- Email: [email protected]
Fever, thrombocytopenia, anasarca, and acute renal failure in a 50-year-old woman
RENAL BIOPSY TEACHING CASE
Fever, Thrombocytopenia, Anasarca, and Acute Renal Failure in a 50-Year-Old Woman Simin Goral, MD, Robert Horn, MD, John Brouillette, MD, and Agnes Fogo, MD ● INDEX WORDS: Hemolytic uremic syndrome; acute renal failure; microangiopathy.
W
E PRESENT a patient with fever, respiratory distress, oliguria, edema, bilateral pleural effusions, ascites, and acute renal failure (ARF). Multiple cultures and biopsies were pursued over the course of 3 weeks before a renal biopsy shed light on the nature of her systemic disease process. CASE REPORT
A 50-year-old white woman was admitted to hospital with a 3-week history of oliguria, shortness of breath, edema, and frequent loose stools. Her medical history was significant for diarrhea with two to three loose stools a day for the last 3 years, peptic ulcer disease, and asthma. She had total abdominal hysterectomy and bilateral salpingo-oophorectomy for recurrent bleeding from fibroids and ovarian cysts several years ago. Her medications on admission were omeprazole, estrogen/progesterone hormone replacement, albuterol inhaler as needed, and loperamide. She had 20 pounds weight gain over the previous 6 weeks. The week before admission, she had observed a decrease in the frequency of her urination and that her urine was the color of cherry cola the day before admission. The patient was married and a textile plant seamstress of 31 years. Her physical examination was remarkable for a temperature of 102.1°F, pulse of 115, respiratory rate of 24, and blood pressure of 137/74 mm Hg. She was ill-appearing with mild respiratory distress. There was no rash. Lung examination showed rales with bilateral dullness to percussion at the bases. Moderate peripheral edema was noted. Her neurological examination was normal. Laboratory evaluation on admission showed the following results: blood urea nitrogen (BUN), 23 mg/dL; serum creatinine, 1.4 mg/dL; serum albumin, 1.9 g/dL; total protein, 4.8 g/dL; hematocrit, 28%; platelets, 47,000/µL; erythrocyte sedimentation rate, 119 mm/hr. Liver function tests and lactate dehydrogenase (LDH) were normal. There were no schistocytes seen on peripheral smear, and her reticulocyte count was 2.1%. Hepatitis B and C serologies were
From the Departments of Medicine and Pathology, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN. Received and accepted January 27, 1998. Address reprint requests to Simin Goral, MD, Assistant Professor of Medicine, Vanderbilt University Medical Center, Division of Nephrology, S-3223 MCN, Nashville, TN 37232. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0024$3.00/0 890
negative; anticardiolipin antibodies, antiplatelet antibodies, antinuclear antibody, and anti-DNA were negative, and complement levels were normal. Urinalysis showed 3⫹ protein with 2 to 5 red blood cells, 0 to 2 white blood cells, no casts, and no bacteria. No Bence-Jones protein was detected in the urine. A 24-hour specimen of urine showed 180 mg protein. Admission chest radiograph showed bilateral pleural effusions with no focal infiltrates and a normal cardiac silhouette. The patient was begun empirically on ceftriaxone and erythromycin. Blood, sputum, and urine cultures remained negative. Serologies for tularemia, brucella, and legionella were negative. Evaluation of her stool showed no white blood cells, ova, parasites, or Clostridium diffıcile toxin. Her folate and vitamin B12 levels were 9.3 ng/mL and 94 ng/mL, respectively, for which she was started on daily folate and B12 replacement. An ultrasound of her abdomen showed no urinary obstruction and no evidence of hydronephrosis, right and left kidney size of 10.1 and 9.2 cm, respectively, a small amount of ascites, and mild splenomegaly with an echogenic liver. A transthoracic echocardiogram showed a small pericardial effusion with no wall motion abnormalities and an ejection fraction of 65%. The patient remained febrile after 6 days of hospitalization with worsening shortness of breath as well as oliguria refractory to high-dose intravenous diuretics and persistence of her frequent loose stools. She underwent a therapeutic thoracentesis, which showed 43 white blood cells/mm3, 485 red blood cells/mm3, and no microorganisms. No malignant cells were seen on cytology. The pleural fluid chemistries showed an LDH of 324 U/L and total protein of 2.6 g/L. Antibiotic therapy was stopped. Computed tomography (CT) scan of her chest showed preaortic and axillary adenopathy, and small pericardial effusion. The CT scan of the abdomen showed mild splenomegaly and distension of the portal and hepatic veins with ascites but no adenopathy. A bone marrow biopsy showed a hypercellular marrow, increased numbers of megakaryocytes, and no infiltration by tumor, granulomas, or plasma cells. Acid-fast bacilli (AFB) and fungal stains were negative. Biopsy of the small bowel showed chronic inflammation of the lamina propria with plasma cells and lymphocytes. Subsequent colonoscopy showed diverticula throughout the colon without visible evidence of active bleeding or inflammation. Biopsy of the colon showed mild lymphocytic infiltration of the lamina propria. Congo red stain of both the small and large intestine was negative. She continued to have a fever up to 101.5°F. Her urine output decreased further, and her BUN and creatinine had increased to 37 mg/dL and 2.4 mg/dL, respectively. She had worsening peripheral edema with flank edema on examination consistent with anasarca. The cause of her systemic illness and renal failure continued to remain obscure. A diagnostic kidney biopsy was performed. The clinical differ-
American Journal of Kidney Diseases, Vol 31, No 5 (May), 1998: pp 890-895
FEVER, THROMBOCYTOPENIA, ANASARCA, AND ARF
ential diagnosis included systemic lupus erythematosus (SLE), vasculitis, subacute bacterial endocarditis, underlying inflammatory bowel disease, liver failure with cirrhosis, microangiopathy in association with an occult carcinoma, and thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS).
