Open Journal of Nephrology, 2013, 3, 120-123
http://dx.doi.org/10.4236/ojneph.2013.33022 Published Online September 2013 (http://www.scirp.org/journal/ojneph)
Late and Reversible Kidney-Lung Failure after
Intra-Bladder BCG Therapy
Olivier Mat1*, Rim Kada1, Patrick Philippart2, Quentin Mat2, Steffy Larroze2, Myriam Remmelink3,
Selda Aydin4, Vincent Colombie5
1Department of Nephrology of EpiCURA, Ath, Belgium
2Department of Surgery of EpiCURA, Ath, Belgium
3Department of Lung Path ology, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium
4Department of Renal Pathology, Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium
5Department of Infectious Diseases of EpiCURA, Ath, Belgium
Received May 9, 2013; revised June 15, 2013; accepted July 3, 2013
Copyright © 2013 Olivier Mat et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
We observed a 76-year-old man who presented “acute kidney-lung failure” 9 months after intravesical Bacillus Cal-
mette-Guérin (BCG) adjuvant treatment for a T1 bladder cancer. He had inflammatory infiltration on chest radiog raphy
and required dialysis for acute rena l failure. A percutaneous renal biopsy was performed and revealed tubulointerstitial
nephritis with a moderate eosinophilic infiltrate without granulomatous lesion. After a few days, an open lung biopsy
was also done due to respiratory deterioration. The anatomopathologic specimen demonstrated moderate fibrosis with
lympho-neutrophilic infiltration and few aspecific granulomatous lesions without caseous necrosis. Sarcoïdosis was
suspected and high dose oral methylprednisolone was started. Three weeks later, Mycobacterium bovis was identified
by Polymerase Chain Reaction on open lung b iopsy. He responded well to steroids and tuberculostatic tri-therapy. After
one month of immunosuppressive treatment, renal function was resolved and hemodialysis could be discontinued. De-
spite the frequent use of adj uvant BCG immunoth erapy, systemic complicatio ns such as hepatitis, pn eumonitis, spondy-
lodiscitis or multiorg an failure are rare (<1%). Hematogenous dissemination which occurs a few weeks after traumatic
instillations is usually suspected but not demonstrated because of absence of mycobacterium in histological specimen.
Our case differs from those previously reported by the simultaneous presence of acid-fast bacilli highlighted on lung
samples. We discuss the pathophysiology of BCG complications, the use of prophylactic or therapeutic treatment and
recommend guidelines to prevent such complication s .
Keywords: Corticosteroids; Hemodialysis; Intravesical BCG; Mycobacterium bovis; Pulmonary Granulomatosis;
Renal Failure; Tubulointerstitial Nephritis; Urothelial Carcinoma
1. Introduction
Combined intravesical instillations of BCG remain the
gold standard for intermediate and high risk non-invasive
urothelial carcinoma of the bladder. Although the a pp e ar-
ance of hematuria, dysuria or cystitis is po ssible, region al
or systemic complications are exceptional. The hemato-
genous spread of mycobacterium from the bladder which
occurs a few weeks after traumatic instillatio ns is usually
suspected but not demonstrated because of absence of
pathogen in histological specimen. Our case correlates
tubulointerstitial nephritis to mycobacterial infection by
the simultaneous presence of acid-fast bacilli hig hlighted
on lung samples.
2. Case Report
In March 2012, a 76-year-old man was admitted to the
hospital because of acute renal failure associated with
progressive grade II dyspnea and recurrent low grade
fever for 3 weeks. He also reported tiredness, an 8 kg
weight loss and night sweats. He had a history of arterial
hypertension and a non invasive (T1) transitional cell
carcinoma (TCC) of the bladder. TCC was first treated
during the second half of 2008 by cauterizatio n followed
by mitomycin instillations for 6 months. Because of the
recurrence of polyps, the patient was treated by cauteri-
zation and one month later, he received 10 intravesical
*Corresponding author.
C
opyright © 2013 SciRes. OJNeph

O. MAT ET AL. 121
instillations of Baccile Calmette-Guerin (BCG) between
November 2010 and July 2011. Current medications
were amlodipine 10 mg and acétylsalicylate 100 mg/day.
