Kaohsiung Journal of Medical Sciences (2013) 29, 337e342

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CASE REPORT

Glomerulonephritis associated with tuberculosis:A case report and literature review

Yalcin Solak a,*, Abduzhappar Gaipov a, Melih Anil a, Huseyin Atalay a, Orhan Ozbek b,Kultigin Turkmen a, Ilker Polat c, Suleyman Turk a

aDivision of Nephrology, Department of Internal Medicine, Meram School of Medicine, Konya University,Meram, Konya, TurkeybDepartment of Radiology, Meram School of Medicine, Konya University, Meram, Konya, TurkeycDepartment of Internal Medicine, Meram School of Medicine, Konya University, Meram, Konya, Turkey

Received 21 March 2012; accepted 6 June 2012Available online 16 January 2013

KEYWORDSAnti-tuberculosistreatment;Crescenticglomerulonephritis;Pulmonarytuberculosis;Renal failure

* Corresponding author. Konya UniveHemodiyaliz Sekreterligi, Meram, 420

E-mail address: yalcinsolakmd@gm

1607-551X/$36 Copyright ª 2012, Kaohttp://dx.doi.org/10.1016/j.kjms.201

Abstract Rapidly progressive glomerulonephritis caused mycobacterium tuberculosis is rare;however, three case have been reported to date. Crescentic glomerulonephritis is a life-threatening disease and together with the presence of tuberculous infection is associated witha poor outcome if treatment is inadequate and delayed. We describe the case of a 31-year-oldfemale patient with nephrotic syndrome and progressive renal failure secondary to pulmonarytuberculosis. Renal biopsy showed crescent formation in 14 out of 27 glomeruli, and there wasdiffuse linear staining of immunoglobulin G deposits. Treatment included corticosteroids incombination with antituberculosis drugs for 2 months, and resulted in a significant improve-ment in renal function, the disappearance of proteinuria and pulmonary symptoms. We alsopresent a review of the pertinent literature and discuss the pathophysiology of tuberculosis-related acute postinfectious glomerulonephritis.Copyright ª 2012, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rightsreserved.

Introduction

Historically, various pathogens have been reported to causepostinfectious glomerulonephritis, including bacteria,

rsitesi, Meram Tip Fakultesi,90 Konya, Turkey.ail.com (Y. Solak).

hsiung Medical University. Publish2.10.008

viruses, fungi and parasites. [1]. Tuberculosis may be seen inthe urinary system in 4e5% of all cases of extrapulmonarytuberculosis, and renal involvement may occur by directinfection of the kidney and/or through secondary amyloid-osis [2]. The disease usually develops 5e25 years after theprimary tuberculosis infection [3]. Glomerulonephritissecondary to tuberculosis is uncommon in the group of post-infectious nephritides [4]. Although several cases of

ed by Elsevier Taiwan LLC. All rights reserved.

338 Y. Solak et al.

tuberculosis associated with various forms of glomerulone-phritis have been reported, only three reports of well-documented crescentic glomerulonephritis associated withtuberculosis have been published [5e7].

Crescentic glomerulonephritis is potentially life-threatening and is frequently associated with a rapid clin-ical deterioration and poor outcome [8]. If treatment isdelayed, patients will develop renal failure within days orweeks of diagnosis [9,10]. The presence of tuberculosisassociated with progressive glomerulonephritis complicatesthe choice and sequence of therapeutic options of immuno-suppressive agents and/or anti-tuberculosis drugs. It is veryimportant to make an early diagnosis of nephropathy asso-ciated with tuberculosis and to start appropriate treatment.We report on a patient with crescentic glomerulonephritissecondary to pulmonary tuberculosis in which antitubercu-losis treatment ameliorated renal function. We also discussthe related cases reported in the literature.

