| | Kidney Biopsy Findings in a Patient With Fever, Bilateral Pulmonary Infiltrates, and Acute Renal FailureReceived 22 June 2007; accepted 16 November 2007. published online 01 February 2008. An early diagnosis is necessary in patients presenting with pulmonary disease and acute renal failure to initiate the proper therapy and avoid irreversible renal and/or pulmonary damage or death. The differential diagnosis in such cases includes several distinct clinicopathological entities, such as Goodpasture syndrome, Wegener granulomatosis and other vasculitides, systemic lupus erythematosus, Henoch-Schönlein purpura, sarcoidosis, and systemic infections. Correct diagnosis requires a combination of clinical, laboratory, and histopathologic findings. We present a case that illustrates how detailed histopathologic examination on renal biopsy can be essential in making a correct diagnosis in a patient with an elusive clinical picture. Case Report  Clinical History The patient is a 67-year-old African-American man who presented with general malaise, weight loss, and multiple febrile episodes that started several weeks before his first admission. The patient had a medical history significant for type 2 diabetes mellitus, chronic kidney disease, prostate cancer status post–radiation therapy, gout, and congestive heart failure. On review of systems, the patient reported shortness of breath and cough, but denied chest pain, hemoptysis, abdominal pain, nausea, vomiting, diarrhea, dysuria, hematuria, melena, headaches, or visual changes. The patient was admitted for further evaluation. Physical examination showed blood pressure of 110/64 mm Hg, heart rate of 60 beats/min, respiratory rate of 20 breaths/min, and temperature of 38.2°C. Cardiac examination findings were unremarkable. Lungs were clear to auscultation. The abdomen was soft, nontender, and nondistended and had no palpable hepatosplenomegaly. No significant edema was noted in the extremities. Laboratory studies on this admission showed the following values: hemoglobin, 12.0 g/dL (120 g/L); hematocrit, 36.0%; white blood cell count, 2.4 × 103/μL (2.4 × 109/L), and platelet count of 196 × 103/μL (196 × 109/L). Automated differential showed 60% granulocytes, 17% lymphocytes, 23% monocytes, and 1% eosinophils. Blood urea nitrogen level was 47 mg/dL (16.8 mmol/L), and serum creatinine level was 4.3 mg/dL (328 μmol/L). Electrolytes on admission were as follows: sodium, 136 mEq/L (mmol/L); potassium, 4.2 mEq/L (mmol/L); chloride, 102 mEq/L (mmol/L); bicarbonate, 23 mEq/L (mmol/L); and total calcium, 10 mg/dL (2.5 mmol/L). Urinalysis showed specific gravity of 1.010, pH of 5.5, protein level of 0.3 g/dL (3.0 g/L), and small amount of hemoglobin, whereas bilirubin, leukocyte esterase, nitrate, glucose, and ketones were negative. The patient underwent extensive workup to rule out infectious and autoimmune processes that included human immunodeficiency virus serological tests, cytomegalovirus titers, legionella titers, legionella antibody, coxsackievirus antibody, and adenovirus antibody; all had negative results. A purified protein derivative was placed and was negative. Bacterial, fungal, and mycobacterial blood cultures, as well as bacterial urine cultures, were negative. Serological studies for antineutrophil cytoplasmic antibodies (ANCAs) and antinuclear antibodies were also negative. Complement levels were normal. Computed tomography (CT) of the chest showed focal subpleural scarring, predominantly in the upper lobes; no air space disease or effusions were present. Abdominal CT and ultrasonography identified 2 cystic lesions in the upper and lateral midpole of the right kidney, whereas the left kidney was atrophic; studies to further characterize the unilateral cystic process were not performed at this time. CT of the head was unremarkable. Gallium scan showed no abnormalities, and transesophageal echocardiogram did not show signs of endocarditis. A bone marrow biopsy was performed and showed normocellular marrow with the presence of focal noncaseating granulomas, which were negative for acid-fast bacilli (AFB) and fungal organisms. At this point, the patient’s symptoms were attributed to a noninfectious cause, most likely sarcoidosis. The patient was discharged and scheduled for outpatient follow-up with no specific therapy instituted at this time. The patient was readmitted approximately 3 months later with increasing lethargy, confusion, shortness of breath, and cough. No interval history could be obtained from the patient because of his altered mental status. Vital signs on this admission were as follows: blood pressure, 166/85 mm Hg; pulse, 63 beats/min; respiratory rate, 18 breaths/min; temperature, 39.4°C; and pulse oximetry on room air, 86%. Breath sounds were decreased bilaterally. Cardiac and abdominal examination showed normal findings. Neurological examination did not show focal deficits. Trace bilateral lower-extremity edema was present. Admission laboratory data showed the following values: sodium, 131 mEq/L (mmol/L); potassium, 3.8 mEq/L (mmol/L); chloride, 101 mEq/L (mmol/L); bicarbonate, 19 mEq/L (mmol/L); blood urea nitrogen, 97 mg/dL (34.6 mmol/L); and creatinine, 6.2 mg/dL (473 μmol/L). Urinalysis confirmed specific gravity of 1.010, with 2+ protein and 3+ blood on dipstick, 20 to 30 red blood cells/high-power field, and occasional white blood cells. Based on protein-creatinine ratio, proteinuria was estimated to be protein of about 2.0 g/24 h; a 24-hour urine collection for protein quantification was not performed at this time. White blood cell count was 14.0 × 103 (14 × 109/L; neutrophils, 81.9%; lymphocytes, 4.5%; monocytes, 13.3%; eosinophils, 0%; and basophils, 0.3%), hemoglobin level was 10.1 g/dL (101 g/L), hematocrit was 31.2%, and platelet count was 155 × 103/μL (155 × 109/L). Bacterial and fungal blood cultures were sent, as were sputum cultures for mycobacteria. Bilateral interstitial infiltrates were seen on a chest radiograph; CT of the chest showed diffuse, bilaterally increased interstitial markings. CT of the head was negative for any acute intracranial process. Ultrasound of the abdomen showed an atrophic left kidney and increased echogenicity of the upper pole of the right kidney. Hemodialysis therapy was begun on admission, and the patient was empirically started on azithromycin, 1 g/d, and ceftriaxone, 500 mg/d. A renal biopsy was performed to determine the cause of the renal failure with nephritic urinary sediment. In the background of the patient’s respiratory and systemic symptoms, pauci-immune glomerulonephritis and processes of infectious cause were considered in the differential diagnosis. Kidney Biopsy The sample submitted for light microscopic examination consisted of renal medulla and cortex with 9 glomeruli, 2 of which were globally sclerosed. The preserved glomeruli were enlarged and showed diffuse mesangial expansion, in some places nodular, caused by an increase in amount of mesangial matrix. There was no significant hypercellularity of glomeruli; endocapillary proliferation or cellular crescents were not seen. A single glomerulus was infarcted, in association with fibrinoid necrosis of its arteriole (Fig 1A and B). The interstitium showed large areas of caseating necrosis, alternating with areas of viable kidney parenchyma infiltrated by numerous lymphocytes, macrophages, some neutrophils, and scattered multinucleated giant cells (Fig 1C and D). Tubules showed various degenerative and reactive changes, including distension of the lumens, attenuated epithelium, nuclear enlargement, and a few mitotic figures, in the absence of viral inclusions. The necrotizing interstitial process extended into adjacent tubules in several foci. Arteries and arterioles showed subintimal sclerosis, with focal luminal narrowing. One arteriole in particular was surrounded by interstitial caseating necrosis and showed fibrinoid necrosis of its wall, probably caused by direct extension of the surrounding necrotizing interstitial process (Fig 1B). Fungal organisms were not detected on several periodic acid–Schiff–stained sections. Staining for Ziehl-Neelsen AFB showed few pink-red rod-like microorganisms in areas of caseating necrosis and was interpreted as positive; the Fite-Feraco modified acid-fast stain was used to confirm the result. Material submitted for immunofluorescence studies contained only renal medulla. There was focal reactivity for complement C3 in a few arterioles. Several intratubular casts showed polyclonal reactivity for immunoglobulin A. There was no significant reactivity for immunoglobulin G, immunoglobulin M, C4, or C1q. A single glomerulus available for ultrastructural examination showed focal effacement of visceral epithelial cell foot processes, irregular thickening of glomerular basement membranes, and mesangial expansion caused by an increase in extracellular matrix. No electron-dense deposits or endothelial tubuloreticular inclusions were identified in glomeruli. Numerous inflammatory cells were seen in the interstitium and consisted mainly of lymphocytes and macrophages, with some polymorphonuclear inflammatory cells. Microorganisms were not detected. Diagnosis The major finding in this kidney biopsy specimen is extensive necrotizing granulomatous interstitial nephritis (GIN) caused by AFB infection, shown by positive tissue Ziehl-Neelsen AFB stain. Additionally, there was evidence for moderately advanced diffuse and nodular glomerulosclerosis in this patient with long-standing diabetes mellitus. Clinical Follow-up After the renal biopsy, the patient was started on rifampin, isoniazid, pyrazinamide, and ethambutol treatment. Cerebrospinal fluid, blood, bronchoalveolar lavage, and renal biopsy tissue cultures were submitted for mycobacterial culture. Bronchoalveolar lavage and renal biopsy tissue were positive for Mycobacterium tuberculosis on day 38 of culture. Sensitivity studies were performed and showed sensitivity to isoniazid, rifampin, and ethambutol. Cerebrospinal fluid cultures were negative for mycobacteria. The patient began to have slight improvement in mental status 15 days after initiation of therapy, but delirium persisted despite continuation of treatment. Because of his persistently altered mental status, poor general condition, and dialysis dependence, the family in conjunction with the clinical team decided to transfer the patient to a