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Acute renal failure presenting as a granulomatous interstitial nephritis due to cryptococcal infection
the renal consult
http://www.kidney-international.org & 2009 International Society of Nephrology
Acute renal failure presenting as a granulomatous interstitial nephritis due to cryptococcal infection Sungjin Chung1, Cheol W. Park1, Hyun W. Chung1 and Yoon S. Chang1 1
Division of Nephrology, Department of Internal Medicine, St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
CASE PRESENTATION A 64-year-old man was referred to our hospital because of acute renal failure of unknown etiology; he had a 2-week history of intermittent fever, chills, easy fatigue, cough, and exertional dyspnea. In addition, he reported generalized edema and a weight gain of 6 kg over 1 month. The past medical history was remarkable for pulmonary tuberculosis treated 15 years earlier and previous tobacco abuse. The patient denied recent travel, exposure to animals, and medications; he had been generally healthy without systemic disease, including diabetes and hypertension. Six months before presentation, a routine medical evaluation at a local hospital showed that he had no health problems.
Correspondence: Yoon S. Chang, Division of Nephrology, Department of Internal Medicine, St. Mary’s Hospital, The Catholic University of Korea, 62, Yeouido-dong, Yeongdeungpo-gu, Seoul 150-713, Republic of Korea. E-mail: [email protected] Kidney International (2009) 76, 453–458; doi:10.1038/ki.2008.494; published online 1 October 2008 Received 25 November 2007; revised 24 June 2008; accepted 29 July 2008; published online 1 October 2008 Kidney International (2009) 76, 453–458
On admission the physical examination showed a body temperature of 37.8 1C, the blood pressure was 110/ 70 mm Hg, the pulse rate was 110 beats/min, and the respiratory rate was 28 breaths/min. There were no signs or symptoms indicating a neurological disorder. There was no palpable regional lymphadenopathy or abnormally pigmented skin lesions. Coarse inspiratory crackles were audible bilaterally over the basal lung fields. The abdomen was flat and soft without organomegaly. However, tenderness was noted at both costovertebral angles. In addition, there was pitting edema of both lower legs. The urine dipstick test was positive for protein (2 þ ), with leukocyturia and microscopic hematuria on microscopic examination; the 24-h urine collection had 810 mg of protein. The other biochemical values are summarized in Table 1. All viral markers were negative, including hepatitis B surface antigen, hepatitis C antibody, cytomegalovirus immunoglobulin M antibody, herpes simplex immunoglobulin M antibody, human immunodeficiency virus (HIV), and hantavirus antibody. An initial chest X-ray showed no active lung lesions, except for fibrocalcified opacities at both upper lung fields. The renal ultrasound revealed enlargement of both kidneys with normal corticomedullary differentiation, suggesting acute renal parenchymal disease. The patient was treated with intravenous fluid administration and empirical antibiotics for presumed acute bilateral bacterial pyelonephritis. The initial and follow-up cultures of the blood, urine, and sputum revealed no organisms. Despite a change of the antibiotics later, the pyuria persisted, the leukocytosis worsened over the following days, and the serum creatinine increased up to 4.26 mg/100 ml. The worsening azotemia and newly developed pulmonary edema required hemodialysis. Additional laboratory data including serologies were normal: negative antinuclear antibodies, negative antineutrophilic cytoplasmic antibodies, negative cryoglobulins, and normal complements levels. There was no sign of disseminated intravascular coagulation by tests of the clotting and fibrinolytic systems. The serum and urine protein electrophoresis revealed a slight acute phase response and the urine test for the Bence Jones protein was negative. A computerized tomographic scan of the abdomen and pelvis showed marked increase in the size of both kidneys (the left was 14.7 cm and the right 17.0 cm in length) with diffusely decreased enhancement, but gave no additional information 453
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Table 1 | Laboratory data at presentation Blood test (unit) White blood count ( 109/l) Hemoglobin (g/100 ml) Hematocrit (%) Platelet ( 109/l) ESR (mm/h) CRP (mg/l) Sodium (mmol/l) Potassium (mmol/l) Chloride (mmol/l) Blood urea nitrogen (mg/100 ml) Creatinine (mg/100 ml) Glucose (mg/100 ml) Total protein (g/100 ml) Albumin (g/100 ml) AST (IU/l) ALT (IU/l) Creatinine phosphokinase (IU/l)
Reference range
On admission
5.0–10.0 14–18 42–52 150–450 0–10 o5 135–148 3.5–5.1 98–108 8–23 0.5–1.2 60–110 6.7–8.3 3.8–5.3 13–36 5–40 26–400
7.4 11.8 33.7 36 120 184.19 132 6.6 97 96.2 3.98 72 5.68 2.62 41 31 40
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
Figure 1 | An abdominal computed tomography (CT) of the kidneys shows marked enlargement of both kidneys.
(Figure 1). We considered initially that the acute renal failure was because of a bacterial pyelonephritis or a renal abscess. However, there was no evidence of a specific infection from the biochemical studies or the culture results. The renal function of the patient continued to worsen without response to the antibiotics. A rapidly progressive glomerulonephritis was thought to be the probable diagnosis. A renal biopsy was performed to ascertain the etiology of the acute renal failure. RENAL BIOPSY FINDINGS
Light microscopic examination disclosed one core of cortex containing only two glomeruli, which were not sclerotic. The renal tubules showed atrophic changes. The interstitium was markedly infiltrated by abundant mononuclear cells and neutrophils with noncaseating granulomas (Figure 2a). There was a mild degree of interstitial fibrosis. The immunofluorescent studies were negative for immunoglobulins and 454
Figure 2 | Representative microphotographs of the first renal biopsy from the patient. Low-power view shows interstitial inflammation and granulomatous changes (a; original magnification 200, hematoxylin and eosin). High-power view (b; original magnification 400, PAS) reveals several interstitial yeast forms (arrowhead). The yeast (arrowhead) stained positively for Fontana-Masson silver (c; original magnification 400, Fontana-Masson silver).
complements. Special stains for microorganisms were performed to exclude infectious etiologies. Periodic acidSchiff (PAS) and silver methenamine revealed a few scattered fungal yeast-like organisms within the cortical interstitium (Figure 2b). Although the etiology of the yeast forms could be not identified, a presumptive diagnosis of granulomatous interstitial nephritis (GIN) due to a fungal infection was made based on the renal pathological findings. Treatment with oral fluconazole, 200 mg/day orally, was started. Because the first biopsy was an insufficient specimen, for clarification Kidney International (2009) 76, 453–458
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Serum creatinine (mg/100 ml)
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1 st Bx 2nd Bx
4.5 4 3.5 3 2.5 2 1.5 1 0.5 0
3 rd Bx
Fluconazole
HD 0
1
2
3
5
6
7
25
42
Week
Figure 3 | Clinical course of the patient. Serum creatinine level decreases slowly after fluconazole treatment but does not return to completely normal (Bx, renal biopsy; HD, hemodialysis).