Renal Biopsy Findings The biopsy specimen contained 20 glomeruli; one or two were remotely obsolescent, and the remainder were generally intact and similar. Almost all glomeruli were congested with impacted red cells (Fig 1). A large proportion of these red cells was fragmented, with many irregular and small pieces of erythrocytes (Fig 2). Endocapillary cellularity was mildly increased. No necrotizing or crescentic features were present. Basement membranes showed no irregularities by silver stain. No occlusive plugs or materials resembling fibrin clot were evident. The tubules were generally intact without significant casts. Some distal tubules showed mild luminal dilatation consistent with acute tubular injury. There was no interstitial hemorrhage or infiltrate. Arterioles and arteries showed no lesions. Staining with monospecific antisera for immunoglobulin (Ig)G, IgA, IgM, C3 complement, and kappa and lambda light chains did not show any significant glomerular, tubular, or nuclear staining. Congo red stains were negative for amyloid. Electron microscopy showed normal thickness and density of glomerular basement membranes. No basement membrane or mesangial deposits were evident. Endocapillary cellularity was markedly increased, primarily because of large numbers of erythrocytes, as well as proliferation of endothelial and mesangial cells (Fig 3). Many erythrocytes were irregular in outline and fragmented, with some of the fragments within mononuclear cells and mesangial cells. In many loops, there was complete loss of endothelial cells, and erythrocytes and erythrocyte fragments were in immediate contiguity to the
Fig 1. Glomeruli congested with impacted red cells. (Hematoxylin-eosin, original magnification ⴛ375.)
891
inner aspect of the bare glomerular basement membrane. No fibrin tactoids were detected.
Diagnosis Although fibrin-containing clots were not detected in the biopsy specimen, diffuse and quite well-defined endothelial loss and erythrocyte fragmentation were strongly suggestive of a microangiopathic hemolytic process. The morphological findings suggested acute severe endothelial injury with hemolysis. A diagnosis of atypical microangiopathy consistent with a hemolytic process was made.
Clinical Course The patient was started on plasmapheresis with fresh frozen plasma. She subsequently required ultrafiltration on a daily basis during her initial therapy with plasmapheresis and hemodialysis three times a week. She was also started on dipyridamole 75 mg by mouth four times daily and aspirin 325 mg by mouth once per day. All cultures remained negative. Although she became afebrile and her respiratory symptoms resolved, her anemia, thrombocytopenia, edema, ascites, and diarrhea did not resolve completely. Six months after her initial presentation, she remains on dialysis. The cause of her HUS-like disease was not discovered.
DISCUSSION
We present a patient with thrombocytopenia and anemia with evidence of hemolysis only on the kidney biopsy, massive edema, and ARF in whom a kidney biopsy showed an atypical microangiopathy. HUS is usually characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia, microvascular thrombosis, and multiple organ dysfunction including the kid-
892
GORAL ET AL
Fig 2. Fragmented red cells evidenced by irregular, small pieces of erythrocytes within glomerulus. (Hematoxylin-eosin, original magnification ⴛ600.)
neys. Although the hospital mortality has decreased significantly in the last two decades, HUS is still associated with a significant mortality rate, ranging between 16% and 25% despite the widespread use of plasmapheresis.1,2 Typical (epidemic, diarrhea-associated, D⫹) HUS is associated with diarrhea, which is usually bloody. It occurs mainly in children, although rarely adults, especially the elderly, also may be affected. Verotoxin-producing Escherichia coli was responsible for many outbreaks of HUS around the world.3 The source of the infection was usually contaminated meat or apple cider. On binding to their specific receptors, toxins localize on the colonic mucosa, invade epithelial cells, and cause cell destruction. The damage to the vessels of the colonic mucosa causes hemorrhagic colitis. Elevated white cell count, a severe gastrointestinal prodrome, anuria early in the course, and an age younger than 2 years are the predictors of the severity of the illness.3 Atypical (non–diarrhea-associated, D–) or adult forms may be associated with pregnancy, malignant hypertension, oral contraceptives, chemotherapy, cyclosporine, HUS SLE, urinary tract infection, or human immunodeficiency virus (HIV) infection and usually manifest without prodromal diarrhea.4-7 HUS also may be familial and then frequently has a relapsing and progressive course.8 Our patient had a history of longstanding diarrhea associated with certain foods.