On admission, physical examination was unremarkable
excepted fever of 37.9˚C, oliguria and few spread crack-
les in both lung fields and moderate edema of lower
limbs. Regular hemodialysis sessions were initiated
based on clinical status and blood sample evaluation.
Laboratory investigatio n show ed hemoglobin 1.2 g/dL,
a white blood cell count of 4.6 × 10³ /µL with moderate
inflammatory signs (C-reactive protein 30 mg/L, sedi-
mentation rate 30 mm/h), serum creatinine 699 µmol/L.
Electrolytes and Lactatate deshydrogenase were normal,
aspartate aminotransferase 51 IU/L , alcaline phosphatase
208 IU/L and gamma glutamyl transferase 269 IU/L.
Total protein count 47.7 g/L with protein electrophoresis
demonstrates albumin 25.1 g/L and a thin monoclonal
peak of gamma-globulin; the myelogram was normal.
Serologic screenings for anti-nuclear antibody, antineu-
trophil cytoplasmic antibody, anti basal membrane anti-
body, immunoglobin A and hepatitis B or C antibodies
were negative. Plasma complement and coagulation tests
were also normal. Angiotensine Converting Enzyme was
increased at 140 IU/L (range 8.0 - 52.0) and normal
Urine analysis showed proteinuria of 0.4 g/L, sterile leu-
cocyturia without hematuria.
The standard chest X-ray demonstrated a bilateral in-
filtration of the lung fields. Chest computed tomography
confirmed an interstitial syndrome with a “ground glass”
appearance associated with small mediastinal lympha-
denopathies; there was no pleural effusion, nor micro
nodular lesion. Bronchoalveolar lavage was performed
and demonstrated no specific lesion; the microscopic
examination revealed lympho-monocytic cells with rare
neutrophils; mycobacterium culture stayed permanently
sterile. A purified protein derivate (PPD) skin test was
negative despite a 10 IU dose. Transesophageal cardiac
echography excluded infectious endocarditis.
An abdominal CT tomography was performed and
demonstrated normal kidneys, no hepatic enlargement
and moderate splenomegaly. A percutaneous needle bi-
opsy was performed and revealed tubulointerstitial ne-
phritis with a moderate eosinophilic infiltrate without
granulomatous lesion (Figure 1). Glomeruli and arteri-
oles appeared normal; there was no histological evidence
of rapidly progressive glomerulonephritis. Immunofluo-
rescence was negative and electronic microscopy was
unremarkable. After a few days, an open lung biopsy was
also done due to respiratory deterioration. The anatomo-
pathologic specimen demonstrated moderate fibrosis with
lympho-neutrophilic infiltration and few aspecific granu-
lomatous lesions without caseous necrosis or Langhans
giant cells (Figure 2). Mycotic identification remained
negative. Specific mycobacterium culture was started.
Sarcoïdosis was suspected and high dose oral methyl-
prednisolone was started (1 mg/kg/day). The patient’s
general condition began to improve after two weeks of
corticosteroid therapy in conjunction with intermittent
extra-renal epuration and a supportive permanent par-
enteral nutrition. Fever resolved, weight increased, chest
infiltrates disappeared. In the same time, the serum
creatinine began to decrease as shown in Figure 3. After
one month of immunosuppressive treatment, renal func-
tion resolved and hemodialysis could be discontinued.
On day 27, culture of lung biopsy samples in Batec 12B
medium grew acid-fast bacilli that were identified as
Mycobacterium bovis by Polymerase Chain Reaction
(Pasteur Institute, Brussels). Cultures of urine, alveolar
fluid lavage and blood specimens remained definitely
negative. Tuberculostatic agents were promptly initiated
as rifadine 600 mg/day, myambutol 1200 mg/2 days,
nicotibine 300 mg/day and pyridoxine 250 mg/day. Cor-
ticosteroid therapy was gradually reduced and stopped.
Figure 1. Kidney sample.
Figure 2. Lung biopsy.

O. MAT ET AL. 122
Figure 3. Recovery of renal function under corticosteroid
therapy.
