In-Depth Review AKI Associated with Macroscopic Glomerular Hematuria: Clinical and Pathophysiologic Consequences Juan Antonio Moreno,* Catalina Martı´n-Cleary,* Eduardo Gutie´rrez,† Oscar Toldos,‡ Luis Miguel Blanco-Colio,* Manuel Praga,† Alberto Ortiz,* § and Jesu´s Egido* § Summary *Division of Nephrology and Hematuria is a common finding in various glomerular diseases. This article reviews the clinical data on glomerular Hypertension, IIS- hematuria and kidney injury, as well as the pathophysiology of hematuria-associated renal damage. Although Fundacio´n Jime´nez glomerular hematuria has been considered a clinical manifestation of glomerular diseases without real Dı´az, Autonoma consequences on renal function and long-term prognosis, many studies performed have shown a relationship University, Madrid, Spain; †Division of between macroscopic glomerular hematuria and AKI and have suggested that macroscopic hematuria-associated Nephrology and AKI is related to adverse long-term outcomes. Thus, up to 25% of patients with macroscopic hematuria– ‡Department of associated AKI do not recover baseline renal function. Oral anticoagulation has been associated with glomerular Pathology, Instituto de macrohematuria–related kidney injury. Several pathophysiologic mechanisms may account for the tubular injury Investigacio´n Hospital found on renal biopsy specimens. Mechanical obstruction by red blood cell casts was thought to play a role. More 12 de Octubre, Madrid, Spain; and recent evidence points to cytotoxic effects of oxidative stress induced by hemoglobin, heme, or iron released from §Fundacion Renal red blood cells. These mechanisms of injury may be shared with hemoglobinuria or myoglobinuria-induced AKI. Inigo~ Alvarez de Heme oxygenase catalyzes the conversion of heme to biliverdin and is protective in animal models of heme Toledo/Instituto toxicity. CD163, the recently identified scavenger receptor for extracellular hemoglobin, promotes the activation Reina Sofia de Investigacion of anti-inflammatory pathways, opening the gates for novel therapeutic approaches. Nefrologica Clin J Am Soc Nephrol 7: 175–184, 2012. doi: 10.2215/CJN.01970211 (FRIAT/IRSIN), Madrid, Spain Introduction Macroscopic Glomerular Hematuria and AKI Correspondence: Glomerular hematuria, when not accompanied by mild IgA nephropathy, Alport syndrome, and thin base- Dr. Jesus Egido, IIS-Fundacio´n Jime´nez to severe proteinuria, has been considered a benign ment membrane disease (TBMD) are three frequent Dı´az, Avda. Reyes manifestation of glomerular diseases that does not causes of glomerular hematuria. Rapidly progressive Cato´licos 2, 28040 influence long-term prognosis. Nevertheless, macro- GN, vasculitis, and acute glomerular inflammation, as Madrid, Spain. scopic hematuria can induce AKI through a direct observed in postinfectious GN or lupus, may also be Email: [email protected] harmful effect on renal tubules. Information on path- associated with glomerular hematuria. Tubules filled ogenesis and long-term consequences of such macro- with RBC casts, with associated acute tubular necro- hematuria-induced AKI is remarkably scarce. The aim sis, are common findings in these conditions, and their of this article is to review the clinical data on hema- contribution to final renal function outcome deserves turia and glomerular disease, as well as the pathophys- specific investigations. iology of hematuria-associated AKI. AKI during gross hematuria in IgA nephropathy can be oligo-anuric and may necessitate transient he- Hematuria and Hemoglobinuria modialysis. Reversible AKI due to glomerular macro- Hematuria is defined as the presence of red blood hematuria was first reported by Kincaid-Smith and cells (RBCs) in urine (1). Macroscopic hematuria is colleagues in 1983 (2). Most macroscopic glomerular always pathologic and is characterized by massive hematuria–related AKI cases reported since have presence of RBCs in urine. Microscopic hematuria is been IgA nephropathy (Table 1). Initially, hematuria defined by the presence of more than 2 RBCs per was thought to be innocuous, and AKI, if present, high-power field in urine sediment in the absence of was considered an infrequent feature caused by func- colored urine. Macroscopic hematuria may be differ- tional factors (3). In 1985, however, Praga and entiated from hemoglobinuria and myoglobinuria: a coworkers reported a 38% incidence of AKI during heme-positive red supernatant may contain hemoglo- macrohematuria bouts in IgA nephropathy (4). Dura- bin or myoglobin, whereas RBCs are observed in the tion of hematuria, but not age, was a significant prog- sediment in hematuria. Smoky gray–colored urine, nostic factor for development of AKI. All patients thepresenceofRBCcasts,anddysmorphicRBCs recovered baseline renal