Therefore, tests for verotoxin-producing E coli were not done. She did not have any evidence for SLE or HIV infection clinically or in the renal biopsy. The morphology of renal lesion usually does not allow distinction of the underlying cause, except where HUS occurs secondary to another distinct renal lesion such as SLE. There was no history of HUS in her family. We cannot rule out the possibility of the estrogen/progesterone hormone replacement therapy or the history of a urinary tract infection several weeks before presentation as the causative agents of her disease. Although HUS primarily affects the kidney, other organs such as brain, colon, liver, and heart also can be affected. Interestingly, verotoxin receptors that mediate cytotoxic effects have been found in the kidneys, especially in the glomeruli, as well as in other organs (brain, lungs, and colon), suggesting the underlying reason for distribution of microvascular lesions in HUS.6 Autopsies on five patients with HUS showed multiple fibrin/platelet thrombi in organs other than the kidney, including brain, heart, and liver.2 Renal microvascular damage leads to macrohematuria or microhematuria, proteinuria (rarely nephrotic range), oliguria, and hypertension. Multiple mechanisms likely contribute to thrombocytopenia and hemolysis. Endothelial cell dysfunction, caused by infectious agents, including bacterial endotoxins and exotoxins (Shiga-like toxin, verotoxins produced by E coli), antibod-
FEVER, THROMBOCYTOPENIA, ANASARCA, AND ARF
893
Fig 3. Increased endocapillary cellularity, proliferation of endothelial and mesangial cells (A), many fragmented and irregular erythrocytes (A, B) with some of the fragments within mononuclear cells and mesangial cells (A), and extensive loss of endothelium (B). (Transmission electron micrograph, original magnification ⴛ5,200 [A], ⴛ6,500 [B].)
ies, immune complexes, certain drugs such as mitomycin, quinine and cyclosporine, or vasoactive peptides, is an important factor leading to intravascular platelet aggregation.9,10 The presence of unusually large von Willebrand factor (vWF) multimers, a glycoprotein that mediates platelet interaction with injured vessel walls, also contributes to microvascular platelet aggre-
gation.11 Consequently, thrombocytopenia occurs. Mechanical fragmentation of erythrocytes during passage along the vessels partially occluded by platelets and fibrin causes hemolysis. This may occur locally, for example, within the kidney and not be evident by examination of the peripheral smear. In the current case, the patient had normocytic and normochromic anemia with-
894
out evidence of hemolysis on peripheral smear with normal values of LDH, serum glutamic oxalacetic transaminase (SGOT), and haptoglobin. Although microangiopathic hemolytic anemia is one of the typical features of thrombotic microangiopathy, overt signs of hemolysis may not be present by the time patients present. Several case reports illustrate that lack of schistocytes on peripheral smear does not exclude the diagnosis of thrombotic microangiopathy.12-16 Five adult HUS patients without the presence of schistocytes on peripheral smear were reported in 1979 by Morel-Maroger and colleagues.12 In another case report, a Japanese female who had a diarrheal illness with E coli serotype O157:H7 developed ARF and thrombocytopenia.14 Renal biopsy showed mesangiolysis in glomeruli and necrosis in proximal tubules; arterioles and small arteries were normal. No thrombi were found. Electron microscopy showed separation of the endothelium from the basement membrane with fluffy material in the newly formed space and mesangial interposition and wrinkling of the basement membrane. Although histopathology of the specimen suggested HUS, there was no evidence of blood cell trapping or fibrin in the capillaries. In another patient with ARF, anasarca, and anemia without evidence of red cell fragmentation on peripheral-blood smear, kidney biopsy showed congested glomeruli with red cell fragments. Approximately 10 days after the kidney biopsy, peripheral blood smear showed very few schistocytes.13 Two additional cases of HUS without evidence of microangiopathic hemolytic anemia on peripheral blood smear, one with ARF, nephrotic syndrome, and indirect evidence of hemolysis suggested by an elevated serum LDH and one following allogeneic bone marrow transplantation, were recently reported.15,16 Our case illustrates an important point: namely, that HUS may, albeit rarely, occur without the detectable presence of schistocytes in the peripheral blood. In those circumstances, renal biopsy might be required to confirm the diagnosis, as in the case presented here. Severe renal involvement based on serum creatinine levels at the onset of the disease is associated with a long-term adverse prognosis, as in our patient. In a series of 43 adult patients, 20 patients (46%) had primary and 23 patients (54%) had secondary forms of HUS (due to malignant hypertension, preeclampsia, scleroderma, malignancies, and vasculitis).1 Thirty of 40 patients
GORAL ET AL
