å¡ CASE REPORT å¡

Tubulointerstitial Nephritis Associated with Legionnaires ' Disease Kazutaka Nishitarumizu, Yasuharu Tokuda*, Hajime Uehara*, Masaaki Taira** and Keiki Taira***

Abstract downnear the stairway of his home. He had consumed alcohol regularly for manyyears. He had A47-year-old manwas admitted to our hospital for com- acute pancreatitis 3 years previously. One day before admis- munity- acquired pneumoniacomplicated with acute renal sion he was doing well and had played golf with his friends. In failure. Legionella pneumophila serogroup type 1 was the morning on the day of admission he complained of fatigue grown in BCYE(buffered charcoal yeast extract) agar for and chills. He had severe generalized myalgia. And then he sputum culture. Although his respiratory illness responded was found by his family lying downand brought to our hospi- to intravenous erythromycin therapy, renal failure wors- tal. He had no headache, cough, dyspnea, palpitation, chest ened and necessitated hemodialysis. Renal biopsy showed pain, vomiting, abdominal pain, diarrhea, gross hematuria, or profound tubulointerstitial nephritis. After initiation of ste- seizure. roid therapy his renal function improved and he was dis- On examination, he looked sick and drowsy. His blood pres- charged thereafter. These findings suggest that in Legion- sure was 98/60 mmHg,pulse rate 147/min, respiratory rate 54/ naires' disease with acute renal failure, tubulointerstitial min, and temperature 39.8°C. Extremities were cyanotic with nephritis should also be considered and steroid therapy may diffuse mottling. Neck was supple. Crackles were heard over be an effective modality for the renal complication. the left lung base. Jugular venous pressure and heart sound (Internal Medicine 39: 150-153, 2000) was normal. He had hepatomegaly but no splenomegaly. Ex- tremity muscles were tender. Neurological examination showed Keywords: acute renal failure, renal biopsy generalized muscle weakness and hyporeflexia without focal deficits. Laboratory findings were leukocytes 9,300/mm3 with nor- mal differentials, hemoglobin 1 6.5 g/dl, platelets 106,000/mm3, Introduction blood urea nitrogen 17 mg/dl, creatinine 2.2 mg/dl, sodium 124 mEq//, potassium 3.0 mEq//, chloride 83 mEq//, calcium Tubulointerstitial nephritis and acute renal failure in asso- 8.4 mg/dl, phosphate 6. 1 mg/dl, aspartate aminotransferase ciation with infectious diseases has been occasionally reported 1,509 IU//, alanine aminotransferase 100 IU//, alkaline phos- in diseases, such as Yersiniosis, Leptospirosis, Chlamydial and phatase 98 IU//, lactate dehydrogenase 2,713 IU//, gamma- viral infection (1). glutamyl transpeptidase 644 IU//, creatine phosphokinase Although Legionnaires' disease was also reported to be one 13,637 IU//, total bilirubin 2.7 mg/dl, direct bilirubin 2.5 mg/ of the infectious causes associated with tubulointerstitial ne- dl, glucose 95 mg/dl, total cholesterol 83 mg/dl. prothrombin phritis worldwide (2), no such case in Japan has been reported. time 13.9 seconds (standard 12.0), activated partial thrombo- Werecently treated a case with Legionnaires' disease who plastin time 46. 1 second (standard 29.7), and C-reactive pro- also developed acute renal failure which is histologically re- tein 26.5 mg/dl. Serology for hepatitis B, C and HTLV-1 was vealed to be tubulointerstitial nephritis. This may be the first negative. Arterial blood gas analysis showed pH 7.46, PCO2 such case reported in Japan. 20 mmHg, PO2 68 mmHg, HCO314 mEq//, and oxygen satu- ration 94%. Chest film showed left lower lung infiltrates (Fig. Case Report 1). His sputum looked like orange jelly. SputumGram's stain showedno visible bacteria. A 47-year-old man was brought to the emergency depart- Diagnosis of community-acquired pneumoniawas suggested ment in Okinawa Miyako Hospital since he was found lying and intravenous erythromycin 3 g per day and cefotaxime 3 g/

From Iwao Hospital, Kagoshima, *OkinawaChubu Hospital, Okinawa, **Okinawa Miyako Hospital, Okinawa and ***the Department of Microbiology, Okinawa Miyako Hospital, Okinawa Received for publication February 22, 1999; Accepted for publication August 13, 1999 Reprint requests should be addressed to Dr. Kazutaka Nishitarumizu, Iwao Hospital, 17- 1 8, Koutukichou, Kagoshima 892-0837

150 Internal Medicine Vol. 39, No. 2 (February 2000) Legionellosis and Acute Renal Failure

Figure 2. PAS staining of renal biopsy (x400).