of the etiology of the fungal infection, a repeat renal biopsy was performed. The light microscopy confirmed the findings of the first biopsy. The yeast forms were negative for Alcian blue and mucicarmine stains, but they were positive for the Fontana-Masson stain (Figure 2c), suggesting a capsuledeficient cryptococcal infection. CLINICAL FOLLOW-UP
The serially repeated results of the serum cryptococcal antigen test were negative. With the continued administration of fluconazole, the renal function recovered slowly in association with an improved general condition (Figure 3). At discharge, in September 2004, the creatinine level was 1.78 mg/100 ml. In May 2005, 4 months after cessation of 6 months of fluconazole therapy, a post-treatment renal biopsy was performed to determine why the renal function did not return to normal. The light microscopic examination showed that 10 of 90 glomeruli had global sclerosis and all of the others had segmental sclerosis. The renal tubules showed marked atrophic changes with no frank necrosis. A moderate degree of mononuclear cell infiltration and marked fibrotic changes were seen in the interstitium (Figure 4). The special stains were all negative. In August 2006, at the last visit to our clinic the patient was doing well except for the elevation of his creatinine to 2.98 mg/100 ml. DISCUSSION
A granulomatous inflammatory response is ubiquitous in pathology; it is a manifestation of many infectious, toxic, allergic, autoimmune, and neoplastic diseases as well as conditions of unknown etiology.1,2 Recognition of the characteristics of the granuloma with regard to its etiology, degradability, and immunogenicity is important for patient management.2 In the field of renal pathology, granuloma formation can be encountered in the limited setting of acute interstitial nephritis. For example, in the report by Viero and Cavallo,3 granulomas were detected in only 12 cases (incidence: 5.9%) of 203 renal biopsies during a 20-year period; Bijol et al.4 identified 46 cases (0.5%) of GIN over a 17-year period at a single institution. Recently, Joss et al.5 also reported their experience with only 18 patients (o1%) among their renal biopsies during a 15-year period. The Kidney International (2009) 76, 453–458
Figure 4 | Representative microphotograph of the posttreatment renal biopsy from the patient. A marked degree of interstitial fibrosis with mononuclear cell infiltration and tubular atrophy is shown, consistent with chronic interstitial nephritis (original magnification 200, PAS).
Table 2 | Causes of granulomatous interstitial nephritis Cause Drug BCG, intravesical Antibiotics (ampicillin, vancomycin, cefuroxime, clarithromycin, fluoroquinolone, rifampin, etc.) NSAIDs Diuretics (thiazide) Allopurinol Anticonvulsant (lamotrigine) Omeprazole Bisphosphonate All-trans retinoic acid Heroin abuse Infection Bacteria (E. coli, rhodococcus, etc.) Mycobacterium tuberculosis Virus (adenovirus, HIV, etc.) Fungus (histoplasma, candida, cryptococcus, etc.) Inflammatory or systemic condition Sarcoidosis Wegener’s granulomatosis Tubulointerstitial nephritis and uveitis syndrome Crohn’s disease Hematologic malignancy (leukemia, multiple myeloma) Idiopathic
Reference 4,6 5,7–11
5,11 5,11 5,12 5,16 13 14 15 17
3,11,18,19 11 20–22 11,23–25
3,4,5 3,5 5 26 27
5,28
BCG, Bacille Calmette-Guerin; HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs.
cause of GIN varies. Among the more common causes are drugs and sarcoidosis; approximately 25–45% of cases with GIN are drug induced.3,4 The medications that are commonly implicated are antibiotics, nonsteroidal anti-inflammatory drugs, allopurinol, and diuretics, as shown in Table 2. In addition to drugs, other agents or conditions commonly associated with GIN include infections, allergies, autoimmune, and neoplastic disorders and in some cases the etiology is idiopathic. The pathogenic mechanism underlying GIN is poorly understood. However, evidence derived from various 455
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observations suggests a T-cell-mediated reaction.2,3 The predominance of mononuclear cells in the interstitial infiltrates, the presence of mostly T cells, the presence of granulomas, and the absence of immunoglobulin deposition in the tubules or interstitium support a T-cell-mediated mechanism.3 Because GIN occurs with diverse conditions, the mechanisms of tissue injury and/or the components of the granuloma can also vary. When GIN is infection related, there is an abundance of neutrophils, which predominates over all other cell types, although in such biopsies the number of T cells, macrophages, and B cells is also impressive and consistent with the findings of biopsies from drug- and sarcoid-related granulomatous GIN.3 Infection-related GIN accounts for only a small percentage of cases, about 6.7% of the total number of cases from the three largest series reported.4,5,23 Mycobacteria and fungi are the main etiologies of the infectious causes and account for most cases of infectious GIN in renal transplants.3,5 GIN secondary to fungal infection, mainly with the Histoplasma and Candida species, has been described in a few cases,3,23–25 primarily in patients who are immunocompromised. In the case presented here we identified another fungal infection, Cryptococcus, as a cause of GIN in an immunocompetent host. The encapsulated yeast, Cryptococcus species, is a major opportunistic fungal pathogen that is recognized worldwide.29 More than 30 species are included in the genus Cryptococcus. The pathogenic yeasts of Cryptococcus currently consist of two species: C. neoformans and C. gatti. In the environment, C. neoformans is primarily found worldwide in association with the excrement of certain birds, such as pigeons and tree hollows. C. gatti has been found primarily in tropical and subtropical regions. However, more currently, there has been unprecedented emergence of these isolates on Vancouver Island since 1999, demonstrating that the distribution and ecology of this organism is now changing; it is now associated with a wide range of trees, such as firs and oaks.30 The specific source of the infection and the form responsible for human infections have not been definitely established. Direct evidence for human infection from either eucalyptus trees or pigeon excrement has not been established. However, it is recommended that individuals at risk for Cryptococcus avoid sites that are contaminated with pigeon excrement and avoid having certain birds, such as pigeons, canaries, and cockatoos, as pets.30 In general, cryptococcal infection is an uncommon systemic fungal infection that occurs primarily in patients who have impaired immunity, such as patients with hematologic malignancies, organ transplants, and those taking systemic corticosteroids or other immunosuppressants. Since the epidemic of HIV infections, Cryptococcus has become an important opportunistic infection in HIVinfected individuals; as a result its incidence has increased dramatically.30,31Solid organ transplant recipients are also recognized to be at increased risk for Cryptococcus 456
