unpublished data).

The present study has some limitations:-the relative small size population should be balanced by the fact that HSP-nephritis represents at most 10% of all IgA nephropathies;-it is clearly a retrospective study but with prospective and homogenous collection of data in the patients chart similar to our prospective cohort of primary IgAN;-and this monocentric study warrants more homogeneity in the diagnosis and management of the patients than a multicentric study, which however will have permitted to include more patients.

The question of including a marker of renal function in our model was already discussed in our original paper [3]:-we thought that it was not appropriate to use the same item such as GFR both as risk factor and as primary end-point (dialysis with GFR in stage V);-nevertheless, eGFR staging (1 to 5) at diagnosis was tested but substituted to HT and proteinuria ≥1 g/d in the subgroup of patients with already chronic renal failure, CRF (eGFR < 60 ml/mn/1.73). In this small cohort, we found no significant impact of CRF tested as additional dichotomous covariate (yes or no) together with either ARR (0 to 3) or with the 3 covariates (HT, proteinuria ≥ 1 g/d, and GOS ≥ 8); see Additional file 1: Table S1.

It is remarkable to notice the similarities between this HSP cohort and our prospective cohort of primary IgA nephropathy, IGAN-STET-CO: -The distribution of the three major risk factors was very similar: respectively for HSP and IGAN-STET-CO, 39% versus 36% for HT present at diagnosis; 43% versus 30% for proteinuria ≥ 1 g/d at diagnosis; and 40% versus 36% for GOS ≥8 (the mean GOS values were also very closed: 7.17 versus 7.00); -The values of eGFR at diagnosis and at last FU were also very closed with similar staging distribution: 23% versus 26% of patients in CKD-3+; but finally at last follow-up, we have observed D/D events in 26% of HSP-IgAN patients versus 14% in primary IgAN patients; -In the Cox analyses," the respective weight of each risk factor was difficult to appreciate totally in this paper because of the limited number of patients in this HSP cohort; the β/SE ratios for each dichotomous factor was in the following order: greater for the absence of GOS ≥ 8, then absence of proteinuria ≥1 g/d and last absence of HT. From the difference in the number of final D/D events between HSP-IgAN and primary IgAN, we could not derived any conclusion because one cohort was retrospective and the other prospective; in addition, patients with HSP-IgAN received less and later therapy with ACEI or ARBs which could have decreased survival without D/D.

Many clinical studies concerning HSP nephritis in adults have been published [7‐11]; few focused on long-term prognosis with characterization of risk factors [12‐16]; and others on comparisons between adults and children [17‐21]. The long-term prognosis of HSP nephritis was found worse in adults than in children/adolescent. The main clinical risk factors were also proteinuria over 1 g/d and hypertension. Just recently, an observational study [22] demonstrated that the final prognosis in adults was similar in HSP-IgAN and in primary IgAN, when fully matched by propensity score method (but HT was included as a comorbid condition in the matching and not as an individual risk factor for progression).

Concerning renal pathology, the most predictive optical glomerular lesions for end-stage renal failure were the presence of crescents and endocapillary hypercellularity. To our knowledge, there has been no specific use of Oxford classification in SHP-IgAN for potential validation, but a recent study in primary IgA nephropathy confirmed that the % of crescents was a poor prognosis marker and should be included in the revised Oxford classification [23] for primary IgAN. We have new information [24] (plus Berthoux F et al., unpublished data) in a subgroup of 151 patients with primary IgAN concerning the equivalence between our Local classification (GOS) and the International/Oxford classification (MEST):-the linear correlation is excellent (R = 0.79; P < 0.0001) with the formula “MEST = (+0.256*GOS)-0.725 “;-the respective range is 0 to 20 for GOS and 0 to 5 for MEST;-MEST ≥2 correspond to GOS ≥8;-and the respective power of MEST and GOS in predicting dialysis is similar in multivariate Cox and multivariate logistic regressions analyses with continuous or dichotomous covariates.

It should be mentioned that the % of crescents was integrated in the glomerular index of our local classification with final higher GOS values. By monovariate Cox regression for prediction of dialysis alone, the variable “% of crescents” had a significant effect (p > 0.0001).

The similarities between primary IgAN and HSP-IgAN have been stressed since a long time, but recently the common pathogenesis was demonstrated [25, 26] with data on the autoantigen, galactose-deficient IgA1, and specific autoantibodies (IgG and IgA subclasses); a common genetic background for this galactose-deficient IgA1 was also described [27].

It is out of our scope to review the treatment of HSP-IgAN [28] but obviously the treatment should target the risk factors when present: adequate control of hypertension with blood pressure below 130/80; reduction of proteinuria with ACE inhibitors and ARB’s; steroid treatment for severe renal lesions eventually associated to immunosuppressive agents.

In our study, the use of ACEI and/or ARBs was limited: overall respectively 63% and 58% of all patients with HT at anytime (31/49) and proteinuria ≥1 g/d at anytime (21/36) received such treatment; however in the subgroup of patients diagnosed since 1990 (N = 49), this % rose to 74 and 68% respectively. Nevertheless, survival without dialysis/death was strictly similar in the two subgroups: <1990 versus ≥1990.

In a retrospective cohort of 74 adult patients with IgA nephropathy secondary to Henoch-Schönlein Purpura, we have validated the Absolute Renal Risk concept in the prediction at time of diagnosis of future outcome (dialysis/death or dialysis alone).