The longer the better: follow-up in seemingly ‘benign’ immunoglobulin A nephropathy Free

IgA nephropathy (IgAN), the most common primary glomerulonephritis in Caucasian and Asian patients, can have a highly variable course ranging from minor urinary abnormalities to rapidly progressive kidney failure. Cases coming to medical attention probably represent the tip of an iceberg, as up to 1.5% of European and Asian populations may have asymptomatic IgAN [1–3]. Thus IgAN is easily missed in countries without urinary screening programmes in children and young adults and given the frequent reservation to perform a kidney biopsy in a patient with isolated microhaematuria, little proteinuria, normotension and normal glomerular filtration rate (GFR). If biopsies are performed in these latter patients, the diagnosis is IgAN in 14–40% if there is no evidence of a urologic pathology [4–7]. In such IgAN patients, the prognosis is generally believed to be excellent and, in fact, up to a third of the patients will experience a spontaneous complete remission of the disease over the next 5–10 years [8–11]. The large majority of non-remitting patients will maintain good renal function and over a 10-year follow-up <5% of patients will have progressive disease (i.e. proteinuria increasing beyond 1 g/day and/or GFR decreasing) [9, 12]. So far, no reliable clinical predictors prospectively identify these few progressive patients. Thus there is currently wide consensus, backed by guidelines [13], to just periodically monitor these patients.

Against the above background, Knoop et al. [11] used a national kidney biopsy registry to identify 145 Norwegian patients with mild IgAN, defined as a median proteinuria of 0.3 g/day (interquartile range 0–0.5), normotension and normal GFR. Of these, 84% of the biopsies were re-examined using the Oxford [mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis (MEST)] criteria [14] and this confirmed mild disease with mostly absent tubulointerstitial damage. The unique feature of this study is a median follow-up of 22 years, which is more than twice as long as in most previous studies on this topic [15–20]. After this long-term follow-up ∼15% of the patients exhibited chronic kidney disease (CKD) Stage 3b (GFR <45 mL/min) or higher and 3% of the patients had progressed to end-stage renal disease (Figure 1). From a large array of clinical and histologic parameters, once again essentially none carried a significant predictive value that would have allowed us to prospectively identify the patients who progressed. Only albuminuria at any time point of follow-up was correlated with a more rapid decline of estimated GFR (eGFR; most pronounced in patients with >100 mg albumin/mmol creatinine, whose annual decline in eGFR was almost 7-fold higher compared with patients with normal urinary albumin).

FIGURE 1

Outcome of so-called benign IgAN with 20–25 years of follow-up based on the study of Knoop et al. [11].

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The inability of Oxford-MEST criteria [14] to reliably identify patients at risk for progression is consistent with earlier data [9, 21] and not surprising given that studies leading to the classification specifically excluded such mild IgAN cases. In contrast, many criteria identified as prognostically important in the Oxford-MEST classification might have become weak or no predictors, had such mild cases been included. This consideration also applies to crescents. Although not specifically addressed in the study of Knoop et al. [11], individual crescents have been described in biopsies of ∼25% of mild IgAN cases [22]. Their occurrence in such a seemingly benign situation appears plausible, given that IgAN is characterized by glomerular bleeding leading to microhaematuria. Once again, the development of crescents in a relatively benign setting would likely dampen the impact of crescents in the context of Oxford-MEST criteria, where a recent study suggested that crescents should be added as a fifth prognostic criterion [23]. Unfortunately, these individual crescents sometimes trigger unnecessary immunosuppression and they clearly should not be confused with the clinical situation of rapidly progressive, ‘vasculitic’ IgAN, in which crescents and necroses affect the majority of glomeruli [24].

The study of Knoop et al. [11] has the potential to become a landmark study in this area, in that it provides considerable new insights. In patients with mild IgAN, currently considered to exhibit a good prognosis, the long-term outcome can no longer be considered benign if almost 15% of patients progressed to an eGFR <45 mL/min. Even though there was no definitive evidence that all of these cases resulted from progression of IgAN and no other pathology, this clearly makes these patients a high-risk group for CKD. Another reason to label such patients with mild, early IgAN as a high-risk group is the observation that almost 40% of all female patients experienced pre-eclampsia in at least one pregnancy [11]. Knoop et al.’s study [11] is entirely consistent with ‘short-term’ follow-up studies of up to 10 years [19], since Knoop et al. found that the bulk of eGFR loss occurred after the first 10 years of follow-up (with risk increasing from 2.1% at 10 years to 18.4% after 25 years). Next and probably worst, progressors cannot be identified at baseline with current standard risk parameters, suggesting that all such patients need to be monitored periodically over many years for increases in albuminuria. Another consequence is that clinical trials in early IgAN appear almost impossible if a third of the patients spontaneously remit and another hard-to-identify 15% need ≥ 20 years to progress. This also nicely illustrates why a 5-year trial of ramipril in early IgAN had no chance to yield conclusive results [25]. Despite this latter inconclusive trial, we believe it nevertheless seems to make a lot of sense to impose a comprehensive supportive care approach even in such ‘benign’ patients [26].

So what are the essential clinical implications of Knoop et al.’s study [11]. First, in younger adults with haematuria not otherwise explained, we agree with Knoop et al. that a more liberal renal biopsy policy may be justified since a definitive biopsy diagnosis of IgAN has important long-term consequences. No histology in most cases equals no specialist care follow-up (see below). Second, mechanisms such as automated reminder systems need to be in place to ensure very-long-term periodic monitoring of such patients. Even in Norway with a very good health care system, 51% of patients stated that they did not have any regular follow-up, 27% visited their primary care physician and only 22% saw a nephrologist regularly [11]. Third, follow-up should be in the hands of nephrologists. Figure 3 of Knoop et al. [11] shows that this was the case in the majority of progressive IgAN patients, in particular those with higher levels of proteinuria. However, a significant percentage was either not seen at all or under the care of non-nephrologists.

CONFLICT OF INTEREST STATEMENT

None declared.

(See related article by Knoop et al. Long-term outcome in 145 patients with assumed benign immunoglobulin A nephropathy. Nephrol Dial Transplant 2017; 32: 1841–1850)

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