(75%) who had moderate to severe renal failure at the onset required dialysis during the acute phase of the disease. At 1-year follow-up, renal function had recovered only in 11 patients (26%). Six of 43 patients died (five of neurological complications), and 11 progressed to end-stage renal failure. However, Conlon et al2 reported that clinical and biochemical factors or need for dialysis at presentation were not indicative of poor outcome in 68 adult patients diagnosed with TTP or HUS.2 Most patients who developed ARF and survived hospital discharge recovered renal function. Morphological features such as extension of thrombotic microangiopathy to arterioles and patchy cortical necrosis also have been reported to be associated with poor renal recovery.12,17 Although these features were not present in our patient, the extent of endothelial injury was quite unusually widespread and severe, which would make regeneration and healing very difficult. Dialysis as the standard supportive therapy plays an important role for short-term survival in HUS. Specific therapies, including plasma infusions, plasmapheresis, corticosteroids, heparin, antiplatelet agents (aspirin, dipyridamole), prostacyclin, ␥-globulins, and vitamin E, have been reported in mainly uncontrolled studies with a small number of patients and are inconclusive.6,18 Larger controlled studies are needed to establish an effective therapy for HUS. Our patient did not respond to prolonged courses of plasmapheresis and the use of antiplatelet agents and remained dialysis dependent 6 months after presentation. Although the kidney biopsy showed specific morphological lesions, pointing to an HUS-like disease, it did not shed light on the underlying cause. Until more specific and effective therapies are available, recognition and diagnosis of the disease process will only be a first step toward improved outcomes for patients with HUS and related diseases. REFERENCES 1. Schieppati A, Ruggenenti P, Cornejo RP, Ferrario F, Gregorini G, Zucchelli P, Remuzzi G, for the Italian Registry of hemolytic uremic syndrome: Renal function at hospital admission as a prognostic factor in adult hemolytic uremic syndrome. J Am Soc Nephrol 2:1640-1644, 1992 2. Conlon PJ, Howell DN, Macik G, Kovalik EC, Smith SR: The renal manifestations and outcome of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in adults. Nephrol Dial Transplant 10:1189-1193, 1995
FEVER, THROMBOCYTOPENIA, ANASARCA, AND ARF
3. Boyce TG, Swerdlow DL, Griffin PM: Escherichia coli O157:H7 and the hemolytic-uremic syndrome. N Engl J Med 333:364-368, 1995 4. Boccia RV, Gelmann EP, Baker CC, Marti G, Longo DL: A hemolytic uremic syndrome with the acquired immunodeficiency syndrome. Ann Intern Med 101:716-717, 1984 5. Giroux L, Bettez P, Giroux L: Mitomycin-C nephrotoxicity: A clinico-pathologic study of 17 cases. Am J Kidney Dis 6:28-39, 1985 6. Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome. Kidney Int 47:2-19, 1995 7. Hassink RI, Zeerleder SS, Truttmann AC, Bianchetti MG: Hemolytic-uremic syndrome after Escherichia coli urinary tract infection. Pediatr Infect Dis 16:828, 1997 8. Berns JS, Kaplan BS, Mackow RC, Hefter LG: Inherited hemolytic uremic syndrome in adults. Am J Kidney Dis 19:331-334, 1992 9. Karmali MA, Petric M, Lim C, Fleming PC, Arbus GS, Lior H: The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis 151:775-782, 1985 10. Neill MA, Agosti J, Rosen H: Hemorrhagic colitis with Escherichia coli O157:H7 preceding adult hemolytic uremic syndrome. Arch Intern Med 145:2215-2217, 1985 11. Moake JL: Studies on the pathophysiology of thrombotic thrombocytopenic purpura. Semin Hematol 34:83-89, 1997 12. Morel-Maroger L, Kanfer A, Solez K, Sraer JD,
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Richet G: Prognostic importance of vascular lesions in acute renal failure with microangiopathic hemolytic anemia (hemolytic-uremic syndrome): Clinicopathologic study in 20 adults. Kidney Int 15:548-558, 1979 13. Scully RE, Mark EJ, McNeely WF, McNeely BU: Case records of the Massachusetts General Hospital, weekly clinicopathological exercises, case 41-1990. N Engl J Med 323:1050-1061, 1990 14. Akashi Y, Yoshizawa N, Oshima S: Hemolytic uremic syndrome without hemolytic anemia: A case report. Clin Nephrol 42:90-94, 1994 15. Brilliant SE, Lester PA, Ohno AK, Takeuchi A, Kubota T, Kondo S, Oda T, Shimuzu J, Ishida A, Nakabayashi I, Nishiyama J, Niwa H: Hemolytic-uremic syndrome without evidence of microangiopathic hemolytic anemia on peripheral blood smear. South Med J 89:342-345, 1996 16. Akiyama H, Yoshinaga H, Endou M, Tanikawa S, Sakamaki H, Tanoue K, Onozawa Y: Microangiopathy without hemolysis in a patient following allogeneic bone marrow transplantation. Bone Marrow Transplant 20:261-263, 1997 17. Siegler RL, Milligan MK, Burningham TH, Christofferson RD, Chang SY, Jorde LB: Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome. J Pediatr 118:195-200, 1991 18. Ruggenenti P, Lutz J, Remuzzi G: Pathogenesis and treatment of thrombotic microangiopathy. Kidney Int 51:S97S101, 1997
Fever, Thrombocytopenia, Anasarca, and Acute Renal Failure in a 50-Year-Old Woman Simin Goral, MD, Robert Horn, MD, John Brouillette, MD, and Agnes Fogo, MD ● INDEX WORDS: Hemolytic uremic syndrome; acute renal failure; microangiopathy.
