EDITORIAL www.jasn.org

Persistent Microscopic episodes of respiratory tract infection, with normal or minor changes of urinary sediment in between. He strongly supported as a Risk Factor for the concept that hematuria was a benign feature, indicating a favorable prognosis.3 From an opposing perspective, Kincaid- Progression of IgA Nephropathy: Smith reported the negative association of heavy and persistent New Floodlight on a Nearly microscopic hematuria on clinical outcomes,4 particularly in rapidly progressive cases.5 A reconciliation of these two positions Forgotten Biomarker considered that patients with persistence of heavy microscopic hematuria between episodes of recurrent gross hematuria are † Rosanna Coppo* and Fernando C. Fervenza clinically distinct, and carry a different risk of progression when *Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, “ ” † compared with those with a clean urinary sediment inbe- Italy; and Division of and , Mayo Clinic, 6 Rochester, Minnesota tween. It was also recognized that macroscopic hematuria is most frequently seen in patients presenting at early stages of J Am Soc Nephrol 28: ccc–ccc, 2017. the disease, whereas it is less common in patients diagnosed later doi: https://doi.org/10.1681/ASN.2017060639 on the disease process. However, the literature reported discour- agingly conflicting data about the relationship between micro- 7–9 “The examination of the urine is the most essential part of the scopic hematuria in IgAN and outcomes, but the quality of physical examination of any patient.” Thomas Addis 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 fol- Hematuria is the most typical presentation of IgA nephro- low-up data. Small studies from selected centers with particular pathy (IgAN). A young person in apparently good health who expertise in the time-consuming task of accurate sediment anal- develops episodes of gross hematuria after a respiratory tract ysis, reported that microscopic hematuria was a risk factor for infection would beget a clinically well founded suspicion of progression.7 Still, this was refuted by other investigators, par- IgAN.1 A finding of persistent microscopic hematuria is not ticularly from centers with large multidisciplinary hospitals and specific for IgAN, but IgAN accounts for half of the glomerular multicenter collaborations. Pooling data from different labora- diseases detected by renal biopsies performed after microscopic tories suffered from the interobserver variability inherent in hematuria is detected through urinary screening programs.2 In fresh urine sediment analysis, whereas 24-hour urine collection patients with IgAN, microscopic hematuria is found in 70%– for count was troublesome, expensive, and affected 100% of cases, particularly in children and young adults in the by typical collection errors, and therefore was not satisfactory. For early phases of their clinical course. Hence, hematuria is an these reasons, standardized measurement of (partic- undisputable biomarker of IgAN, although with insufficient ularly when corrected for urinary ) was widely adopted specificity. Hematuria in IgAN is of glomerular origin, as dem- as the most relevant and reliable urinary biomarker, particularly onstrated by the detection of dysmorphic red blood cells in the for multicenter studies such as the European Validation Study of urinary sediment. This glomerular “” is postulated to the Oxford Classification of IgAN Study.10 result from glomerular capillary wall damage sustained by IgA In this issue of the Journal of the American Society of immune complex deposition and thus is a reflection of glomer- Nephrology (JASN), Sevillano et al.11 report the value of the ular inflammation. In the context of the clinical data, the above- degree of microscopic hematuria in a single-center cohort of mentioned pathophysiologic hypothesis is so conceivable that 112 patients with IgAN followed for a mean of 14 years. Time- a clear relationship between hematuria and activity of IgAN averaged hematuria (TA-hematuria) was calculated as an av- should be expected. However, no biomarker has been more de- erage of the mean of microscopic hematuria values (number bated and despised, abandoned for decades by many clinicians. of red blood cells per high power microscopic field) at every In the 1980s, a great debate arose between two giants of 6 months during the follow-up and was performed in the IgAN, Giuseppe D’Amico and Priscilla Kincaid-Smith. same laboratory. Patients with persistently high TA-hematuria D’Amico was impressed by the favorable outcomes of young during the follow-up had significantly greater decline in re- subjects with recurrent macroscopic hematuria after repeated nal 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 Published online ahead of print. Publication date available at www.jasn.org. analysis demonstrated that TA-hematuria was an independent Correspondence: Dr. Fernando C. Fervenza, Division of Nephrology, Mayo Clinic, predictor of outcome, as were time-averaged proteinuria 200 First Street, SW, Rochester, MN 55905. Email: [email protected] (TA-proteinuria; calculated as the average of mean proteinuria Copyright © 2017 by the American Society of Nephrology measurements at every 6-month period), baseline eGFR, and