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infections. Current estimates suggest that 20–60% of the cases with Cryptococcus infections, that are HIV negative, occur in organ transplant recipients.32,33 Although renal transplant recipients have been thought to have the lowest incidence of fungal infection compared with other organ transplants, 3.5–5% of infections, in renal transplant recipients, are due to fungi,34,35 and among the fungal infections, Cryptococcus is the third most common in renal transplant recipients after candida and aspergillus, as well as in all solid organ transplant recipients.35,36 More importantly, despite the initiation of therapy, the mortality rate associated with this infection, in this patient population, remains high.32 In addition to patients with renal transplants, nephrologists encounter cryptococcal infections in patients treated with immunosuppressive agents, those have renal failure37,38 or on dialysis.39 Patients on dialysis have a nearly 10-fold increased risk for hospitalizations resulting from fungal infections compared to the general population.39 Of the leading etiologies of fungal infections in dialysis patients, Cryptococcus (6%) has been reported to be the second most common after candida (79%).39 Because patients with chronic renal failure and patients on maintenance dialysis therapy have been shown to have a wide range of immune deficiencies and increased risk for infection following instrumentation, it is not surprising that this patient population has an increased risk for being hospitalized for fungal infections including Cryptococcus.38,39 The central nervous system and respiratory tract are the most common organs involved in cryptococcal infection. In a review of non-HIV-infected patients, 36% of cases had only pulmonary involvement, 51% of cases had central nervous system disease, and the remainder had other or multiple sites of infection.31 In fact, this yeast can cause disease in every organ of the human body, including skin, eyes, bone, blood, prostate, and the urinary tract.30 Cryptococcus enters the body through the lungs, the most common portal of entry for infection, and becomes disseminated hematologically with a predilection for the central nervous system and skin and less frequently to other sites such as the urinary tract and kidneys.30,32,33 Most cases with Cryptococcus of the kidneys have disseminated disease in immunocompromised hosts; generally the infection begins in the lungs and spreads to the brain and meninges.40–44 Reviews of patients with disseminated Cryptococcus have demonstrated renal involvement in 26–51.2% of cases.34,42 There may be signs and symptoms of cystitis, pyuria, hematuria, moderate proteinuria, and laboratory evidence of renal insufficiency.44 The characteristic lesion in the kidney is a non-suppurating granuloma.41 The fungi spread through the blood stream and lodge within the glomeruli where they can form abscesses followed by granulomatous inflammation.40 A caseous appearance is sometimes produced by the widespread death of the cryptococci, possibly due to the development of hypersensitivity host responses.40,41 Cortical and medullary abscesses, caseation necrosis and interstitial inflammation, fibrosis, and papillary necrosis have also been noted.43,44 However, Kidney International (2009) 76, 453–458
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without such characteristic lesions, only extensive necrosis and suppuration may be present.41 The histopathological features may vary according to the immune status of the infected host. In an immunocompetent individual, a typical granuloma is usually observed at the site of the cryptococcal infection. However, no purulent inflammatory responses are usually observed in the cryptococcal lesions of AIDS patients.45 Granulomatous inflammation, like any inflammatory reaction, frequently results in tissue damage during the active phase and fibrosis during the healing process.1,5 Granulomas can resolve but are often replaced by scar tissue. This is the likely explanation for the renal function not returning to normal in our patient. The treatment of choice for Cryptococcus depends on the anatomical site of involvement and the host’s immune status. The guidelines published by the Infectious Disease Society of America provide recommendations for clinicians and can be used at the beginning of treatment to guide clinical decisions for patients with Cryptococcus infections. However, the guidelines are not absolute or definitive and a given specific clinical situation may demand creative management.29 Treatment strategies for Cryptococcus of the kidney vary. Randal et al.44 treated one case with intravenous amphotericin B in daily doses of 20–30 mg for 38 days in a total amount of 1 g and the patient improved clinically. In a case of cryptococcal pyelonephritis and disseminated Cryptococcus, in a renal transplant recipient, the therapy included amphotericin B, 0.3 mg/kg/day and flucytosine, 60 mg/kg/ day for 4 weeks; this treatment did not eradicate the Cryptococcus from the kidney and was associated with hepatotoxicity.43 In another case of a renal allograft infection, the patient continued intravenous amphotericin B lipid complex 400 mg q.d. and flucytosine 3 g p.o. q.d. for 1 month.34 In our patient, fluconazole 200 mg p.o. q.d. for 6 months was planned without amphotericin B induction therapy. Treatment with oral fluconazole was followed by a prolonged remission, as was confirmed by the follow-up biopsy. To summarize, we demonstrate here that an immunocompetent patient had an unusual cryptococcal GIN, which was treated successfully with fluconazole. This is the first report of GIN due to Cryptococcus without disseminated disease in a host that was not immunocompromised. Although a renal infection is a relative contraindication to a renal biopsy, a pathological work-up with special stains of the renal biopsy tissue helps in the differential diagnosis of a patient with worsening renal failure of unknown etiology. Failure to recognize GIN due to Cryptococcus and initiate the appropriate treatment may lead to an irreversible renal outcome or even a fatal result. When properly recognized and treated, recovery from GIN is possible but the possibility of post-inflammatory renal impairment requires continued monitoring.
REFERENCES 1. 2. 3. 4.
5. 6.
7.
8.
9. 10. 11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22. 23. 24. 25.
26.
27.
28.