hospice facility. Discussion A variety of conditions can cause simultaneous kidney and lung disease. The most common causes include various forms of primary systemic vasculitis associated with ANCA (Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis), Goodpasture syndrome (anti–glomerular basement membrane disease with pulmonary capillaritis), systemic lupus erythematosus, sarcoidosis, and systemic infections1; all of these should be carefully considered in the differential diagnosis of concurrent pulmonary and renal disease. ANCA-associated vasculitides are the most common form of primary systemic vasculitides in adults, frequently presenting with both pulmonary and renal disease. ANCA-associated vasculitides are also the most common cause of pulmonary-renal syndrome, defined by the coexistence of pulmonary hemorrhage and glomerulonephritis.2 Goodpasture syndrome is much less common, but frequently is a very aggressive disease. Most patients present acutely with pulmonary hemorrhage and renal failure, but patients with a slowly progressive course and mild respiratory or renal symptoms, posing diagnostic difficulties, also were described.3, 4 Both ANCA-associated vasculitides and Goodpasture syndrome typically present with a crescentic pattern of glomerular injury on kidney biopsy; immunofluorescence studies are fundamental in distinguishing between the 2 entities. Systemic infections, in particular, mycobacterial and fungal, must be considered in the differential diagnosis of simultaneous pulmonary and renal disease.5 The genitourinary system is the second most common site of extrapulmonary tuberculosis, accounting for 15% to 20% of nonpulmonary infections.5 In patients with a diagnosis of genitourinary tuberculosis, 10% show signs of active pulmonary tuberculosis, 25% have a known history of previous pulmonary infection, and only 25% to 50% of patients have radiographic evidence of subclinical or remote pulmonary infection. When there is a history of pulmonary infection, the latency period is generally long, ranging from 5 to 40 years from the time of the initial infection and diagnosis with renal disease.5 Tuberculosis may involve the kidney as a localized process or a component of disseminated disease.6 In either scenario, kidney infection results from hematogenous seeding of M tuberculosis to the renal capillary bed from a pulmonary source of primary infection.7, 8 Initially infecting the lung parenchyma, bacilli will spread through the lymphatic system to lymph nodes draining the infected area and from there, reach the thoracic duct and ultimately gain access to the systemic venous circulation, subsequently seeding various organs. In the kidneys, granulomas are initially formed in the renal cortices around glomeruli, where high blood perfusion and favorable oxygen tension allow proliferation of mycobacteria.8 In most individuals with intact cellular immunity, mycobacterial proliferation will be contained within granulomas and the infection may remain latent for decades or indefinitely.7, 8 However, in some cases, the microorganisms are able to evade the host’s defense mechanisms and cause active disease. In these instances, mycobacteria proliferate, eventually gaining access to the proximal tubules and loops of Henle, and cause a more extensive inflammatory reaction, often with formation of coalescent necrotizing granulomas, which can evolve to highly destructive lesions of the kidney. During this process, local spread of the infection to adjacent renal pelvis, ureters, bladder, and genital organs may take place. Kidney damage and dysfunction is complicated further by the fibrosis, strictures of the collecting system, and tissue calcium deposition that occurs secondary to the chronic inflammatory process.8 Clinical manifestations of genitourinary tuberculosis are variable and may mimic the presentation of other more common genitourinary diseases, often causing the diagnosis of this condition to be delayed or even missed. Patients may present with a variety of symptoms, including back pain, hematuria, symptoms of “conventional” bacterial cystitis, or constitutional symptoms. The diagnosis is often suspected when patients present with symptoms otherwise characteristic of urinary tract infections and positive urine leukocytes, but no associated bacterial isolates on routine cultures (sterile pyuria). Symptoms and laboratorial findings of renal failure may also be present in patients with advanced disease.6 The clinical picture in patients with disseminated (miliary) tuberculosis is often subtle and nonspecific and very often occurs as a result of primary infection, but sometimes may be a result of progressive untreated tuberculosis. Importantly, the signs of chronic genitourinary tuberculosis are commonly absent.9 The absence of miliary pattern on chest radiograph does not exclude disseminated disease.9 Renal tuberculous and mycotic infections typically present with necrotizing GIN on kidney biopsy. In general terms, GIN is seen rarely on renal biopsy and is caused infrequently by infections. Several large case series documented the incidence of GIN in renal biopsy specimens at only 0.5% to 0.9%, with only 5% of cases caused