Persistent Microscopic Hematuria as a Risk Factor for Progression of IgA Nephropathy: New Floodlight on a Nearly Forgotten Biomarker

“The examination of the urine is the most essential part of the physical examination of any patient.” Thomas Addis

Hematuria is the most typical presentation of IgA nephropathy (IgAN). A young person in apparently good health who develops episodes of gross hematuria after a respiratory tract infection would beget a clinically well founded suspicion of IgAN.¹ A finding of persistent microscopic hematuria is not specific for IgAN, but IgAN accounts for half of the glomerular diseases detected by renal biopsies performed after microscopic hematuria is detected through urinary screening programs.² In patients with IgAN, microscopic hematuria is found in 70%–100% of cases, particularly in children and young adults in the early phases of their clinical course. Hence, hematuria is an undisputable biomarker of IgAN, although with insufficient specificity. Hematuria in IgAN is of glomerular origin, as demonstrated by the detection of dysmorphic red blood cells in the urinary sediment. This glomerular “bleeding” is postulated to result from glomerular capillary wall damage sustained by IgA immune complex deposition and thus is a reflection of glomerular inflammation. In the context of the clinical data, the above-mentioned pathophysiologic hypothesis is so conceivable that a clear relationship between hematuria and activity of IgAN should be expected. However, no biomarker has been more debated and despised, abandoned for decades by many clinicians.

In the 1980s, a great debate arose between two giants of IgAN, Giuseppe D’Amico and Priscilla Kincaid-Smith. D’Amico was impressed by the favorable outcomes of young subjects with recurrent macroscopic hematuria after repeated episodes of respiratory tract infection, with normal or minor changes of urinary sediment in between. He strongly supported the concept that hematuria was a benign feature, indicating a favorable prognosis.³ From an opposing perspective, Kincaid-Smith reported the negative association of heavy and persistent microscopic hematuria on clinical outcomes,⁴ particularly in rapidly progressive cases.⁵ A reconciliation of these two positions considered that patients with persistence of heavy microscopic hematuria between episodes of recurrent gross hematuria are clinically distinct, and carry a different risk of progression when compared with those with a “clean” urinary sediment inbetween.⁶ It was also recognized that macroscopic hematuria is most frequently seen in patients presenting at early stages of the disease, whereas it is less common in patients diagnosed later on the disease process. However, the literature reported discouragingly conflicting data about the relationship between microscopic hematuria in IgAN and outcomes,^7–9 but the quality of the studies was poor and made on the basis of analysis of one or a few urinary sediments at the time of renal biopsy, without follow-up data. Small studies from selected centers with particular expertise in the time-consuming task of accurate sediment analysis, reported that microscopic hematuria was a risk factor for progression.⁷ Still, this was refuted by other investigators, particularly from centers with large multidisciplinary hospitals and multicenter collaborations. Pooling data from different laboratories suffered from the interobserver variability inherent in fresh urine sediment analysis, whereas 24-hour urine collection for red blood cell count was troublesome, expensive, and affected by typical collection errors, and therefore was not satisfactory. For these reasons, standardized measurement of proteinuria (particularly when corrected for urinary creatinine) was widely adopted as the most relevant and reliable urinary biomarker, particularly for multicenter studies such as the European Validation Study of the Oxford Classification of IgAN Study.¹⁰

In this issue of the Journal of the American Society of Nephrology (JASN), Sevillano et al.¹¹ report the value of the degree of microscopic hematuria in a single-center cohort of 112 patients with IgAN followed for a mean of 14 years. Time-averaged hematuria (TA-hematuria) was calculated as an average of the mean of microscopic hematuria values (number of red blood cells per high power microscopic field) at every 6 months during the follow-up and was performed in the same laboratory. Patients with persistently high TA-hematuria during the follow-up had significantly greater decline in renal function compared with those with no or minimal TA-hematuria (30% versus 10.6% reaching ESRD and 37% versus 15.2% with 50% reduction in eGFR, P<0.01). Multivariate analysis demonstrated that TA-hematuria was an independent predictor of outcome, as were time-averaged proteinuria (TA-proteinuria; calculated as the average of mean proteinuria measurements at every 6-month period), baseline eGFR, and degree of interstitial fibrosis. Disappearance of hematuria was associated with a significantly lower decline in renal function (from −6.45 to −0.18 ml/min per 1.73 m² per year; P=0.001). Interestingly, when patients with TA-proteinuria >0.75 g/d (which represented a threshold risk for progression) were subcategorized according to the persistence or disappearance of microscopic hematuria, those with persistent hematuria (more than five red blood cells per high power field) had a significantly worse outcome. Hence, TA-hematuria is proposed to enhance the predictive value of TA-proteinuria. Patients with microscopic hematuria more frequently had active mesangial lesions with proliferative changes on kidney biopsy. In patients who received immunosuppressive treatment, TA-hematuria decreased significantly (P=0.001). Sevillano et al.¹¹ concluded that persistence and magnitude of hematuria during follow-up is a significant biomarker for IgAN progression, and correlations with mesangial proliferation along with benefit of immunosuppression are suggested.