DISCLOSURE
The authors declared no competing interests. Kidney International (2009) 76, 453–458
Williams G, Williams WJ. Granulomatous inflammation—a review. J Clin Pathol 1983; 36: 723–733. Sheffiled EA. The granulomatous inflammatory response. J Pathol 1990; 160: 1–2. Viero RM, Cavallo T. Granulomatous interstitial nephritis. Hum Pathol 1995; 26: 1347–1353. Bijol V, Mendez GP, Nose´ V et al. Granulomatous interstitial nephritis: a clinicopathologic study of 46 cases from a single institution. Int J Surg Pathol 2006; 14: 57–63. Joss N, Morris S, Young B et al. Granulomatous interstitial nephritis. Clin J Am Soc Nephrol 2007; 2: 222–230. Hong S, Valderrama E, Mattana J et al. Vancomycin-induced acute granulomatous interstitial nephritis: therapeutic options. Am J Med Sci 2007; 334: 296–300. Tong JE, Howell DN, Foreman JW. Drug-induced granulomatous interstitial nephritis in a pediatric patient. Pediatr Nephrol 2007; 22: 306–309. Audimoolam VK, Bhandari S. Clarithromycin-induced granulomatous tubulointerstitial nephritis. Nephrol Dial Transplant 2006; 21: 2654–2655. Lomaestro BM. Fluoroquinolone-induced renal failure. Drug Saf 2000; 22: 479–485. Meehan SM, Josephson MA, Haas M. Granulomatous tubulointerstitial nephritis in the renal allograft. Am J Kidney Dis 2000; 36: E27. Magner P, Sweet J, Bear RA. Granulomatous interstitial nephritis associated with allopurinol therapy. CMAJ 1986; 135: 496–497. Montseny JJ, Meyrier A. Immunoallergic granulomatous interstitial nephritis following treatment with omeprazole. Am J Nephrol 1998; 18: 243–246. Pen˜a de la Vega L, Fervenza FC, Lager D et al. Acute granulomatous interstitial nephritis secondary to bisphosphonate alendronate sodium. Ren Fail 2005; 27: 485–489. Tomita N, Kanamori H, Fujita H et al. Granulomatous tubulointerstitial nephritis induced by all-trans retinoic acid. Anticancer Drugs 2001; 12: 677–680. Kennedy SE, Shrikanth S, Charlesworth JA. Acute granulomatous tubulointerstitial nephritis caused by intravesical BCG. Nephrol Dial Transplant 2006; 21: 1427–1429. Fervenza FC, Kanakiriya S, Kunau RT et al. Acute granulomatous interstitial nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with lamotrigine treatment. Am J Kidney Dis 2000; 36: 1034–1040. do Sameiro Faria M, Sampaio S, Faria V et al. Nephropathy associated with heroin abuse in Caucasian patients. Nephrol Dial Transplant 2003; 18: 2308–2313. Tse KC, Chan TM, Wong SS et al. Granulomatous interstitial nephritis of the allograft kidney associated with rhodococcal pulmonary infection. Nephrol Dial Transplant 2004; 19: 486–490. Yang CW, Lee SH, Choi YJ et al. Chronic granulomatous interstitial nephritis: unusual complication of acute pyelonephritis. Nephron 1996; 72: 305–307. Alsaad KO, Tobar A, Belanger E et al. Late-onset acute haemorrhagic necrotizing granulomatous adenovirus tubulointerstitial nephritis in a renal allograft. Nephrol Dial Transplant 2007; 22: 1257–1260. Izzedine H, Brocheriou I, Martinez V et al. Immune reconstitution inflammatory syndrome and acute granulomatous interstitial nephritis. AIDS 2007; 21: 534–535. Asim M, Chong-Lopez A, Nickeleit V. Adenovirus infection of a renal allograft. Am J Kidney Dis 2003; 41: 696–701. Adams AL, Cook WJ. Granulomatous interstitial nephritis secondary to histoplasmosis. Am J Kidney Dis 2007; 50: 681–685. Nasr SH, Koscica J, Markowitz GS et al. Granulomatous interstitial nephritis. Am J Kidney Dis 2003; 41: 714–719. Ahuja TS, Remmers A, Rajaraman S et al. Acute renal failure in a patient with AIDS: histoplasmosis-induced granulomatous interstitial nephritis. Am J Kidney Dis 1998; 32: E3. Unal A, Sipahioglu MH, Akgun H et al. Crohn’s disease complicated by granulomatous interstitial nephritis, choroidal neovascularization, and central retinal vein occlusion. Intern Med 2008; 47: 103–107. Kamat AV, Goldsmith D, O’Donnell P et al. Renal failure with granulomatous interstitial nephritis and diffuse leukemic renal infiltration in chronic lymphocytic leukemia. Ren Fail 2007; 29: 763–765. Fong P, Sepandj F, Trillo A. Idiopathic acute granulomatous interstitial nephritis leading to renal papillary necrosis. Nephrol Dial Transplant 1997; 12: 1043–1045.
457
the renal consult
29. 30. 31.
32. 33.
34. 35. 36.
37.
458
Perfect JR, Casadevall A. Cryptococcosis. Infect Dis Clin North Am 2002; 16: 837–874. Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am 2006; 20: 507–544. Pappas PG, Perfect JR, Cloud GA et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis 2001; 33: 690–699. Vilchez RA, Fung J, Kusne S. Cryptococcosis in organ transplant recipients: an overview. Am J Transplant 2002; 2: 575–580. Vilchez R, Shapiro R, McCurry K et al. Longitudinal study of cryptococcosis in adult solid-organ transplant recipients. Transpl Int 2003; 16: 336–340. Hill-Edgar AA, Nasr SH, Borczuk AC et al. A rare infectious cause of renal allograft dysfunction. Am J Kidney Dis 2002; 40: 1103–1107. Nampoory MR, Khan ZU, Johny KV et al. Invasive fungal infections in renal transplant recipients. J Infect 1996; 33: 95–101. Abbott KC, Hypolite I, Poropatich RK et al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis 2001; 3: 203–211. Fukuchi M, Mizushima Y, Hori T et al. Cryptococcal pleural effusion in a patient with chronic renal failure receiving long-term
S Chung et al.: Cryptococcal granulomatous interstitial nephritis
38.
39.
40. 41. 42. 43.
44. 45.
corticosteroid therapy for rheumatoid arthritis. Intern Med 1998; 37: 534–537. Sabbatani S, Manfredi R, Pavoni M et al. Voriconazole proves effective in long-term treatment of a cerebral cryptococcoma in a chronic nephropathic HIV-negative patient, after fluconazole failure. Mycopathologia 2004; 158: 165–171. Abbott KC, Hypolite I, Tveit DJ et al. Hospitalizations for fungal infections after initiation of chronic dialysis in the United States. Nephron 2001; 89: 426–432. Raghavan R, Date A, Bhaktaviziam A. Fungal and nocardial infections of the kidney. Histopathology 1987; 11: 9–20. MacGillivray JB. Two cases of cryptococcosis. J Clin Pathol 1966; 19: 424–428. Salyer WR, Salyer DC. Involvement of the kidney and prostate in cryptococcosis. J Urol 1973; 109: 695–698. Hellman RN, Hinrichs J, Sicard G et al. Cryptococcal pyelonephritis and disseminated cryptococcosis in a renal transplant recipient. Arch Intern Med 1981; 141: 128–130. Randall Jr RE, Stacy WK, Toone EC et al. Cryptococcal pyelonephritis. N Engl J Med 1968; 279: 60–65. Shibuya K, Hirata A, Omuta J et al. Granuloma and cryptococcosis. J Infect Chemother 2005; 11: 115–122.
