Macroscopic Hematuria as a Presenting Manifestation of Oliguric Acute Tubular Necrosis

Macroscopic Hematuria as a Presenting Manifestation of Oliguric Acute Tubular Necrosis Joseph Outlot, MO, Arthur H. Cohen, MO, and Sharon Adler, MO • Macroscopic hematuria associated with acute renal failure usually results from glomerulonephritis or structural abnormalities (stones, tumors, or infections). Acute tubular necrosis is rarely associated with macroscopic hematuria in the absence of other genitourinary abnormalities. We describe a patient who presented with macroscopic hematuria, in whom only acute tubular necrosis could be identified as a causative factor. © 1993 by the National Kidney Foundation, Inc. INDEX WORDS: Hematuria; acute tubular necrosis.

4 CUTE tubular necrosis (A TN) is a term used f t to describe acute renal failure with a specific

microscopic appearance, consisting of mild to severe tubular cell damage and/or necrosis. This may be caused by toxins, drugs, or ischemic insults. The type of injury may dictate the extent and the severity of tubular cell injury. 1·4 Urinalysis characteristically shows muddy brown granular casts, renal tubular epithelial cells, debris, and minimal to moderate proteinuria. Hematuria is rarely reported in the literature to accompany ATN. 4,5 To our knowledge, macroscopic hematuria has not been specifically reported to be a manifestation of ischemic ATN in the absence of additional urinary tract pathology (eg, arteriovenous malformation, stones, tumors, etc), although it is mentioned in passing, unreferenced, in occasional textbook chapters concerning ATN.1-4 The following case report describes a young man who presented with community-acquired acute renal failure and macroscopic hematuria whose renal biopsy disclosed only ATN and who did not have demonstrable urinary tract lesions to otherwise account for the hematuria. CASE REPORT A 25-year-old Hispanic man who was in good health until 1 week prior to admission presented with lower abdominal pain, diarrhea, nausea, and vomiting for 3 days' duration. Initially periumbilical, the pain subsequently radiated to the right lower quadrant. Urinary output decreased and dyspnea occurred. The patient took one dose of cimetidine and Mylanta (Johnson & Johnson Merck Consumer Pharmaceuticals Co., Fort Washington, PAl I day before coming to the hospital. The patient denied fever, dysuria, joint pains, skin rash, or substance abuse. On the basis of the history and physical examination, a diagnosis of acute appendicitis was made. The medical history was significant for pulmonary tuberculosis treated for 8 months in El Salvador, which was treated again in Boston from June 1990 to February 1991 with three drugs. On physical examination, the patient was alert, oriented, and in mild distress due to abdominal pain. The blood pressure

was 167/88 mm Hg; the temperature was 98°F, the pulse was 89 beats/min, and the respiratory rate was 16 breaths/min. Head and neck examinations were unremarkable. Chest examination revealed few right basilar crackles. Examination of the abdomen disclosed diminished bowel sounds and right lower quadrant tenderness with focal rebound. Rectal examination was unremarkable. Stool sampling for occult blood was negative. The extremities had no edema. Neurologic examination was normal. Laboratory data revealed a serum sodium of 113 mmol/L, potassium 4.3 mmoljL, chloride 68 mmol/L, total CO 2 20 mmoljL, blood urea nitrogen 46.1 mmol/L, and creatinine 1.6 mmol/L. Liver function tests, amylase, prothrombin time, partial thromboplastin time, and creatine phosphokinase, were normal. A complete blood cell count revealed a white blood cell count of 17.5, hematocrit of 38.8%, and platelet count of 228,000. A differential blood count indicated 85 polymorphonuclear leukocytes, seven lymphocytes, five monocytes, and three eosinophils. Room air arterial blood gas revealed pH 7.42, PA02 42 mm Hg, Peo2 32 mm Hg, and Sa02 79%. A chest x-ray film showed scattered fine nodular interstitial opacities bilaterally, consistent with an atypical pulmonary edema pattern, and linear stranding of the left mid-lung field. suggestive of scarring secondary to old granulomatous disease. The cardiac silhouette was normal. In the emergency room, the patient had several episodes of spontaneously voided gross hematuria. A urinary catheter had not been previously passed. Urinalysis revealed trace protein, isomorphic erythrocytes that were too numerous to count, two to three vacuolated tubular epithelial cells ("bubble cells") per high-power field, and no casts. Urine sodium was 70 mmolj L, urine chloride was 48 mmoljL, and urine creatinine was 4.4 mmol/L. The fractional excretion of sodium was 22%. Urinary red blood cell mean corpuscular volume was 82 femtoliters (fl). An abdominal ultrasound showed no periappendiceal inflammation or other cause for an acute atxlomen. The kidneys From the Division ofNephrology and Hypertension, HarborUCLA Medical Center. Torrance, CA; and the Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA. Received July 21, 1992; accepted in revised form April 25, 1993. Dr Dujlot was fimded in part by a grant from the National Kidney Foundation of Southern California. Address reprint requests to Sharon Adler, MD, Division of Nephrology, Harbor-UCL4 Medical Center, 1000 WCarson St, Torrance. CA 90509. © 1993 by the National Kidney Foundation, Inc. 0~72-6386/93/2204-0019$3.00/0