W
E PRESENT a patient with fever, respiratory distress, oliguria, edema, bilateral pleural effusions, ascites, and acute renal failure (ARF). Multiple cultures and biopsies were pursued over the course of 3 weeks before a renal biopsy shed light on the nature of her systemic disease process. CASE REPORT
A 50-year-old white woman was admitted to hospital with a 3-week history of oliguria, shortness of breath, edema, and frequent loose stools. Her medical history was significant for diarrhea with two to three loose stools a day for the last 3 years, peptic ulcer disease, and asthma. She had total abdominal hysterectomy and bilateral salpingo-oophorectomy for recurrent bleeding from fibroids and ovarian cysts several years ago. Her medications on admission were omeprazole, estrogen/progesterone hormone replacement, albuterol inhaler as needed, and loperamide. She had 20 pounds weight gain over the previous 6 weeks. The week before admission, she had observed a decrease in the frequency of her urination and that her urine was the color of cherry cola the day before admission. The patient was married and a textile plant seamstress of 31 years. Her physical examination was remarkable for a temperature of 102.1°F, pulse of 115, respiratory rate of 24, and blood pressure of 137/74 mm Hg. She was ill-appearing with mild respiratory distress. There was no rash. Lung examination showed rales with bilateral dullness to percussion at the bases. Moderate peripheral edema was noted. Her neurological examination was normal. Laboratory evaluation on admission showed the following results: blood urea nitrogen (BUN), 23 mg/dL; serum creatinine, 1.4 mg/dL; serum albumin, 1.9 g/dL; total protein, 4.8 g/dL; hematocrit, 28%; platelets, 47,000/µL; erythrocyte sedimentation rate, 119 mm/hr. Liver function tests and lactate dehydrogenase (LDH) were normal. There were no schistocytes seen on peripheral smear, and her reticulocyte count was 2.1%. Hepatitis B and C serologies were
From the Departments of Medicine and Pathology, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN. Received and accepted January 27, 1998. Address reprint requests to Simin Goral, MD, Assistant Professor of Medicine, Vanderbilt University Medical Center, Division of Nephrology, S-3223 MCN, Nashville, TN 37232. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3105-0024$3.00/0 890
negative; anticardiolipin antibodies, antiplatelet antibodies, antinuclear antibody, and anti-DNA were negative, and complement levels were normal. Urinalysis showed 3⫹ protein with 2 to 5 red blood cells, 0 to 2 white blood cells, no casts, and no bacteria. No Bence-Jones protein was detected in the urine. A 24-hour specimen of urine showed 180 mg protein. Admission chest radiograph showed bilateral pleural effusions with no focal infiltrates and a normal cardiac silhouette. The patient was begun empirically on ceftriaxone and erythromycin. Blood, sputum, and urine cultures remained negative. Serologies for tularemia, brucella, and legionella were negative. Evaluation of her stool showed no white blood cells, ova, parasites, or Clostridium diffıcile toxin. Her folate and vitamin B12 levels were 9.3 ng/mL and 94 ng/mL, respectively, for which she was started on daily folate and B12 replacement. An ultrasound of her abdomen showed no urinary obstruction and no evidence of hydronephrosis, right and left kidney size of 10.1 and 9.2 cm, respectively, a small amount of ascites, and mild splenomegaly with an echogenic liver. A transthoracic echocardiogram showed a small pericardial effusion with no wall motion abnormalities and an ejection fraction of 65%. The patient remained febrile after 6 days of hospitalization with worsening shortness of breath as well as oliguria refractory to high-dose intravenous diuretics and persistence of her frequent loose stools. She underwent a therapeutic thoracentesis, which showed 43 white blood cells/mm3, 485 red blood cells/mm3, and no microorganisms. No malignant cells were seen on cytology. The pleural fluid chemistries showed an LDH of 324 U/L and total protein of 2.6 g/L. Antibiotic therapy was stopped. Computed tomography (CT) scan of her chest showed preaortic and axillary adenopathy, and small pericardial effusion. The CT scan of the abdomen showed mild splenomegaly and distension of the portal and hepatic veins with ascites but no adenopathy. A bone marrow biopsy showed a hypercellular marrow, increased numbers of megakaryocytes, and no infiltration by tumor, granulomas, or plasma cells. Acid-fast bacilli (AFB) and fungal stains were negative. Biopsy of the small bowel showed chronic inflammation of the lamina propria with plasma cells and lymphocytes. Subsequent colonoscopy showed diverticula throughout the colon without visible evidence of active bleeding or inflammation. Biopsy of the colon showed mild lymphocytic infiltration of the lamina propria. Congo red stain of both the small and large intestine was negative. She continued to have a fever up to 101.5°F. Her urine output decreased further, and her BUN and creatinine had increased to 37 mg/dL and 2.4 mg/dL, respectively. She had worsening peripheral edema with flank edema on examination consistent with anasarca. The cause of her systemic illness and renal failure continued to remain obscure. A diagnostic kidney biopsy was performed. The clinical differ-
American Journal of Kidney Diseases, Vol 31, No 5 (May), 1998: pp 890-895
FEVER, THROMBOCYTOPENIA, ANASARCA, AND ARF
ential diagnosis included systemic lupus erythematosus (SLE), vasculitis, subacute bacterial endocarditis, underlying inflammatory bowel disease, liver failure with cirrhosis, microangiopathy in association with an occult carcinoma, and thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS).