Kidney International (2009) 76, 453–458
http://www.kidney-international.org & 2009 International Society of Nephrology
Acute renal failure presenting as a granulomatous interstitial nephritis due to cryptococcal infection Sungjin Chung1, Cheol W. Park1, Hyun W. Chung1 and Yoon S. Chang1 1
Division of Nephrology, Department of Internal Medicine, St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
CASE PRESENTATION A 64-year-old man was referred to our hospital because of acute renal failure of unknown etiology; he had a 2-week history of intermittent fever, chills, easy fatigue, cough, and exertional dyspnea. In addition, he reported generalized edema and a weight gain of 6 kg over 1 month. The past medical history was remarkable for pulmonary tuberculosis treated 15 years earlier and previous tobacco abuse. The patient denied recent travel, exposure to animals, and medications; he had been generally healthy without systemic disease, including diabetes and hypertension. Six months before presentation, a routine medical evaluation at a local hospital showed that he had no health problems.
Correspondence: Yoon S. Chang, Division of Nephrology, Department of Internal Medicine, St. Mary’s Hospital, The Catholic University of Korea, 62, Yeouido-dong, Yeongdeungpo-gu, Seoul 150-713, Republic of Korea. E-mail: [email protected] Kidney International (2009) 76, 453–458; doi:10.1038/ki.2008.494; published online 1 October 2008 Received 25 November 2007; revised 24 June 2008; accepted 29 July 2008; published online 1 October 2008 Kidney International (2009) 76, 453–458
On admission the physical examination showed a body temperature of 37.8 1C, the blood pressure was 110/ 70 mm Hg, the pulse rate was 110 beats/min, and the respiratory rate was 28 breaths/min. There were no signs or symptoms indicating a neurological disorder. There was no palpable regional lymphadenopathy or abnormally pigmented skin lesions. Coarse inspiratory crackles were audible bilaterally over the basal lung fields. The abdomen was flat and soft without organomegaly. However, tenderness was noted at both costovertebral angles. In addition, there was pitting edema of both lower legs. The urine dipstick test was positive for protein (2 þ ), with leukocyturia and microscopic hematuria on microscopic examination; the 24-h urine collection had 810 mg of protein. The other biochemical values are summarized in Table 1. All viral markers were negative, including hepatitis B surface antigen, hepatitis C antibody, cytomegalovirus immunoglobulin M antibody, herpes simplex immunoglobulin M antibody, human immunodeficiency virus (HIV), and hantavirus antibody. An initial chest X-ray showed no active lung lesions, except for fibrocalcified opacities at both upper lung fields. The renal ultrasound revealed enlargement of both kidneys with normal corticomedullary differentiation, suggesting acute renal parenchymal disease. The patient was treated with intravenous fluid administration and empirical antibiotics for presumed acute bilateral bacterial pyelonephritis. The initial and follow-up cultures of the blood, urine, and sputum revealed no organisms. Despite a change of the antibiotics later, the pyuria persisted, the leukocytosis worsened over the following days, and the serum creatinine increased up to 4.26 mg/100 ml. The worsening azotemia and newly developed pulmonary edema required hemodialysis. Additional laboratory data including serologies were normal: negative antinuclear antibodies, negative antineutrophilic cytoplasmic antibodies, negative cryoglobulins, and normal complements levels. There was no sign of disseminated intravascular coagulation by tests of the clotting and fibrinolytic systems. The serum and urine protein electrophoresis revealed a slight acute phase response and the urine test for the Bence Jones protein was negative. A computerized tomographic scan of the abdomen and pelvis showed marked increase in the size of both kidneys (the left was 14.7 cm and the right 17.0 cm in length) with diffusely decreased enhancement, but gave no additional information 453
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Table 1 | Laboratory data at presentation Blood test (unit) White blood count ( 109/l) Hemoglobin (g/100 ml) Hematocrit (%) Platelet ( 109/l) ESR (mm/h) CRP (mg/l) Sodium (mmol/l) Potassium (mmol/l) Chloride (mmol/l) Blood urea nitrogen (mg/100 ml) Creatinine (mg/100 ml) Glucose (mg/100 ml) Total protein (g/100 ml) Albumin (g/100 ml) AST (IU/l) ALT (IU/l) Creatinine phosphokinase (IU/l)
Reference range
On admission
5.0–10.0 14–18 42–52 150–450 0–10 o5 135–148 3.5–5.1 98–108 8–23 0.5–1.2 60–110 6.7–8.3 3.8–5.3 13–36 5–40 26–400
7.4 11.8 33.7 36 120 184.19 132 6.6 97 96.2 3.98 72 5.68 2.62 41 31 40
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
Figure 1 | An abdominal computed tomography (CT) of the kidneys shows marked enlargement of both kidneys.
(Figure 1). We considered initially that the acute renal failure was because of a bacterial pyelonephritis or a renal abscess. However, there was no evidence of a specific infection from the biochemical studies or the culture results. The renal function of the patient continued to worsen without response to the antibiotics. A rapidly progressive glomerulonephritis was thought to be the probable diagnosis. A renal biopsy was performed to ascertain the etiology of the acute renal failure. RENAL BIOPSY FINDINGS
Light microscopic examination disclosed one core of cortex containing only two glomeruli, which were not sclerotic. The renal tubules showed atrophic changes. The interstitium was markedly infiltrated by abundant mononuclear cells and neutrophils with noncaseating granulomas (Figure 2a). There was a mild degree of interstitial fibrosis. The immunofluorescent studies were negative for immunoglobulins and 454
Figure 2 | Representative microphotographs of the first renal biopsy from the patient. Low-power view shows interstitial inflammation and granulomatous changes (a; original magnification 200, hematoxylin and eosin). High-power view (b; original magnification 400, PAS) reveals several interstitial yeast forms (arrowhead). The yeast (arrowhead) stained positively for Fontana-Masson silver (c; original magnification 400, Fontana-Masson silver).
complements. Special stains for microorganisms were performed to exclude infectious etiologies. Periodic acidSchiff (PAS) and silver methenamine revealed a few scattered fungal yeast-like organisms within the cortical interstitium (Figure 2b). Although the etiology of the yeast forms could be not identified, a presumptive diagnosis of granulomatous interstitial nephritis (GIN) due to a fungal infection was made based on the renal pathological findings. Treatment with oral fluconazole, 200 mg/day orally, was started. Because the first biopsy was an insufficient specimen, for clarification Kidney International (2009) 76, 453–458
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Serum creatinine (mg/100 ml)
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Figure 3 | Clinical course of the patient. Serum creatinine level decreases slowly after fluconazole treatment but does not return to completely normal (Bx, renal biopsy; HD, hemodialysis).