by infection.10, 11, 12, 13 The most common causes of GIN in the United States are drugs (nonsteroidal anti-inflammatory agents, anticonvulsant drugs, antibiotics, and antihypertensive agents) and sarcoidosis, both of which account for approximately 75% of all cases. Wegener granulomatosis is also a rare cause of GIN, with the incidence varying from 5% to 25% of all causes, and is usually non-necrotizing.10, 13 The presence of microorganisms can be proved in granulomas by using AFB or auramine O stains for mycobacteria and periodic acid–Schiff or silver-based stains for fungal organisms. AFB stains are notorious for low sensitivity in histological preparations, varying from 32% to 43% in some reports.14, 15, 16 Combinations with immunohistochemical stains14 or polymerase chain reaction17 are suggested to increase both the sensitivity and specificity of AFB stains, but these methods are not widely used or available in everyday practice. The auramine O stain shows better sensitivity, but lower specificity, compared with Ziehl-Neelsen AFB stain18 and therefore should be used to complement rather than replace the standard Ziehl-Neelsen stain. Because tissue biopsy is an invasive procedure with low sensitivity and specificity of microorganism detection, there is a need for rapid and sensitive laboratory detection of M tuberculosis. Traditionally, urine culture was considered the gold standard for the diagnosis of genitourinary tuberculosis. Because of its low sensitivity (as low as 37%),19 at least 3 first-morning-void urine samples should be submitted for culture.6, 20 More recently, DNA amplification techniques proved useful for the rapid diagnosis of M tuberculosis in numerous types of tissue and body fluid specimens. Mycobacterial polymerase chain reaction on urine samples had sensitivity and specificity of 84% to 95% and 85% to 98%, respectively.19, 21 Polymerase chain reaction provides a quick and noninvasive approach to the diagnosis of genitourinary tuberculosis. However, it does not obviate the need for a culture diagnosis because there currently is no way to assess antibiotic sensitivities except by culture. Our case describes a patient presenting with fever, cough, shortness of breath, and worsening renal function with development of active urinary sediment that prompted the kidney biopsy. An extensive and prolonged laboratory workup was believed to have ruled out an infectious cause during the patient’s first admission; bacterial, fungal, and mycobacterial blood cultures and bacterial urine cultures were negative. The patient’s purified protein derivative test was repeatedly negative. His pulmonary presentation was atypical for tuberculosis (no hemoptysis or signs of cavitation or consolidation on chest radiograph), and signs or symptoms characteristic of renal tuberculosis (pyuria, hematuria, and flank and abdominal pain) were not present throughout the course. The patient’s chronic renal failure was attributed to his long-standing diabetes mellitus; cystic lesions seen on ultrasound and abdominal CT during his first admission were believed to be related to the chronic renal disease and dismissed as irrelevant to the patient’s underlying systemic disease. At the later time, the patient’s mental status deteriorated and he developed bilateral pulmonary interstitial infiltrates and rapid deterioration of renal function with active urinary sediment. The differential diagnosis of this elusive clinical presentation was broad and included systemic vasculitides, autoimmune diseases, and systemic infection. The kidney biopsy was essential in providing the correct diagnosis of renal tuberculosis. Subsequently, it was concluded that the patient had a miliary form of tuberculosis characterized by vague clinical presentation, nonspecific pulmonary infiltrates, concurrent granulomatous disease in the bone marrow, and renal involvement. In summary, genitourinary tuberculosis is a rare cause of renal failure in the United States. The low prevalence, along with the nonspecific presentation of the disease, makes it a difficult clinical diagnosis. However, it is an especially important consideration in the differential diagnosis of acute or worsening chronic renal failure in the background of pulmonary symptoms because it is easily treatable and early diagnosis can prevent irreversible end-organ damage. A high index of suspicion and diagnostic awareness on the part of the clinician are necessary to prevent significant unnecessary morbidity in patients with this disease. Acknowledgements Support: None. Financial Disclosure: None. References 1. 1Jara LJ, Vera-Lastra O, Calleja MC. Pulmonary-renal vasculitic disorders: Differential diagnosis and management. Curr Rheumatol Rep. 2003;5:107–115. MEDLINE |
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Department of Pathology, Emory University School of Medicine, Atlanta, GA.  Address correspondence to Vanesa Bijol, MD, Pathology and Lab Medicine, Emory University, EUH, H188, 1364 Clifton Rd NE, Atlanta, GA 30322.
PII: S0272-6386(07)01589-2 doi:10.1053/j.ajkd.2007.11.014 © 2008 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved. | |
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