Renal Biopsy Findings The biopsy specimen contained 20 glomeruli; one or two were remotely obsolescent, and the remainder were generally intact and similar. Almost all glomeruli were congested with impacted red cells (Fig 1). A large proportion of these red cells was fragmented, with many irregular and small pieces of erythrocytes (Fig 2). Endocapillary cellularity was mildly increased. No necrotizing or crescentic features were present. Basement membranes showed no irregularities by silver stain. No occlusive plugs or materials resembling fibrin clot were evident. The tubules were generally intact without significant casts. Some distal tubules showed mild luminal dilatation consistent with acute tubular injury. There was no interstitial hemorrhage or infiltrate. Arterioles and arteries showed no lesions. Staining with monospecific antisera for immunoglobulin (Ig)G, IgA, IgM, C3 complement, and kappa and lambda light chains did not show any significant glomerular, tubular, or nuclear staining. Congo red stains were negative for amyloid. Electron microscopy showed normal thickness and density of glomerular basement membranes. No basement membrane or mesangial deposits were evident. Endocapillary cellularity was markedly increased, primarily because of large numbers of erythrocytes, as well as proliferation of endothelial and mesangial cells (Fig 3). Many erythrocytes were irregular in outline and fragmented, with some of the fragments within mononuclear cells and mesangial cells. In many loops, there was complete loss of endothelial cells, and erythrocytes and erythrocyte fragments were in immediate contiguity to the
Fig 1. Glomeruli congested with impacted red cells. (Hematoxylin-eosin, original magnification ⴛ375.)
891
inner aspect of the bare glomerular basement membrane. No fibrin tactoids were detected.
Diagnosis Although fibrin-containing clots were not detected in the biopsy specimen, diffuse and quite well-defined endothelial loss and erythrocyte fragmentation were strongly suggestive of a microangiopathic hemolytic process. The morphological findings suggested acute severe endothelial injury with hemolysis. A diagnosis of atypical microangiopathy consistent with a hemolytic process was made.
Clinical Course The patient was started on plasmapheresis with fresh frozen plasma. She subsequently required ultrafiltration on a daily basis during her initial therapy with plasmapheresis and hemodialysis three times a week. She was also started on dipyridamole 75 mg by mouth four times daily and aspirin 325 mg by mouth once per day. All cultures remained negative. Although she became afebrile and her respiratory symptoms resolved, her anemia, thrombocytopenia, edema, ascites, and diarrhea did not resolve completely. Six months after her initial presentation, she remains on dialysis. The cause of her HUS-like disease was not discovered.
DISCUSSION
We present a patient with thrombocytopenia and anemia with evidence of hemolysis only on the kidney biopsy, massive edema, and ARF in whom a kidney biopsy showed an atypical microangiopathy. HUS is usually characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia, microvascular thrombosis, and multiple organ dysfunction including the kid-
892
GORAL ET AL
Fig 2. Fragmented red cells evidenced by irregular, small pieces of erythrocytes within glomerulus. (Hematoxylin-eosin, original magnification ⴛ600.)
neys. Although the hospital mortality has decreased significantly in the last two decades, HUS is still associated with a significant mortality rate, ranging between 16% and 25% despite the widespread use of plasmapheresis.1,2 Typical (epidemic, diarrhea-associated, D⫹) HUS is associated with diarrhea, which is usually bloody. It occurs mainly in children, although rarely adults, especially the elderly, also may be affected. Verotoxin-producing Escherichia coli was responsible for many outbreaks of HUS around the world.3 The source of the infection was usually contaminated meat or apple cider. On binding to their specific receptors, toxins localize on the colonic mucosa, invade epithelial cells, and cause cell destruction. The damage to the vessels of the colonic mucosa causes hemorrhagic colitis. Elevated white cell count, a severe gastrointestinal prodrome, anuria early in the course, and an age younger than 2 years are the predictors of the severity of the illness.3 Atypical (non–diarrhea-associated, D–) or adult forms may be associated with pregnancy, malignant hypertension, oral contraceptives, chemotherapy, cyclosporine, HUS SLE, urinary tract infection, or human immunodeficiency virus (HIV) infection and usually manifest without prodromal diarrhea.4-7 HUS also may be familial and then frequently has a relapsing and progressive course.8 Our patient had a history of longstanding diarrhea associated with certain foods.