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were 13 cm bilaterally, with no increased echogenicity, obstruction, stones, or perinephric fluid collection. Surgery was postponed and hemodialysis was performed on hospital days I, 2, 3, 4, 6, and 8. In the first 24 hours, abdominal pain diminished and subsequently disappeared, but oligoanuria (200 mL/24 hr) was documented and hematuria persisted. The chest x-ray findings cleared with dialysis. A renal biopsy was performed on day 2. Additional studies were done after the renal biopsy. Urine and blood cultures were negative four times for urinary tract pathogens, including mycobacteria. Urine cytology did not disclose malignant cells. A computed tomography scan of the abdomen revealed no stones and no renal or ureteral masses. A flexible cystoscopy performed 8 days after admission when hematuria resolved showed a normal bladder and ureteral orifices. Hepatitis A, B, and C serologies, antinuclear antibody, human immunodeficiency virus. and VDRL tests were negative. C3 and C4 were normal. Urine output increased after I week and serum creatinine decreased. The patient was discharged 15 days after admission with a serum creatinine of 0.2 mmol/L and complete resolution of hematuria and abdominal pain. At a 6-month follow-up examination, the serum creatinine was 0.09 mmol/L. The patient had no microscopic hematuria and no evidence of a systemic disorder.

Biopsy Findings The major changes in the biopsy specimen taken for light microscopy, which consisted of cortex only, affected tubules from all nephron segments. While many proximal tubular cells had a normal appearance, in the remainder there was loss of brush border staining associated with flattening of cells and relative dilatation of lumina (Fig I). Scattered tubular profiles, both proximal and distal, were incompletely lined by cells, with denuded stretches of basement membranes; some of these tubules contained cytoplasmic debris in the lumina. There were mitotic figures in some tubular cells. Serial sections through the entire block failed to reveal discontinuities in tubular basement membranes or interstitial, capillary, or venular masses of Tamm-Horsfall protein. Some tubules contained luminal erythrocytes. The interstitium was mildly edematous, with only few scant infiltrates of lymphocytes and plasma cells. There were rare isolated atrophic tubules. All 18 glomeruli had no structural abnormalities of the tufts; there was tubular metaplasia of parietal epithelial cells in several. Arteries and arterioles were devoid of alterations. Immunofluorescence microscopy revealed a lack of deposits in all five glomeruli evaluated. C3 in low intensity was present in the walls of scattered arterioles. Electron microscopic examination indicated structurally normal glomeruli; basement membranes were of normal thickness and appearance, electron-dense deposits were absent, and the foot processes of visceral epithelial cells were discrete. Brush borders of some proximal tubular cells were markedly abnormal; microvilli were often absent, diminished in number and length, or irregular in distribution. The cytoplasm of some of these cells was rarified, with diminished organelles and/or swollen mitochondria. Some lumina contained degenerate desquamated epithelial cells, often with dilated Iysosomes, while some also contained few erythrocytes (Fig 2). Breaks in tubular basement membranes were not observed in either the thin or thick sections prepared for light microscopy.

Fig 1. Representative glomerulus without structural abnormalities. The tubule at the 6 o'clock position of the glomerulus (arrowhead) is incompletely lined by epithelium and the lumen contains necrotic debris. Similar material is in an adjacent tubule (arrow). (Periodic acidmethenamine silver stain; magnification x220.)