J Am Soc Nephrol 28: ccc–ccc,2017 ISSN : 1046-6673/2810-ccc 1 EDITORIAL www.jasn.org degree of interstitial fibrosis. Disappearance of hematuria was infiltration and mediator release. This process may ultimately associated with a significantly lower decline in renal function produce the capillary wall lesions that allow red blood cell ex- (from 26.45 to 20.18 ml/min per 1.73 m2 per year; P50.001). travasation, and thus clinically evident hematuria.19 Twenty five Interestingly, when patients with TA-proteinuria .0.75 g/d years ago, Nath was the first to suggest that hematuria contrib- (which represented a threshold risk for progression) were subcate- utes to progressive CKD by virtue of the following: (1) glomer- gorized according to the persistence or disappearance of micro- ular disease leads to the appearance of red blood cells in the scopic hematuria, those with persistent hematuria (more than five urinary space, which are phagocytosed by renal tubules with red blood cells per high power field) had a significantly worse out- intratubular release of hemoglobin; (2) injection of red blood come.Hence,TA-hematuriaisproposedtoenhancethepredictive cells into proximal tubules in rodents causes tubular red blood value of TA-proteinuria. Patients with microscopic hematuria cell uptake, intratubular hemoglobin accumulation, and tubulo- more frequently had active mesangial lesions with proliferative interstitial disease; and (3) hemoglobin promotes iron-dependent changes on biopsy. In patients who received immunosup- oxidant cellular damage.20 Although the true incidence of AKI pressive treatment, TA-hematuria decreased significantly occurring during episodes of macroscopic hematuria in IgAN is (P50.001). Sevillano et al.11 concluded that persistence and mag- unknown, GFR does not return to baseline after resolution of the nitude of hematuria during follow-up is a significant biomarker for AKI episode in up to 25% of affected patients.16 IgAN progression, and correlations with mesangial proliferation The article published in this issue of JASN11 provides new along with benefit of are suggested. evidence that persistent microscopic hematuria is a risk factor The authors did not evaluate the presence and the extent of for progression of IgAN, and underscores its importance in the crescents, which have been recently found to be independent presence of persistent proteinuria. The damage induced by he- predictors of outcome and rescued in the new classification of maturia does not appear to be unique to IgAN, as recently re- IgAN.12 Kincaid-Smith published in 1985 that “persistently ported by the same investigators who found hematuria to be high indicates a continuing activity in the closely associated with more rapid decline in eGFR in a variety form of focal and segmental crescents.”13 The independent or of proteinuria disorders other than IgAN, especially in younger associated value of microscopic hematuria and crescents in patients.21 Although persistent proteinuria can reflect active cap- IgAN progression deserves further investigation. In addition, illary and podocyte lesions, it can also be due to hyperfiltration in complement activation is considered a potential mediator of chronic, irreversible cases. In IgAN, proteinuria by itself cannot uncontrolled chronic inflammation and sclerotic damage. In- discriminate between active inflammation versus chronic dam- deed, there is a strong association between C4d deposits and age. The recognition that persistent hematuria AND proteinuria progression of IgAN in both adults and children.14,15 It would reflects active inflammatory disease is important because future be of interest to investigate the correlation between persistence clinical trials testing the effects of immunosuppressive regimens of microscopic hematuria and C4d deposits in IgAN because should target patients with both hematuria and proteinuria, and the two processes might be interdependent. exclude IgAN patients without persistent hematuria. These stud- At any rate, the study confirms what nephrologists involved ies will also need to demonstrate that reduction or disappearance in taking care of patients with IgAN have long suspected: that of hematuria is associated with better outcomes. Examination of patients with IgAN with proteinuria but no hematuria are not urinary sediment may be a valuable tool, but it is time consum- the same as those with proteinuria and hematuria together, and ing, and not all nephrologists today are taught to adequately this association portends a worse outcome. examine the urinary sediment. New and more sensitive methods Hematuria has been largely neglected in nephrology and was for quantifying hematuria and reliably measuring hemoglobin often considered benign other than in disorders with rapidly in urine may, in the near future, help to place persistent hema- progressive courses, such as antiglomerular basement membrane turia in the proper perspective. At a time when significant time disease or renal vasculitides. Persistent isolated microscopic he- and money has been expended searching for novel and “fancy” maturia is considered a typical but benign finding of thin mem- biomarkers, we can say that, at least for IgAN, there is one: the brane nephropathy (TBMN), in which collagen abnormalities of old, cheap, and nearly forgotten hematuria. the glomerular basement membrane confer some fragility re- sponsible for microhematuria not related to the progression of the disease,16 although this view may be changing. DISCLOSURES On the other hand, persistent glomerular hematuria was None. 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 REFERENCES young Israeli adults followed for over 20 years.18 Of note, 15% – of the patients with isolated hematuria who developed ESRD 1. Wyatt RJ, Julian BA: IgA nephropathy. NEnglJMed368: 2402 2414, 2013 2. Park YH, Choi JY, Chung HS, Koo JW, Kim SY, Namgoong MK, Park YS, had IgAN. In IgAN, the pathologic process leading to hematuria fl Yoo KH, Lee KY, Lee DY, Lee SJ, Lee JE, Chung WY, Hah TS, Cheong HI, results from chronic in ammation elicited by IgA immune com- Choi Y, Lee KS: Hematuria and proteinuria in a mass school urine plexes deposition, mesangial activation, and inflammatory cell screening test. Pediatr Nephrol 20: 1126–1130, 2005

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