Therefore, tests for verotoxin-producing E coli were not done. She did not have any evidence for SLE or HIV infection clinically or in the renal biopsy. The morphology of renal lesion usually does not allow distinction of the underlying cause, except where HUS occurs secondary to another distinct renal lesion such as SLE. There was no history of HUS in her family. We cannot rule out the possibility of the estrogen/progesterone hormone replacement therapy or the history of a urinary tract infection several weeks before presentation as the causative agents of her disease. Although HUS primarily affects the kidney, other organs such as brain, colon, liver, and heart also can be affected. Interestingly, verotoxin receptors that mediate cytotoxic effects have been found in the kidneys, especially in the glomeruli, as well as in other organs (brain, lungs, and colon), suggesting the underlying reason for distribution of microvascular lesions in HUS.6 Autopsies on five patients with HUS showed multiple fibrin/platelet thrombi in organs other than the kidney, including brain, heart, and liver.2 Renal microvascular damage leads to macrohematuria or microhematuria, proteinuria (rarely nephrotic range), oliguria, and hypertension. Multiple mechanisms likely contribute to thrombocytopenia and hemolysis. Endothelial cell dysfunction, caused by infectious agents, including bacterial endotoxins and exotoxins (Shiga-like toxin, verotoxins produced by E coli), antibod-
FEVER, THROMBOCYTOPENIA, ANASARCA, AND ARF
893
Fig 3. Increased endocapillary cellularity, proliferation of endothelial and mesangial cells (A), many fragmented and irregular erythrocytes (A, B) with some of the fragments within mononuclear cells and mesangial cells (A), and extensive loss of endothelium (B). (Transmission electron micrograph, original magnification ⴛ5,200 [A], ⴛ6,500 [B].)
ies, immune complexes, certain drugs such as mitomycin, quinine and cyclosporine, or vasoactive peptides, is an important factor leading to intravascular platelet aggregation.9,10 The presence of unusually large von Willebrand factor (vWF) multimers, a glycoprotein that mediates platelet interaction with injured vessel walls, also contributes to microvascular platelet aggre-
gation.11 Consequently, thrombocytopenia occurs. Mechanical fragmentation of erythrocytes during passage along the vessels partially occluded by platelets and fibrin causes hemolysis. This may occur locally, for example, within the kidney and not be evident by examination of the peripheral smear. In the current case, the patient had normocytic and normochromic anemia with-
894
out evidence of hemolysis on peripheral smear with normal values of LDH, serum glutamic oxalacetic transaminase (SGOT), and haptoglobin. Although microangiopathic hemolytic anemia is one of the typical features of thrombotic microangiopathy, overt signs of hemolysis may not be present by the time patients present. Several case reports illustrate that lack of schistocytes on peripheral smear does not exclude the diagnosis of thrombotic microangiopathy.12-16 Five adult HUS patients without the presence of schistocytes on peripheral smear were reported in 1979 by Morel-Maroger and colleagues.12 In another case report, a Japanese female who had a diarrheal illness with E coli serotype O157:H7 developed ARF and thrombocytopenia.14 Renal biopsy showed mesangiolysis in glomeruli and necrosis in proximal tubules; arterioles and small arteries were normal. No thrombi were found. Electron microscopy showed separation of the endothelium from the basement membrane with fluffy material in the newly formed space and mesangial interposition and wrinkling of the basement membrane. Although histopathology of the specimen suggested HUS, there was no evidence of blood cell trapping or fibrin in the capillaries. In another patient with ARF, anasarca, and anemia without evidence of red cell fragmentation on peripheral-blood smear, kidney biopsy showed congested glomeruli with red cell fragments. Approximately 10 days after the kidney biopsy, peripheral blood smear showed very few schistocytes.13 Two additional cases of HUS without evidence of microangiopathic hemolytic anemia on peripheral blood smear, one with ARF, nephrotic syndrome, and indirect evidence of hemolysis suggested by an elevated serum LDH and one following allogeneic bone marrow transplantation, were recently reported.15,16 Our case illustrates an important point: namely, that HUS may, albeit rarely, occur without the detectable presence of schistocytes in the peripheral blood. In those circumstances, renal biopsy might be required to confirm the diagnosis, as in the case presented here. Severe renal involvement based on serum creatinine levels at the onset of the disease is associated with a long-term adverse prognosis, as in our patient. In a series of 43 adult patients, 20 patients (46%) had primary and 23 patients (54%) had secondary forms of HUS (due to malignant hypertension, preeclampsia, scleroderma, malignancies, and vasculitis).1 Thirty of 40 patients