DISCUSSION

We describe a patient with established acute renal failure and macroscopic hematuria. Acute tubular necrosis was the only pathologic entity found despite multiple investigations to seek an alternative explanation for gross hematuria. The presence of isomorphic rather than dysmorphic hematuria6 composed of red blood cells with a mean corpuscular volume greater than 72 fl 7 ,8 support a nonglomerular bleeding site. The presence of vacuolated urinary tubular epithelial cells9 and a fractional excretion of sodium of 22%10 support the diagnosis of ATN. The association of microscopic hematuria and ATN is described but not well established. In standard renal textbooks, the hematuria of ATN is either not mentioned or is reported as rarely seen,I,3.4 although some investigators allude to occasional red blood cells in the urine. 3,4 Because an association between macroscopic hematuria and uncomplicated ATN has not been previously reported, other conditions associated with gross hematuria were sought. The possibility

HEMATURIA IN ACUTE TUBULAR NECROSIS

Fig 2. Electron micrograph of proximal tubule. There is loss of brush border formation in a few cells (arrowheads). The lumen contains epithelial cells in varying degrees of degeneration. There are also two erythrocytes in the lumen. (Magnification x2.000.)

of genitourinary tuberculosis was considered, but negative imaging studies, cystoscopy, and cultures made this diagnosis unlikely. Acute glomerulonephritis (especially IgA nephropathy) may be complicated by acute renal failure due to ATN during periods of macroscopic hematuria. II - 13 The tubular damage may be secondary to the toxic effects of erythrocyte ingestion by renal tubular cells. However, in our patient, biopsy revealed normal glomeruli without IgA or other deposits. A recent report by Julian et al described four patients presenting with macroscopic hematuriaY Initial renal biopsies in three of these patients showed mesangial proliferation and expanded mesangial matrix but without mesangial IgA deposits. In only one of the patients were glomeruli normal. A second biopsy, performed in each patient months to years later because of recurrence of hematuria, revealed IgA nephropathy. The investigators suggested that the initial hematuria was due to IgA nephropathy that was not yet evident by immunofluorescence microscopy. Although this is a possible explanation for

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our patient's hematuria, the lack of mesangial proliferation or matrix expansion in our patient makes this unlikely. We considered the possibility that our patient had ATN with nephrolithiasis, renal papillary necrosis, genitourinary neoplasm, or infectious cystitis or urethritis. However, no clinical or radiographic evidence supported these diagnoses. Loin pain hematuria syndrome may be suggested by our patient's history. However, it is uncommon in males and rarely, if ever, is associated with acute renal failure. Acute cortical necrosis frequently presents with hematuria, 14 but the patient's subsequent complete recovery makes this diagnosis unlikely.15 Kleinknecht et al reported that survivors of complete and incomplete cortical necrosis all demonstrate substantial loss of renal function at follow-up examination. 15 One may speculate that tubulovenous herniations may be a pathogenic explanation for this patient's macroscopic hematuria. This morphologic finding has been described in tubular necrosis associated with the "crush" syndrome, hydronephrosis, acute transplant rejection, myeloma kidney, acute unilateral hematuria of unknown etiology, and ATN. 16-24 This is considered to be the result of extrusion ofTamm-Horsfall protein from ruptured tubules into the interstitium and then into veins, resulting in vascular "polyps" ofTamm-Horsfall protein. In addition, a communication between vessels and tubules is formed, thereby allowing erythrocytes to enter tubules. Clinically, however, significant hematuria is uncommonly seen even when this lesion is noted morphologically, although nephrectomy was necessary to treat the resultant gross hematuria in several patients with unilateral macroscopic hematuria. 16 Morphologic examination revealed intratubular hemorrhage associated with tubulovenous herniation, implying a direct cause and effect relationship. Significant hematuria was not mentioned in the reports of tubulovenous communication associated with ATN. 19 ,24 In the patient reported here, despite the careful study of serial sections of the entire renal biopsy specimen, neither tubulovenous communications nor areas of cortical necrosis were found. This, of course, does not exclude the possibility that sampling error precluded the identification of either of these. Tubulovenous communications are usually found at the corticomedullary junc-

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tion,18.20.22,23 which was not sampled in our biopsy. Cortical necrosis may be focal or patchy and therefore missed. In conclusion, in our patient there are four potential explanations for the association of hematuria with ATN. First. gross hematuria may have been an incidental process unrelated to the ATN. However, no obvious etiology of the hematuria apart from ATN was discerned. Second, gross hematuria may have been evidence of severe ischemic damage such as is present in complete or incomplete cortical necrosis. We did not find cortical necrosis on renal biopsy. Furthermore, the total recovery of renal function in our patient strongly argues against this diagnosis. Third, glomerular hematuria may have caused ATN. This occurs in IgA nephropathy, but our patient had no evidence supporting this diagnosis. Finally, hematuria may have been a manifestation of ATN. We find this explanation to be the most compelling. ACKNOWLEDGMENT Carlos Ayala provided excellent secretarial support.