of the etiology of the fungal infection, a repeat renal biopsy was performed. The light microscopy confirmed the findings of the first biopsy. The yeast forms were negative for Alcian blue and mucicarmine stains, but they were positive for the Fontana-Masson stain (Figure 2c), suggesting a capsuledeficient cryptococcal infection. CLINICAL FOLLOW-UP
The serially repeated results of the serum cryptococcal antigen test were negative. With the continued administration of fluconazole, the renal function recovered slowly in association with an improved general condition (Figure 3). At discharge, in September 2004, the creatinine level was 1.78 mg/100 ml. In May 2005, 4 months after cessation of 6 months of fluconazole therapy, a post-treatment renal biopsy was performed to determine why the renal function did not return to normal. The light microscopic examination showed that 10 of 90 glomeruli had global sclerosis and all of the others had segmental sclerosis. The renal tubules showed marked atrophic changes with no frank necrosis. A moderate degree of mononuclear cell infiltration and marked fibrotic changes were seen in the interstitium (Figure 4). The special stains were all negative. In August 2006, at the last visit to our clinic the patient was doing well except for the elevation of his creatinine to 2.98 mg/100 ml. DISCUSSION
A granulomatous inflammatory response is ubiquitous in pathology; it is a manifestation of many infectious, toxic, allergic, autoimmune, and neoplastic diseases as well as conditions of unknown etiology.1,2 Recognition of the characteristics of the granuloma with regard to its etiology, degradability, and immunogenicity is important for patient management.2 In the field of renal pathology, granuloma formation can be encountered in the limited setting of acute interstitial nephritis. For example, in the report by Viero and Cavallo,3 granulomas were detected in only 12 cases (incidence: 5.9%) of 203 renal biopsies during a 20-year period; Bijol et al.4 identified 46 cases (0.5%) of GIN over a 17-year period at a single institution. Recently, Joss et al.5 also reported their experience with only 18 patients (o1%) among their renal biopsies during a 15-year period. The Kidney International (2009) 76, 453–458
Figure 4 | Representative microphotograph of the posttreatment renal biopsy from the patient. A marked degree of interstitial fibrosis with mononuclear cell infiltration and tubular atrophy is shown, consistent with chronic interstitial nephritis (original magnification 200, PAS).
Table 2 | Causes of granulomatous interstitial nephritis Cause Drug BCG, intravesical Antibiotics (ampicillin, vancomycin, cefuroxime, clarithromycin, fluoroquinolone, rifampin, etc.) NSAIDs Diuretics (thiazide) Allopurinol Anticonvulsant (lamotrigine) Omeprazole Bisphosphonate All-trans retinoic acid Heroin abuse Infection Bacteria (E. coli, rhodococcus, etc.) Mycobacterium tuberculosis Virus (adenovirus, HIV, etc.) Fungus (histoplasma, candida, cryptococcus, etc.) Inflammatory or systemic condition Sarcoidosis Wegener’s granulomatosis Tubulointerstitial nephritis and uveitis syndrome Crohn’s disease Hematologic malignancy (leukemia, multiple myeloma) Idiopathic
Reference 4,6 5,7–11
5,11 5,11 5,12 5,16 13 14 15 17
3,11,18,19 11 20–22 11,23–25
3,4,5 3,5 5 26 27
5,28
BCG, Bacille Calmette-Guerin; HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs.
cause of GIN varies. Among the more common causes are drugs and sarcoidosis; approximately 25–45% of cases with GIN are drug induced.3,4 The medications that are commonly implicated are antibiotics, nonsteroidal anti-inflammatory drugs, allopurinol, and diuretics, as shown in Table 2. In addition to drugs, other agents or conditions commonly associated with GIN include infections, allergies, autoimmune, and neoplastic disorders and in some cases the etiology is idiopathic. The pathogenic mechanism underlying GIN is poorly understood. However, evidence derived from various 455
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observations suggests a T-cell-mediated reaction.2,3 The predominance of mononuclear cells in the interstitial infiltrates, the presence of mostly T cells, the presence of granulomas, and the absence of immunoglobulin deposition in the tubules or interstitium support a T-cell-mediated mechanism.3 Because GIN occurs with diverse conditions, the mechanisms of tissue injury and/or the components of the granuloma can also vary. When GIN is infection related, there is an abundance of neutrophils, which predominates over all other cell types, although in such biopsies the number of T cells, macrophages, and B cells is also impressive and consistent with the findings of biopsies from drug- and sarcoid-related granulomatous GIN.3 Infection-related GIN accounts for only a small percentage of cases, about 6.7% of the total number of cases from the three largest series reported.4,5,23 Mycobacteria and fungi are the main etiologies of the infectious causes and account for most cases of infectious GIN in renal transplants.3,5 GIN secondary to fungal infection, mainly with the Histoplasma and Candida species, has been described in a few cases,3,23–25 primarily in patients who are immunocompromised. In the case presented here we identified another fungal infection, Cryptococcus, as a cause of GIN in an immunocompetent host. The encapsulated yeast, Cryptococcus species, is a major opportunistic fungal pathogen that is recognized worldwide.29 More than 30 species are included in the genus Cryptococcus. The pathogenic yeasts of Cryptococcus currently consist of two species: C. neoformans and C. gatti. In the environment, C. neoformans is primarily found worldwide in association with the excrement of certain birds, such as pigeons and tree hollows. C. gatti has been found primarily in tropical and subtropical regions. However, more currently, there has been unprecedented emergence of these isolates on Vancouver Island since 1999, demonstrating that the distribution and ecology of this organism is now changing; it is now associated with a wide range of trees, such as firs and oaks.30 The specific source of the infection and the form responsible for human infections have not been definitely established. Direct evidence for human infection from either eucalyptus trees or pigeon excrement has not been established. However, it is recommended that individuals at risk for Cryptococcus avoid sites that are contaminated with pigeon excrement and avoid having certain birds, such as pigeons, canaries, and cockatoos, as pets.30 In general, cryptococcal infection is an uncommon systemic fungal infection that occurs primarily in patients who have impaired immunity, such as patients with hematologic malignancies, organ transplants, and those taking systemic corticosteroids or other immunosuppressants. Since the epidemic of HIV infections, Cryptococcus has become an important opportunistic infection in HIVinfected individuals; as a result its incidence has increased dramatically.30,31Solid organ transplant recipients are also recognized to be at increased risk for Cryptococcus 456