function 15–70 days after ces- favor a glomerular origin of hematuria, and blood clots sation of hematuria. The patients were particularly and bright red urine support a urinary tract origin. young: mean age in the AKI group was 24 years. www.cjasn.org Vol 7 January, 2012 Copyright © 2012 by the American Society of Nephrology 175 176 Clinical Journal of the American Society of Nephrology Table 1. Macroscopic hematuria and AKI in IgA nephropathy Duration of No. of Basal sCr Peak sCr Full Recovery Author (Reference) Age (yr) Anticoagulation Macroscopic Crescents (%) Recovery (d) Patients (mg/dl) (mg/dl) (%) Hematuria (d) Praga et al. (4) 11 2468NA362.0 NA 100 4.861.2 6.5 30619 Delclaux et al. (5) 6 37621 NA 4.961.7 NA 100 38627 20 34 Kveder et al. (6) 7 56611 NA 9.966.1 NA 100a 421NA Gutiérrez et al. (7) 36 46621 1.160.2 4.863.1 NA 75 20.0621.5 11 42663 Feith et al. (8) 3 40623 160.2 5.163.3 NA 100 18.3612.5 14 5961 Martin Cleary et al. (11) 1 51 0.8 9 1 — 210b 20 No Foggazzi et al. (13) 3c 40623.5 160.17 5.663.2 NA 66% 18.3612.5 14 5961.4 August et al. (27) 1 59 NA 12.4 1 100 NA 0 30 Unless otherwise specified, data are expressed as mean 6 SD. sCr, serum creatinine; NA, not available. aBaseline renal function not available. At last follow-up, five patients had CKD stage 2 or 3. bRepeated bouts of macroscopic hematuria. At last follow-up, sCr was 1.3 mg/dl. cOf the three patients, one had focal necrotizing lesion on biopsy. Another had ongoing hematuria at discharge. last visit, 9 was not reportedKveder (6). and Although associates allduration patients of improved, macrohematur at gross hematuria (5). Olderrecovery, patients it seemed to took haveolder, as longer and long although assodes they 10 (5). all months Patients had after inoccurred complete the Declaux even renal and end function during colleagues of of brief gross macroscopic hematuria hematuria as a epi- predictor of AKI (5,6). Severe AKI the percentage of crescents wasassociated usually AKI than inwith those IgA who nephropathy did(4,5,7,8). who not The had (12). frequency macroscopic However, ofchanges, crescents hematuria mesangial was higher proliferation inery was patients of mild renal tonecrosis function. moderate was Contrary a to signi tubules the containing severity RBC of castsout (5). tubular the Severity biopsy of specimens acutethose but tubular researchers noted observed more acute severe tubularcasts lesions (4). necrosis in Other through- reports weretially consistent with reported these onlyhas in been those observed tubules (9 well that as contained phagocytosismosiderin RBC of in RBCs tubular cells bymacroscopic and proximal hematuria interstitial tubular (9,10) macrophages, (Figure as cells, 1 and Table 3). He- statistically signi duration of hematuriarenal longer function. than Multivariate 15episodes days analysis, as as prognostic however, theatinine, factors rendered only for and incomplete absenceturia, recovery of age of previous older than macroscopic(7). Univariate 55 hematuria analysis years, identi higherthe baseline patients serum did cre- published not a recover larger baselineCKD retrospective serum stage study creatinine 2 in or which 3. 25% of In 2007, Gutiérrez and coworkers pattern in patientssegmental proliferation with to IgA be the nephropathy, most macroscopic frequentrenal histologic function and werecrescents absent were in not most associatedas such with can patients. incomplete be recovery observedthought of to in be the the updated cause of data renal (Tables failure 2 (4 and 3), casts are the most salient histologic cells, and leukocytes (4,5,7,8). variable presence ofnot hyaline reported. and Urinaryturia granular sediments but casts, contained did RBCs, tubular notall with series, exceed proteinuria 3 increased g/d;gross during hematuria nephrotic macroscopic and hema- syndrome associatedwere was complications suggested (4,5,7,8). as In ano means differences of in shorteningbular histologic the necrosis, glomerular duration and interstitial features. of creased Steroids age, duration5%; of macrohematuria, severityrenal function of than tu- in thosequently with in full recovery the (43%atinine patients versus levels. who Hemodialysis didAgain, was not 27% of completely necessary patients recover more did not fre- recover baseline serum cre- Subsequent smaller studies did not corroborate duration The series of Bennet and Kincaid-Smith found focal and Acute tubular necrosis and intraluminal obstructive RBC We have updated this series with 16 new cases (Table 2). P , 0.005). Incomplete recovery could be related to in- – 57 months later, fi cant variable. ’ fi – cant risk factor for incomplete recov- 11). Acute tubular necrosis was ini- series, baseline serum creatinine ia and recovery period. In fi fi fi ed duration