The patient is in good condition 6 months after initiation
of antituberculosis therapy; chronic renal failure per-
sisted with a serum creatinine of 220 µmol/L.
3. Discussion
Intravesical immunotherapy with BCG has been safely
used to treat recurrence of superficial transitional cell
carcinoma of the bladder for more than thirty years and
remains a cornerstone for the treatment of intermediate
and high risk non-invasive urothelial carcinoma of the
bladder [1-4]. BCG exerts its antitumor activity through
induction of pro-inflammatory cytokines which may ex-
plain the flu-like syndrome [4,5] (fever, chills and ar-
thralgia) noted in almost 20% of patients receiving ther-
apy. Regional urological complications can occur as
mycobacterium orchi-epidydimitis, prostatis or cystitis.
BCG sepsis is a rare (less than 1%, probably due to his
high molecular weight) and severe complications with
possible multiorgan failure are exceptional [6-9]. Ectopic
localizations are also mentioned: hepatitis, pleural ab-
scess or pneumonitis, spondylodiscitis, arthritis, mycotic
aneurysms, chorioretinitis and retroperitoneal abscess.
The hematogenous dissemination occurs especially after
traumatic bladder instillation. Old age, acute bacterial
cystitis, cumulative doses are additional risk factors
which must be considered before instillations. Prophy-
lactic drug, such as isoniazid, does not seem to reduce
side effects of BCG instillations [2,3]. Contraindications
include recent bladder surgery or polypectomy, recent
radiotherapy treatment, hematuria, active tuberculosis,
current immunosuppressive treatment and acute urine
tract infection. Renal failure with histological evidence
of suspected BCG toxicity is reported in twelve cases
found by screening the National Library of Medecine’s
Medline system. In 9/12 of cases, tubule-interstitial ne-
phritis is presented (5/12 with granuloma) and generally
combined with hepatitis; mesangial glomerulonephritis,
membranous glomerulonephritis and focal segmental
hyalinosis are described as exceptional cases. Mycobac-
terial infection are usually considered as suspected re-
sponsible pathogen but not demonstrated because of ab-
sence of mycobacterium in histological specimen. Our
case differs from those previously reported by the simul-
taneous presence of acid-fast bacilli highlighted on lung
samples. The evidence of Mycobacterium bovis by DNA-
rRNA hybridization strengthens the temporal relatio nsh ip
between BCG instillations and kidney-lung impairment
despite the unusual delayed onset complications since
generally occurring a few weeks after the last instillation
[5-7]. Some authors stratified into early- and late-pres-
entation disease [10]. The first one (within 3 months)
could be result from systemic infection with proliferation
of the organisms causing generalized granulomatous re-
sponse by repeated instillations. The second one (be-
tween 3 months and until more than 1 year) could result
from reactivation of infection after successful immu-
nologic control of early dissemination, which is rather
the case of our patient. Despite severe presentation of
“BCGitis”, corticosteroids administration often results in
a prompt recovery of both renal and lung functions. The
role of corticosteroids in the treatment of the complica-
tions of BCG instillations is not clearly defined within
randomized studies. Nevertheless, their use seems inter-
esting since the objective of BCG instillatio n is to induce
immune reaction of the host and so we can assume that
symptoms may be at least partially related to this me-
chanism. In the present case, positive culture for Myco-
bacterium bovis questioned the only hypothesis of hy-
persensitivity reaction, reason why tuberculostatic drugs
were added to corticosteroids. We also noted th at, desp ite
the absence of tuberculostatic agents during the initial
phase of treatment, no proven dissemination of myco-
bacteria occurred.
4. Conclusion
Unusual complications due to adjuvant BCG immuno-
therapy mostly occur a few weeks after intravesical treat-
ment. Prevention of these adverse events requires avoid-
ing the risk factors (recent bladder surgery or polypec-
tomy, recent radiotherapy treatment, hematuria, active
tuberculosis, current immunosuppressive treatment and
acute urinary tract infection) and regular control of renal
function during prolonged therapy. Treatment by corti-
costeroids improves the outcome of patients and the
question of tuberculos tatic therap y should always be con -
sidered. Prophylactic drug, such as isoniazid, does not
seem to prevent side effects of BCG instillations.
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