Long-term prognosis of clinically early IgA nephropathy is not always favorable

IgA nephropathy (IgAN) is a common glomerular disease and an important cause of kidney failure. This disease accounts for more than half of all forms of primary glomerulonephritis in Korea [1]. Although dominant mesangial IgA deposits represent the diagnostic hallmark of IgAN, its clinical features are highly variable, ranging from simple hematuria with or without proteinuria to a rapidly progressive loss of renal function. Therefore, the renal survival and risk factors of long-term IgAN patients have been studied extensively over the last 30 years [2]. Previous studies indicate that the likelihood of dialysis or death can be estimated using three clinical risk factors: urinary protein excretion of more than 1 g/day, high blood pressure exceeding 140/90 mmHg, and a decreased estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² [3]. Among patients with all three risk factors, about 70–80% reached end-stage renal disease (ESRD) and 45% died within 30 years [4, 5]. These clinical prognostic factors also independently predict a poor clinical course. However, information on the long-term outcomes of IgAN patients with a minor presentation is scarce.

Only a few studies have focused on long-term patient and renal outcomes in IgAN patients who had a renal biopsy performed for microscopic hematuria, normal renal function, and minimal proteinuria. Moreover, the results of previous studies are controversial. A recently published European cohort study found that IgAN patients who presented with minor urinary abnormalities and normal renal function did not progress to ESRD, and that more than one-third of patients achieved clinical remission [6]. Research performed in Hong Kong, however, found that 33% of patients with minimal proteinuria and preserved renal function developed more than 1 g/day of proteinuria [7, 8]. In a cohort of Chinese IgAN patients with isolated microscopic hematuria who were followed for up to 12 years, a decrease in renal function was observed in 24% [9]. These studies suggest that IgAN patients require long-term follow-up due to the potential for progressive disease.

Our previously, reported findings on the mortality of IgAN patients, which were obtained from our long-term follow-up data [4], did not significantly differ from European data [10]. The present study focused on long-term outcomes and prognostic factors for renal survival in clinically early IgAN patients. We hypothesized that even patients presenting with benign manifestations would progress during long-term follow-up.

The clinical course of IgAN is highly variable. However, it is essential to determine whether a patient is at high risk for renal insufficiency in order to establish an individualized management plan. Forecasting the prognosis of benign IgAN on the basis of the currently known prognostic factors or modeling systems is challenging. Experience gathered over a sufficient observation period is essential to address these patients’ renal survival. Based on our long follow-up period, we demonstrated that even clinically early IgAN patients can show a progressive disease trajectory in Korea. More than moderate degree of IF and hypoalbuminemia were independent predictors of renal progression. This study is uniquely placed to clarify the prognosis of clinically early IgAN.

Our results are similar to those of previous Chinese and Japanese studies [8, 9, 16, 17], and are contrary to those of a recent European study [6] (Table 5). In particular, our results evoke awareness of the fact that, even with a clearly benign initial presentation, IgAN patients can have a malignant renal or patient outcome. In this cohort, one in every 25 early IgAN patients progressed to ESRD during their lifetimes. Such an observation has not been reported previously. Considering that baseline characteristics among previous studies were similar, the cause of the varying prognosis of clinically early IgAN requires investigation. One possible explanation is the difference in the definition of outcomes. In the Chinese studies, renal progression was defined only in terms of worsening and not in relation to initial renal function [8, 9]. Conversely, the European study defined renal progression as an increase in serum creatinine levels of ≥50% from initial levels or ESRD progression. However, our study separated ESRD progression and impaired renal function, and our definition of impaired renal function was derived from the European study. Our data indicate that the prognosis of early IgAN patients is relatively worse than that of similar European IgAN patients even when a comparable outcome definition is applied.

The divergence in findings may also be explained by racial differences. Recent publications suggest that an Asian racial origin could be identified as a risk for disease progression in IgAN [18, 19]. Despite the fact that our study and the European study enrolled early IgAN patients with similar baseline renal function and proteinuria levels and used similar outcome definitions, renal prognosis in our cohort was considerably different from that observed in the European cohort. To clarify the influence of ethnicity on these observations, a delicate genetic analysis with consideration of phenotype should be performed.

Lead-time bias may also explain the different outcomes in early IgAN. Because of variations in biopsy practices, the disease is detected at different times in its natural course. Even among early IgAN patients with similar initial presentations, the duration of disease could be different. Some patients visit the clinic immediately after gross hematuria or incidentally detected hematuria, while others visit several years after the initial manifestation. However, clinicians can only conduct assessments at the time of initial visit or biopsy. Therefore, a comparison of these patients using only initial data could be limited by lead-time bias.

Our data also showed that pathological changes including IF can be important for renal risk prediction in clinically early IgAN patients. More than 12% of patients showed a more than moderate degree of tubulo-interstitial changes. Furthermore, IF is an independent predictor of ESRD progression in this study. Such results are consistent with some previous studies [9, 20, 21] and inconsistent with another study [6]. Although IgAN is a glomerular disease, tubulo-interstitial injury via the mesangio-podocytic-tubular crosstalk plays an important role in mediating renal fibrosis and, ultimately resulting in, renal failure [22]. In our study, mesangial hypercellularity or interstitial inflammation was not associated with renal progression. Those are considered relatively early renal injury markers, whereas IF is regarded as relatively advanced marker in IgAN patients with minor abnormalities. Indeed, IF is one component of the Oxford classification, although it is validated mostly in patients with proteinuria of more than 1 g/day [23, 24]. Our study results support the applicability of the Oxford classification even in IgAN patients with a minimal clinical presentation.

We further demonstrated that hypoalbuminemia is a significant predictor of renal outcome. These finding is consistent with those in previous IgAN studies [4, 25] as well as those in other CKD studies [26, 27]. Lower serum albumin levels can be explained by the amount of proteinuria, nutritional status or combined inflammation. In our cohort, 7 patients showed reduced serum albumin levels. Their proteinuria amount was ranged between 0.16 and 0.45 g/day. Three patients had combined inflammation, and one patient suffered from tuberculosis and was subsequently malnourished. In other words, hypoalbuminemia may contribute to a poor renal outcome, independently from proteinuria.

The particular strengths and insights gained from this investigation include the long follow-up duration and large sample size, which is specifically important in IgAN research because of the insidious course of this disease. We were able to assess hard outcomes such as ESRD progression and mortality in this study. Moreover, we were able to suggest racial differences in IgAN prognosis by using baseline characteristics and outcome definitions similar to those used in the prior European study. We were also able to alarm many nephrologists and primary physicians who have managed clinically early IgAN patients with ease, especially in Korea.

However, several shortcomings remain to be resolved. First, the number of outcomes observed in our cohort was too small despite the long follow-up duration. Lack of events hampered our ability to perform robust multivariate predictive modeling. Second, this is a single-center, retrospective study, and therefore, we could not take into account diverse management strategies according to individual clinicians. Although hard outcome data were collected by both medical record review and from a national registry or statistics, the last clinical status remains unknown in some cases. Third, we could not use the Oxford classification in this study. However, we were able to measure each component of the Oxford classification semi-quantitatively, as shown in Table 1. Lastly, we could not clarify the precise reason for progression to ESRD among patients with initially benign clinical presentations. We proposed different outcome definitions, lead-time bias, and ethnicity as potential explanations. However, we could not prove these, and further sequential investigation is therefore warranted.

In this study, we demonstrated that clinically early IgAN does not always show a favorable outcome and may even progress to ESRD. Patients with IF and hypoalbuminemia should be more aggressively monitored, especially in Korea.