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infections. Current estimates suggest that 20–60% of the cases with Cryptococcus infections, that are HIV negative, occur in organ transplant recipients.32,33 Although renal transplant recipients have been thought to have the lowest incidence of fungal infection compared with other organ transplants, 3.5–5% of infections, in renal transplant recipients, are due to fungi,34,35 and among the fungal infections, Cryptococcus is the third most common in renal transplant recipients after candida and aspergillus, as well as in all solid organ transplant recipients.35,36 More importantly, despite the initiation of therapy, the mortality rate associated with this infection, in this patient population, remains high.32 In addition to patients with renal transplants, nephrologists encounter cryptococcal infections in patients treated with immunosuppressive agents, those have renal failure37,38 or on dialysis.39 Patients on dialysis have a nearly 10-fold increased risk for hospitalizations resulting from fungal infections compared to the general population.39 Of the leading etiologies of fungal infections in dialysis patients, Cryptococcus (6%) has been reported to be the second most common after candida (79%).39 Because patients with chronic renal failure and patients on maintenance dialysis therapy have been shown to have a wide range of immune deficiencies and increased risk for infection following instrumentation, it is not surprising that this patient population has an increased risk for being hospitalized for fungal infections including Cryptococcus.38,39 The central nervous system and respiratory tract are the most common organs involved in cryptococcal infection. In a review of non-HIV-infected patients, 36% of cases had only pulmonary involvement, 51% of cases had central nervous system disease, and the remainder had other or multiple sites of infection.31 In fact, this yeast can cause disease in every organ of the human body, including skin, eyes, bone, blood, prostate, and the urinary tract.30 Cryptococcus enters the body through the lungs, the most common portal of entry for infection, and becomes disseminated hematologically with a predilection for the central nervous system and skin and less frequently to other sites such as the urinary tract and kidneys.30,32,33 Most cases with Cryptococcus of the kidneys have disseminated disease in immunocompromised hosts; generally the infection begins in the lungs and spreads to the brain and meninges.40–44 Reviews of patients with disseminated Cryptococcus have demonstrated renal involvement in 26–51.2% of cases.34,42 There may be signs and symptoms of cystitis, pyuria, hematuria, moderate proteinuria, and laboratory evidence of renal insufficiency.44 The characteristic lesion in the kidney is a non-suppurating granuloma.41 The fungi spread through the blood stream and lodge within the glomeruli where they can form abscesses followed by granulomatous inflammation.40 A caseous appearance is sometimes produced by the widespread death of the cryptococci, possibly due to the development of hypersensitivity host responses.40,41 Cortical and medullary abscesses, caseation necrosis and interstitial inflammation, fibrosis, and papillary necrosis have also been noted.43,44 However, Kidney International (2009) 76, 453–458
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without such characteristic lesions, only extensive necrosis and suppuration may be present.41 The histopathological features may vary according to the immune status of the infected host. In an immunocompetent individual, a typical granuloma is usually observed at the site of the cryptococcal infection. However, no purulent inflammatory responses are usually observed in the cryptococcal lesions of AIDS patients.45 Granulomatous inflammation, like any inflammatory reaction, frequently results in tissue damage during the active phase and fibrosis during the healing process.1,5 Granulomas can resolve but are often replaced by scar tissue. This is the likely explanation for the renal function not returning to normal in our patient. The treatment of choice for Cryptococcus depends on the anatomical site of involvement and the host’s immune status. The guidelines published by the Infectious Disease Society of America provide recommendations for clinicians and can be used at the beginning of treatment to guide clinical decisions for patients with Cryptococcus infections. However, the guidelines are not absolute or definitive and a given specific clinical situation may demand creative management.29 Treatment strategies for Cryptococcus of the kidney vary. Randal et al.44 treated one case with intravenous amphotericin B in daily doses of 20–30 mg for 38 days in a total amount of 1 g and the patient improved clinically. In a case of cryptococcal pyelonephritis and disseminated Cryptococcus, in a renal transplant recipient, the therapy included amphotericin B, 0.3 mg/kg/day and flucytosine, 60 mg/kg/ day for 4 weeks; this treatment did not eradicate the Cryptococcus from the kidney and was associated with hepatotoxicity.43 In another case of a renal allograft infection, the patient continued intravenous amphotericin B lipid complex 400 mg q.d. and flucytosine 3 g p.o. q.d. for 1 month.34 In our patient, fluconazole 200 mg p.o. q.d. for 6 months was planned without amphotericin B induction therapy. Treatment with oral fluconazole was followed by a prolonged remission, as was confirmed by the follow-up biopsy. To summarize, we demonstrate here that an immunocompetent patient had an unusual cryptococcal GIN, which was treated successfully with fluconazole. This is the first report of GIN due to Cryptococcus without disseminated disease in a host that was not immunocompromised. Although a renal infection is a relative contraindication to a renal biopsy, a pathological work-up with special stains of the renal biopsy tissue helps in the differential diagnosis of a patient with worsening renal failure of unknown etiology. Failure to recognize GIN due to Cryptococcus and initiate the appropriate treatment may lead to an irreversible renal outcome or even a fatal result. When properly recognized and treated, recovery from GIN is possible but the possibility of post-inflammatory renal impairment requires continued monitoring.
REFERENCES 1. 2. 3. 4.
5. 6.
7.
8.
9. 10. 11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22. 23. 24. 25.
26.
27.
28.