The authors did not evaluate the presence and the extent of crescents, which have been recently found to be independent predictors of outcome and rescued in the new classification of IgAN.¹² Kincaid-Smith published in 1985 that “persistently high microhematuria indicates a continuing activity in the form of focal and segmental crescents.”¹³ The independent or associated value of microscopic hematuria and crescents in IgAN progression deserves further investigation. In addition, complement activation is considered a potential mediator of uncontrolled chronic inflammation and sclerotic damage. Indeed, there is a strong association between C4d deposits and progression of IgAN in both adults and children.^14,15 It would be of interest to investigate the correlation between persistence of microscopic hematuria and C4d deposits in IgAN because the two processes might be interdependent.

At any rate, the study confirms what nephrologists involved in taking care of patients with IgAN have long suspected: that patients with IgAN with proteinuria but no hematuria are not the same as those with proteinuria and hematuria together, and this association portends a worse outcome.

Hematuria has been largely neglected in nephrology and was often considered benign other than in disorders with rapidly progressive courses, such as antiglomerular basement membrane disease or renal vasculitides. Persistent isolated microscopic hematuria is considered a typical but benign finding of thin membrane nephropathy (TBMN), in which collagen abnormalities of the glomerular basement membrane confer some fragility responsible for microhematuria not related to the progression of the disease,¹⁶ although this view may be changing.

On the other hand, persistent glomerular hematuria was associated with CKD progression in kidney donors.¹⁷ Also, persistent isolated microscopic hematuria significantly increased the risk for developing ESRD in a study including 1 million young Israeli adults followed for over 20 years.¹⁸ Of note, 15% of the patients with isolated hematuria who developed ESRD had IgAN. In IgAN, the pathologic process leading to hematuria results from chronic inflammation elicited by IgA immune complexes deposition, mesangial activation, and inflammatory cell infiltration and mediator release. This process may ultimately produce the capillary wall lesions that allow red blood cell extravasation, and thus clinically evident hematuria.¹⁹ Twenty five years ago, Nath was the first to suggest that hematuria contributes to progressive CKD by virtue of the following: (1) glomerular disease leads to the appearance of red blood cells in the urinary space, which are phagocytosed by renal tubules with intratubular release of hemoglobin; (2) injection of red blood cells into proximal tubules in rodents causes tubular red blood cell uptake, intratubular hemoglobin accumulation, and tubulo-interstitial disease; and (3) hemoglobin promotes iron-dependent oxidant cellular damage.²⁰ Although the true incidence of AKI occurring during episodes of macroscopic hematuria in IgAN is unknown, GFR does not return to baseline after resolution of the AKI episode in up to 25% of affected patients.¹⁶

The article published in this issue of JASN¹¹ provides new evidence that persistent microscopic hematuria is a risk factor for progression of IgAN, and underscores its importance in the presence of persistent proteinuria. The damage induced by hematuria does not appear to be unique to IgAN, as recently reported by the same investigators who found hematuria to be closely associated with more rapid decline in eGFR in a variety of proteinuria disorders other than IgAN, especially in younger patients.²¹ Although persistent proteinuria can reflect active capillary and podocyte lesions, it can also be due to hyperfiltration in chronic, irreversible cases. In IgAN, proteinuria by itself cannot discriminate between active inflammation versus chronic damage. The recognition that persistent hematuria AND proteinuria reflects active inflammatory disease is important because future clinical trials testing the effects of immunosuppressive regimens should target patients with both hematuria and proteinuria, and exclude IgAN patients without persistent hematuria. These studies will also need to demonstrate that reduction or disappearance of hematuria is associated with better outcomes. Examination of urinary sediment may be a valuable tool, but it is time consuming, and not all nephrologists today are taught to adequately examine the urinary sediment. New and more sensitive methods for quantifying hematuria and reliably measuring hemoglobin in urine may, in the near future, help to place persistent hematuria in the proper perspective. At a time when significant time and money has been expended searching for novel and “fancy” biomarkers, we can say that, at least for IgAN, there is one: the old, cheap, and nearly forgotten hematuria.

Disclosures

None.