REFERENCES I. Miller RB: Urinalysis, in Massry S, Glassock R (eds): Textbook of Nephrology. Baltimore. MD. Williams & Wilkins, 1989. p 1607 2. Olsen S: Acute tubular necrosis and toxic renal injury, in Tisher C, Brenner B (eds): Renal Pathology With Clinical and Functional Correlations. Philadelphia. PA. Lippincott. 1989. pp 656-699 3. Anderson RJ. Schrier RW: Acute Tubular Necrosis, in Schrier R. Gottschalk C (eds): Diseases of the Kidney. Boston, MA. Little. Brown, 1988, pp 1413-1446 4. Brezis M, Rosen S. Epstein F: Acute renal failure, in Brenner B. Rector F (eds): The Kidney. Philadelphia. PA. Saunders. 1991 . pp 993-1061 5. Balslv J, Jorgensen H: A survey of 499 patients with acute anuric renal insufficiency. Am J Med 34:753-764. 1963 6. Kohler H. Wandel E, Brunck B: Acanthocyturia-A characteristic marker for glomerular bleeding. Kidney Int 40: 115-120. 1991 7. Docci D. Maldini M, Delvecchio C, Baldrati L, Turci F, Gilli P: Urinary red blood volume analysis in the investigation of hematuria. Nephrol Dial Transplant 1:69-70. 1990 (suppl) 8. Goldwasser P, Antignani A, Mittwan N, Rao Y, Mushnik RA. Norbergs A. DiPillo F, Avram MM: Urinary red cell size:

Diagnostic value and determinants. Am J Nephrol 10:148156, 1990 9. Graber M, Lane B. Lamia R. Pastoriza-Munoz E: Bubble cells: Renal tubular cells in the urinary sediment with characteristics of viability. J Am Soc Nephrol 1:999-1004. 1991 10. Miller TR. Anderson RJ. Linas SL. Henrich WL. Berns AS, Gabow PA. Schrier RW: Urinary diagnostic indices in acute renal failure. A prospective study. Ann Intern Med 89: 47-50, 1978 II . Hill P. Davies D, Kincaid-Smith p, Ryan GB: Ultrastructural changes in renal tubules associated with glomerular bleeding. Kidney Int 36:992-997. 1989 12. Lee H, Pyo HJ. Koh H: Acute renal failure associated with hematuria in 19A nephropathy. Am J Kidney Dis 12: 236-239, 1988 13. Julian BA, Cannon YR. Waldo FB. Egido J: Macroscopic hematuria and proteinuria preceding renal IgA deposition in patients with JgA nephropathy. Am J Kidney Dis 17:472-479, 1991 14. Weiss MA. Pollak VE: Renal cortical necrosis. infarction, and atheroembolic disease, in Tisher CC, Brenner BM (eds): Renal Pathology With Clinical a nd Functional Correlations. New York. NY, Lippincott, 1989. p 708 15 . Kleinknecht D. Grunfeld J-P. Gomez PC, Moreau J-F. Garcia-Torres R: Diagnostic procedures and long-term prognosis in bilateral renal cortical necrosis. Kidney Int 4: 390-400. 1973 16. Billis N, Palma P. Prando A, Gouvea AA: Massive intratubular hemorrhage with herniations into renal veins: Report of a case. J Urol 144:963-965, 1990 17. Kawaguchi K. Koike M: Tubulovenous communication in myeloma kidney. Arch Pathol Lab Med 113:512-516. 1989 18. Solez K. Heptinstall R: Intrarenal urinary extravasation with formation of venous polyps containing Tamm-Horsfall protein. J Urol 119:180-183. 1978 19. Solez K. Morel-Maroger L, Sraer J: The morphology of "acute tubular necrosis" in man: Analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine 58: 362-376, 1979 20. Barrie HJ: Herniations into the renal veins with special reference to hydronephrosis. J Pathol Bacteriol 82: 177-182, 1961 21. Zager R, Cotran R. Hoyer J: Pathologic localization ofTamm-Horsfall protein in interstitial deposits in renal disease. Lab Invest 38:52-57. 1978 22. Resnick J, Sisson S, Vernier R: Tamm-Horsfall protein: Abnormal localization in renal disease. Lab Invest 38:550555. 1978 23. Hoyer J, Seiler M: Pathophysiology ofTamm-Horsfall protein. Kidney Int 16:279-289. 1979 24. Olsen S. Burdick JF, Keown PA. Wallace AC, Racusen LC, Solez K: Primary acute renal failure ("acute tubular necrosis") in the transplanted kidney: Morphology and pathogenesis. Medicine 68:173-187,1989