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(75%) who had moderate to severe renal failure at the onset required dialysis during the acute phase of the disease. At 1-year follow-up, renal function had recovered only in 11 patients (26%). Six of 43 patients died (five of neurological complications), and 11 progressed to end-stage renal failure. However, Conlon et al2 reported that clinical and biochemical factors or need for dialysis at presentation were not indicative of poor outcome in 68 adult patients diagnosed with TTP or HUS.2 Most patients who developed ARF and survived hospital discharge recovered renal function. Morphological features such as extension of thrombotic microangiopathy to arterioles and patchy cortical necrosis also have been reported to be associated with poor renal recovery.12,17 Although these features were not present in our patient, the extent of endothelial injury was quite unusually widespread and severe, which would make regeneration and healing very difficult. Dialysis as the standard supportive therapy plays an important role for short-term survival in HUS. Specific therapies, including plasma infusions, plasmapheresis, corticosteroids, heparin, antiplatelet agents (aspirin, dipyridamole), prostacyclin, ␥-globulins, and vitamin E, have been reported in mainly uncontrolled studies with a small number of patients and are inconclusive.6,18 Larger controlled studies are needed to establish an effective therapy for HUS. Our patient did not respond to prolonged courses of plasmapheresis and the use of antiplatelet agents and remained dialysis dependent 6 months after presentation. Although the kidney biopsy showed specific morphological lesions, pointing to an HUS-like disease, it did not shed light on the underlying cause. Until more specific and effective therapies are available, recognition and diagnosis of the disease process will only be a first step toward improved outcomes for patients with HUS and related diseases. REFERENCES 1. Schieppati A, Ruggenenti P, Cornejo RP, Ferrario F, Gregorini G, Zucchelli P, Remuzzi G, for the Italian Registry of hemolytic uremic syndrome: Renal function at hospital admission as a prognostic factor in adult hemolytic uremic syndrome. J Am Soc Nephrol 2:1640-1644, 1992 2. Conlon PJ, Howell DN, Macik G, Kovalik EC, Smith SR: The renal manifestations and outcome of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in adults. Nephrol Dial Transplant 10:1189-1193, 1995
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3. Boyce TG, Swerdlow DL, Griffin PM: Escherichia coli O157:H7 and the hemolytic-uremic syndrome. N Engl J Med 333:364-368, 1995 4. Boccia RV, Gelmann EP, Baker CC, Marti G, Longo DL: A hemolytic uremic syndrome with the acquired immunodeficiency syndrome. Ann Intern Med 101:716-717, 1984 5. Giroux L, Bettez P, Giroux L: Mitomycin-C nephrotoxicity: A clinico-pathologic study of 17 cases. Am J Kidney Dis 6:28-39, 1985 6. Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome. Kidney Int 47:2-19, 1995 7. Hassink RI, Zeerleder SS, Truttmann AC, Bianchetti MG: Hemolytic-uremic syndrome after Escherichia coli urinary tract infection. Pediatr Infect Dis 16:828, 1997 8. Berns JS, Kaplan BS, Mackow RC, Hefter LG: Inherited hemolytic uremic syndrome in adults. Am J Kidney Dis 19:331-334, 1992 9. Karmali MA, Petric M, Lim C, Fleming PC, Arbus GS, Lior H: The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis 151:775-782, 1985 10. Neill MA, Agosti J, Rosen H: Hemorrhagic colitis with Escherichia coli O157:H7 preceding adult hemolytic uremic syndrome. Arch Intern Med 145:2215-2217, 1985 11. Moake JL: Studies on the pathophysiology of thrombotic thrombocytopenic purpura. Semin Hematol 34:83-89, 1997 12. Morel-Maroger L, Kanfer A, Solez K, Sraer JD,
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Richet G: Prognostic importance of vascular lesions in acute renal failure with microangiopathic hemolytic anemia (hemolytic-uremic syndrome): Clinicopathologic study in 20 adults. Kidney Int 15:548-558, 1979 13. Scully RE, Mark EJ, McNeely WF, McNeely BU: Case records of the Massachusetts General Hospital, weekly clinicopathological exercises, case 41-1990. N Engl J Med 323:1050-1061, 1990 14. Akashi Y, Yoshizawa N, Oshima S: Hemolytic uremic syndrome without hemolytic anemia: A case report. Clin Nephrol 42:90-94, 1994 15. Brilliant SE, Lester PA, Ohno AK, Takeuchi A, Kubota T, Kondo S, Oda T, Shimuzu J, Ishida A, Nakabayashi I, Nishiyama J, Niwa H: Hemolytic-uremic syndrome without evidence of microangiopathic hemolytic anemia on peripheral blood smear. South Med J 89:342-345, 1996 16. Akiyama H, Yoshinaga H, Endou M, Tanikawa S, Sakamaki H, Tanoue K, Onozawa Y: Microangiopathy without hemolysis in a patient following allogeneic bone marrow transplantation. Bone Marrow Transplant 20:261-263, 1997 17. Siegler RL, Milligan MK, Burningham TH, Christofferson RD, Chang SY, Jorde LB: Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome. J Pediatr 118:195-200, 1991 18. Ruggenenti P, Lutz J, Remuzzi G: Pathogenesis and treatment of thrombotic microangiopathy. Kidney Int 51:S97S101, 1997