Case report

A 31-year-old female patient presenting with uremia, fever,fatigue, and productive cough was admitted into thenephrology ward with suspicion of contrast-inducednephropathy. Two weeks before admission, the patienthad undergone appendectomy for perforated appendicitis,and after the operation abdominal computed tomography(CT) was performed in order to search for an intra-abdominal abscess. Initially the patient had normal kidneyfunction and she had no prior history of renal or pulmonarydisease. She said that her mother had a history of tuber-culosis. There was no palpable lymphadenopathy and pre-tibial edema. On pulmonary auscultation, there wererhonchi in the middle zone of the left lung. Blood pressurewas 130/80 mmHg and examination of the cardiovascular,gastrointestinal and urogenital systems were unremark-able. Urine output was 3600 mL/24 h on the first day ofadmission. Laboratory examination showed hemoglobin10.7 g/dL, hematocrit 37.2%, white blood cell count11,000/mm3, platelets 298 � 103/mL, erythrocyte sedi-mentation rate 41 mm/h, C-reactive protein 68.5 mg/dL,blood urea nitrogen (BUN) 81 mg/dL, serum creatinine5.7 mg/dL (glomerular filtration rate 9.2 mL/min by

Figure 1. (A) Light microscopy of the renal biopsy shows a cellueosin staining, magnification �100). (B) Direct immunofluorescendeposits (magnification �200).

modification of diet in renal disease formula), potassium6.0 mEq/L, serum albumin 2.8 g/dL, total protein 6.17 mg/dL, and activated partial thromboplastin time 26.8 seconds.Urine analysis yielded 3þ erythrocytes on strip andproteinuria 75 mg/dL. Twenty-four-hour urine collectionshowed protein excretion 9.8 g/24 h, urine microalbumin1980 mg/24 h, urine creatinine 1204 mg/24 h and creatinineclearance of 17.4 mL/min. Renal ultrasonography showedbilateral kidneys with normal size and shape, but increasedparenchymal echogenicity. Markers for immune-associatednephrites [antinuclear antibodies (ANA), antineutrophilcytoplasmic antibodies (ANCA), anti-dsDNA, antiglomerularbasement membrane (GBM) antibody] were negative. Renalbiopsy showed crescent formation in 14 out of 27 glomeruliand there was diffuse linear staining of immunoglobulin Gdeposits (Fig. 1). There were no granulomas and Langhans’giant cells. The sputum and urine culture produceda negative result for mycobacterium tuberculosis. A chestX-ray image showed bilateral upper lobe opacitiescompatible with pneumonic consolidations, which wasmore prominent in the left lung (Fig. 2A). Chest CTconfirmed this pneumonic consolidation (Fig. 3). We diag-nosed pulmonary tuberculosis based on the findings of chestCT and examination of sputum, which was positive foracido-resistant bacilli (ARB). Considering the presence ofnephrotic syndrome and crescent formation, we startedintravenous methylprednisolone pulses of 500 mg/day for 3days, and then methylprednisolone was continued orally ata dose of 64 mg/day. Four-drug antituberculosis treatmentwas also administered after having seen ARB positivity.After 2 months of immunosuppressive and antituberculosistherapy, renal function repaired, plasma creatinine leveldecreased from 5.7 mg/dL to 1.4 mg/dL and the pulmonarysymptoms also responded to the treatment (Fig. 2B). Theclinical course of the patient during her hospitalization isillustrated in Fig. 4.

Discussion

Acute postinfectious glomerulonephritis (APIG) isuncommon in adults and its incidence continues to declinethanks to early and more effective therapies of infections.In a recent series by Nasr et al. [11], the most common

lar crescent (arrow) in one of the glomeruli (hematoxylin andce image shows diffuse linear staining of immunoglobulin G

Figure 2. (A) Chest X-ray film on admission. Bilateral upper lobe opacities are compatible with pneumonic consolidations, and ismore prominent in the left lung. (B) Reduction of this consolidation after 7 weeks.

Figure 3. (A, B) Bilateral pneumonic consolidations that are more prominent on the left, in both lungs in axial sections of chestcomputed tomography.