DISCLOSURE
The authors declared no competing interests. Kidney International (2009) 76, 453–458
Williams G, Williams WJ. Granulomatous inflammation—a review. J Clin Pathol 1983; 36: 723–733. Sheffiled EA. The granulomatous inflammatory response. J Pathol 1990; 160: 1–2. Viero RM, Cavallo T. Granulomatous interstitial nephritis. Hum Pathol 1995; 26: 1347–1353. Bijol V, Mendez GP, Nose´ V et al. Granulomatous interstitial nephritis: a clinicopathologic study of 46 cases from a single institution. Int J Surg Pathol 2006; 14: 57–63. Joss N, Morris S, Young B et al. Granulomatous interstitial nephritis. Clin J Am Soc Nephrol 2007; 2: 222–230. Hong S, Valderrama E, Mattana J et al. Vancomycin-induced acute granulomatous interstitial nephritis: therapeutic options. Am J Med Sci 2007; 334: 296–300. Tong JE, Howell DN, Foreman JW. Drug-induced granulomatous interstitial nephritis in a pediatric patient. Pediatr Nephrol 2007; 22: 306–309. Audimoolam VK, Bhandari S. Clarithromycin-induced granulomatous tubulointerstitial nephritis. Nephrol Dial Transplant 2006; 21: 2654–2655. Lomaestro BM. Fluoroquinolone-induced renal failure. Drug Saf 2000; 22: 479–485. Meehan SM, Josephson MA, Haas M. Granulomatous tubulointerstitial nephritis in the renal allograft. Am J Kidney Dis 2000; 36: E27. Magner P, Sweet J, Bear RA. Granulomatous interstitial nephritis associated with allopurinol therapy. CMAJ 1986; 135: 496–497. Montseny JJ, Meyrier A. Immunoallergic granulomatous interstitial nephritis following treatment with omeprazole. Am J Nephrol 1998; 18: 243–246. Pen˜a de la Vega L, Fervenza FC, Lager D et al. Acute granulomatous interstitial nephritis secondary to bisphosphonate alendronate sodium. Ren Fail 2005; 27: 485–489. Tomita N, Kanamori H, Fujita H et al. Granulomatous tubulointerstitial nephritis induced by all-trans retinoic acid. Anticancer Drugs 2001; 12: 677–680. Kennedy SE, Shrikanth S, Charlesworth JA. Acute granulomatous tubulointerstitial nephritis caused by intravesical BCG. Nephrol Dial Transplant 2006; 21: 1427–1429. Fervenza FC, Kanakiriya S, Kunau RT et al. Acute granulomatous interstitial nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with lamotrigine treatment. Am J Kidney Dis 2000; 36: 1034–1040. do Sameiro Faria M, Sampaio S, Faria V et al. Nephropathy associated with heroin abuse in Caucasian patients. Nephrol Dial Transplant 2003; 18: 2308–2313. Tse KC, Chan TM, Wong SS et al. Granulomatous interstitial nephritis of the allograft kidney associated with rhodococcal pulmonary infection. Nephrol Dial Transplant 2004; 19: 486–490. Yang CW, Lee SH, Choi YJ et al. Chronic granulomatous interstitial nephritis: unusual complication of acute pyelonephritis. Nephron 1996; 72: 305–307. Alsaad KO, Tobar A, Belanger E et al. Late-onset acute haemorrhagic necrotizing granulomatous adenovirus tubulointerstitial nephritis in a renal allograft. Nephrol Dial Transplant 2007; 22: 1257–1260. Izzedine H, Brocheriou I, Martinez V et al. Immune reconstitution inflammatory syndrome and acute granulomatous interstitial nephritis. AIDS 2007; 21: 534–535. Asim M, Chong-Lopez A, Nickeleit V. Adenovirus infection of a renal allograft. Am J Kidney Dis 2003; 41: 696–701. Adams AL, Cook WJ. Granulomatous interstitial nephritis secondary to histoplasmosis. Am J Kidney Dis 2007; 50: 681–685. Nasr SH, Koscica J, Markowitz GS et al. Granulomatous interstitial nephritis. Am J Kidney Dis 2003; 41: 714–719. Ahuja TS, Remmers A, Rajaraman S et al. Acute renal failure in a patient with AIDS: histoplasmosis-induced granulomatous interstitial nephritis. Am J Kidney Dis 1998; 32: E3. Unal A, Sipahioglu MH, Akgun H et al. Crohn’s disease complicated by granulomatous interstitial nephritis, choroidal neovascularization, and central retinal vein occlusion. Intern Med 2008; 47: 103–107. Kamat AV, Goldsmith D, O’Donnell P et al. Renal failure with granulomatous interstitial nephritis and diffuse leukemic renal infiltration in chronic lymphocytic leukemia. Ren Fail 2007; 29: 763–765. Fong P, Sepandj F, Trillo A. Idiopathic acute granulomatous interstitial nephritis leading to renal papillary necrosis. Nephrol Dial Transplant 1997; 12: 1043–1045.
457
the renal consult
29. 30. 31.
32. 33.
34. 35. 36.
37.
458
Perfect JR, Casadevall A. Cryptococcosis. Infect Dis Clin North Am 2002; 16: 837–874. Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am 2006; 20: 507–544. Pappas PG, Perfect JR, Cloud GA et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis 2001; 33: 690–699. Vilchez RA, Fung J, Kusne S. Cryptococcosis in organ transplant recipients: an overview. Am J Transplant 2002; 2: 575–580. Vilchez R, Shapiro R, McCurry K et al. Longitudinal study of cryptococcosis in adult solid-organ transplant recipients. Transpl Int 2003; 16: 336–340. Hill-Edgar AA, Nasr SH, Borczuk AC et al. A rare infectious cause of renal allograft dysfunction. Am J Kidney Dis 2002; 40: 1103–1107. Nampoory MR, Khan ZU, Johny KV et al. Invasive fungal infections in renal transplant recipients. J Infect 1996; 33: 95–101. Abbott KC, Hypolite I, Poropatich RK et al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis 2001; 3: 203–211. Fukuchi M, Mizushima Y, Hori T et al. Cryptococcal pleural effusion in a patient with chronic renal failure receiving long-term
S Chung et al.: Cryptococcal granulomatous interstitial nephritis
38.
39.
40. 41. 42. 43.
44. 45.
corticosteroid therapy for rheumatoid arthritis. Intern Med 1998; 37: 534–537. Sabbatani S, Manfredi R, Pavoni M et al. Voriconazole proves effective in long-term treatment of a cerebral cryptococcoma in a chronic nephropathic HIV-negative patient, after fluconazole failure. Mycopathologia 2004; 158: 165–171. Abbott KC, Hypolite I, Tveit DJ et al. Hospitalizations for fungal infections after initiation of chronic dialysis in the United States. Nephron 2001; 89: 426–432. Raghavan R, Date A, Bhaktaviziam A. Fungal and nocardial infections of the kidney. Histopathology 1987; 11: 9–20. MacGillivray JB. Two cases of cryptococcosis. J Clin Pathol 1966; 19: 424–428. Salyer WR, Salyer DC. Involvement of the kidney and prostate in cryptococcosis. J Urol 1973; 109: 695–698. Hellman RN, Hinrichs J, Sicard G et al. Cryptococcal pyelonephritis and disseminated cryptococcosis in a renal transplant recipient. Arch Intern Med 1981; 141: 128–130. Randall Jr RE, Stacy WK, Toone EC et al. Cryptococcal pyelonephritis. N Engl J Med 1968; 279: 60–65. Shibuya K, Hirata A, Omuta J et al. Granuloma and cryptococcosis. J Infect Chemother 2005; 11: 115–122.
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