Figure 1. Initial chest X-ray. type 1, which were performed on acute and convalescent days (1:40-1:512).(first day and 30th day), revealed a more than four-fold rise day was started. Onthe following day his respiratory condition got worse so Discussion that endotracheal intubation was performed and mechanical ventilation was initiated. Since oliguric acute renal failure also Although severe renal dysfunction associated with Legion- developed and poorly responded to rehydration and large-dose naires ' disease has been occasionally reported worldwide (Table furosemide, hemodialysis was started thereafter. The level of 1), no case in Japan has apparently been reported. The mecha- creatine phosphokinase was 26,021 IU// on the second hospi- nism of renal failure associated with Legionnaires' disease is tal day. probably multifactorial. Amongpossible factors, those associ- On the fourth hospital day, laboratory results showed growth ated with dehydration or shock, rhabdomyolysis, endotoxemia of Legionella bacteria in BCYE(buffered charcoal yeast ex- and direct microbial toxicity were considered. Histologically, tract) agar for sputum culture and later it was identified as renal biopsy usually shows tubulointerstitial nephritis and/or Legionella pneumophila serogroup type 1. Cefotaxime was acute tubular necrosis (3). Existence of Legionella bacteria was discontinued. Oral rifampicin 300 mg per day was added to found by electron microscopy in one report (4). Recent reports erythromycin. on the mechanismof renal dysfunction point to direct renal His respiratory condition gradually improved. He was extu- toxicity from the Legionella organism or a systemic manifes- bated on the 12th hospital day. However, renal failure still per- tation of Legionnaires' disease (4). sisted in spite of recovery of respiratory illness. Weperformed Various infectious diseases can cause renal dysfunction such renal biopsy on the 23rd hospital day. Histologically, focal tu- as tuberculosis, yersiniosis, leptospirosis, chlamydial and viral bular degeneration, atrophy and loss was present (Fig. 2). The infection. The pathophysiology seems almost the same as Le- interstitium around these damaged tubules was infiltrated by gionnaires' disease. lymphocytes, plasma cells and some neutrophils. Tubulitis was Rhabdomyolysisis sometimes seen in severe cases with Le- found with lymphocytes invading beneath the tubular basement gionnaires' disease and could be an etiologic factor for the re- membraneand between tubular epithelial cells. Of the 8 glom- nal dysfunction in the present case. However, the renal histol- eruli studied, 7 appeared normal, 1 showed sclerosis. Electron ogy in our case showedmainly a tubulointerstitial nephritis microscopy showedno specific tubular changes. Noglomeru- pattern. Tubulointerstitial nephritis can be caused by a variety lus was found in the electron microscopy specimen. No of exogenous factors including medications. Although our pa- Legionella organism was noted by electron microscopy. The tient had been given rifampicin and erythromycin for his pul- above findings were compatible with tubulointerstitial nephri- monary disease, renal dysfunction developed before the initia- tis. After we started prednisolone 40 mgper day, urine volume tion of these medications and no allergic signs such as rash or responded gradually and serum creatinine decreased thereaf- eosinophilia were noted, therefore drug-induced tubulointer- ter. He was discharged on the 35th hospital day (Fig. 3). stitial nephritis was not the likely etiology for his renal dys- Fluorescent antibody tests against Legionella pneumophila function.

Internal Medicine Vol. 39, No. 2 (February 2000) 151 Nishitarumizu et al

EM CT X RFP PSL Cr BT Renal biopsy (mg/dl) fC ) I H D 10 ¥ CBrT 40

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Figure 3. Clinical course. EM:erythromycin, RFP: rifampicin, PSL: prednisolone, CTX: cefotaxime, HD: hemodialysis, Cr: creatinine, BT: body temperature.

Table 1. Summaryof 45 Reported Cases of Legionnaire's Disease and Acute Renal Failure N o . of p a t ie n t s Di a l y si s O ut c o m e R en a l Rh a b d o my o l y si s (D eath ) P ath olog y

4 5 2 5 2 3 A T N 6 AT IN 5 R P GN 1 M G N 1 A P N 2 N A 2 9

ATN: acute tubular necrosis, ATIN: acute tubulointerstitial nephritis, RPGN: rapidly progressive glomerulonephritis, MGN: mesangioglomerulonephritis, APN: acute pyelonephritis, NA: not available.

Therapy for Legionnaires' disease consists of early admin- renal failure was considered to be life-saving and inexpensive. istration of large-dose intravenous erythromycin and occasion- Certainly, moreinvestigations are necessary to determine the ally oral rifampin (5). The mortality rate is around 15%even optimal management of tubulointerstitial nephritis. with correct diagnosis and therapy (6). Delayed treatment or In conclusion, we report a case with Legionnaires' disease missed diagnosis maylead to a higher mortality (around 80%) who also developed acute renal failure caused by tubuloin- (7). Cases complicated with acute renal failure are reported to terstitial nephritis. Whenacute renal failure develops in a case have increased mortality (53%) (4). with Legionnaires' disease, tubulointerstitial nephritis should Therapy for tubulointerstitial nephritis in general is contro- also be considered as one of the differential diagnoses. versial, in part due to the lack of randomized controlled trials. Someinvestigators recommendthe use of glucocorticoid, while References others support only conservative treatment. In the present case, we administered oral prednisolone since earlier resolution of 1) Brenner BM. Brenner and Rector's The Kidney. Fifth ed. W. B. Saunders

152 Internal Medicine Vol. 39, No. 2 (February 2000) Legionellosis and Acute Renal Failure

Company, Philadelphia, 1996: 1661-1665. 207, 1992. 2) Haines JD Jr, Calhoon H. Interstitial nephritis in a patient with Legio- 5) Nguyen MH, Stout JE, Yu VL. Legionellosis. Infect Dis Clin North Am nnaires' disease. Postgrad Med 81: 77-79, 1987. 5: 561-584, 1991. 3) Fenves AZ. Legionnaires' disease associated with acute renal failure: a 6) Reese RE, Betts RF. APractical Approach to Infectious Diseases. Fourth report of two cases and review of the literature. Clin Nephrol 23: 96-100, ed. Little, Brown, Boston, 1996: 284-289. 1985. 7) Roig J, Domingo C, Morera J. Legionnaires' disease. Chest 105: 1817- 4) Shah A, Check F, Baskin S, Reyman T, Menard R. Legionnaires' disease 1825, 1994. and acute renal failure: case report and review. Clin Infect Dis 14: 204-

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