Glomerulonephritis associated with tuberculosis 339

pathogens were staphylococci and streptococci. The mostcommon renal histologic pattern related to APIG wasdiffuse endocapillary proliferative and exudative glomeru-lonephritis, while crescent formation was only present in

Figure 4. Clinical course of the patient during hospitalization. ABcytoplasmic antibodies, Anti-GBM e anti-glomerular basement metomography, CI-AKI e contrast induced acute kidney injury, CRP e CRPGN e rapidly progressive glomerulonephritis, TB e tuberculosis.

four out of 86 patients [11]. On immunofluorescencemicroscopy, in 82% of cases the granular staining was seenas the most common pattern in the mesangium andglomerular capillary wall [11].

– antibodies, ANA – antinuclear antibodies, ANCA – antineutrophilmbrane, ARB e acido-resistant bacilli, CCT e Chest computed-reactive protein, CXR e Chest X-ray, GN – glomerulonephritis,

340 Y. Solak et al.

Important points when making a diagnosis of APIG are:evidence of infection preceding the glomerulonephritis,glomerular change consistent with postinfectious glomeru-lonephritis; and the absence of systemic disease that canaccount for the glomerular changes. The favorableresponse to anti-infection therapy also supports the diag-nosis of APIG [12].

Tuberculosis can cause renal disease in a number ofways. The most common form is genitourinary tuberculosisvia direct invasion by the bacilli. Chronic interstitialnephritis and amyloidosis are among the other forms thatmay develop [4]. Usually, renal involvement in tuberculosishistologically consists of epithelioid granuloma, with orwithout caseation, and often contains Langhans-type giantcells [4]. However, glomerulonephritis associated withtuberculosis infection is very rare. To the best of our

Table 1 Overview of previous cases of tuberculosis associated

First author(year)

Patientdetails

Clinical features Proteinuria

Shribman JH,(1983)

45 years,male

Fever, weight loss, HT 1.3 g/24 h

Cohen AJ,(1985)

59 years,male

Microscopic hematuria,casts,

negative

Meyrier A,(1988)

46 years,male

Hematuria, edema andHT

8.0 g/24 h

O’Brien AA(1990)

63 years,male

Nephrotic syndrome 3.9 g/24 h

Sopena B,(1991)

55 years,male

Fever, cough, HT,edema and oligouria

0.7 g/24 h

De Siati L,(1999)

31 years,male

Fever, macroscopichematuria, oligouria

mean,5.13 g/L

Matsuzawa N,(2002)

35 years,female

Edema, fever, pleuraleffusion, abdominalpain

5.6 g/24 h

Keven K,(2004)

36 years,male

Dyspnoea, cough,haematuria and edema

6.8 g/24 h

Coventry S,(2004)

16 years,female

Anasarca 27.9 g/24 h

Fofi C,(2005)

75 years,male

Purpura, anemia,oliguria and hematuria

6.0 g/24 h

Wen YK,(2009)

70 year,male

Caugh, cervicallymphadenopathy, HTand edema

0.6 g/24 h

Singh P,(2009)

34 years,male

Fever, weight loss,erythrocyturia

2.04 mg/dL

Yuan Q,(2010)

50 years,female

Fever, weight loss,low-back pain,hematuria

2.6 g/24 h

Ortmann J,(2010)

36 years,male

Pleural effusions,erythrocyturia, and HT

Proteinuria (?)

Our Case(2011)

31year,female

Uremia, fever,fatigability andproductive cough

9.8 g/24 h

ATD e anti-tuberculous drugs, CGN e crescentic glomerulonephritis, Ctuberculosis, FSGS e focal-segmental glomerulosclerosis, HD e hemodtuberculosis, MCGN e mesangio-capillary glomerulonephritis, MGN eMPGN e mesangio-proliferative glomerulonephritis, MT e miliary tupleuro-pulmonary tuberculosis, PT e pulmonary tuberculosis.

knowledge, 14 cases in which tuberculosis was associatedwith different forms of glomerulonephritis have been re-ported in the literature (Table 1). Histopathologicalchanges were consistent with immunoglobulin A (IgA)nephropathy in six cases [13e18], mesangioproliferativeglomerulonephritis in two cases [19,20], one case of each ofcollapsing glomerulopathy [21], mesangiocapillary [22] andmembranous glomerulonephritis [23], and three cases ofcrescentic glomerulonephritis [5e7].

IgA nephropathy is the most commonly encountered histo-logical subtype of tuberculosis associated glomerulonephritis(TAG). Recent data have started to unveil the basic patho-physiologicalmechanismof this predilection. It is awell knownfact that immune response to mycobacterial infection isprimarily cell mediated. The role of humoral immune system,however, has beendemonstrated including thepresence of IgA

glolomerulonephritis reported in the literature.

GFR orcreatinine

Typeof TBC

Renalbiopsy

Treatmentoptions

Treatmentoutcome

2.9 mg/dL MT MPGN ATD and CS Responded

1.2 mg/dL DT IgAN ATD Responded

55 ml/min DT MCGN ATD andNSAID

Responded

Normal PT MPGN ATD Responded

18 mg/dL PT CGN ATD, CS,CP and HD

Responded

32 ml/min PT IgAN ATD Responded

Normal DT IgAN ATD Responded

116 ml/min PT IgAN ATD Responded

z80 ml/min PT FSGS CS, ATDand MMF

Progressedto ESRD

60 ml/min PT CGNand IgAN

ATD and HD Patient died

Less than10 ml/min

MT CGN ATD and HD Responded

Normal PPT IgAN ATD Responded

27 ml/min LT MGN ATD and CS Responded

1.9 mg/dL PPT IgAN ATD Partialremission

17.4 ml/min PT CGN ATD and CS Responded

P e cyclophosphamide, CS e corticosteroids, DT e disseminatedialysis, HT e hypertension, IgAN e IgA nephropathy, LT e lumbarmembranous glomerulonephritis, MMF e mycophenolate mofetil,berculosis, NSAID e nonsteroid anti-inflammatory drugs, PPT e

Glomerulonephritis associated with tuberculosis 341

antibodies against A-60 mycobacterial antigen, IgA immunecomplexesandmycobacterial antigens in theserumofpatientswith active tuberculosis [24]. Thus, acute tuberculous infec-tion is associated with a marked increase in serum IgA levels.Deposition of these complexes in turn may activate the alter-native complement [25] and the lectin pathway [26], withresultant local injury leading to IgA nephropathy. Thesepreliminary observations may account for the dominance ofthe IgA nephropathy subtype of TAG.

It is arguable, however, whether every patient withrenal tuberculosis develops IgA nephropathy and thusrequires a renal biopsy to document the diagnosis. Obvi-ously only a very small subset of patients with renaltuberculosis presents with IgA nephropathy. On the otherhand, we should bear in mind that in the case of proteinuriaalong with hematuria and sterile pyuria, renal biopsy maybe needed to diagnose concurrent IgA nephropathy.

In 12 cases out of 14, renal function was amelioratedfollowing anti-tuberculosis therapy. One patient with extrac-apillary IgA nephropathy died [7] and another patientdeveloped end-stage renal disease [21]. All patients withrapidly-progressive glomerulonephritis underwent hemodial-ysis therapy, and in one case treatment was combined withimmunosuppressive drugs [5]. Two patients with crescenticglomerulonephritis responded to therapy and renal functionwas restored at the end of the therapy [5,6]. In another case,the patient who did not receive corticosteroids because ofcontraindications died despite anti-tuberculous therapy. Theunsuccessful result in this casewas considered to be related tothe older age of the patient with a long history of hyperten-sion, rifampicin nephrotoxicity, diffuse intra- and extracapil-lary proliferation with cellular crescents and glomerularsclerosis, severe anemia and steady oliguria [7].

Immune-complex crescentic glomerulonephritis (ICCG) isoneofthree formsofcrescenticglomerulonephritis; theothersare pauci-immune and linear deposition [27]. We could notdetectanti-GBMorANCAantibodies inourpatient. ICCGcanbeseen in a number of primary glomerulonephritides includingIgA nephropathy, membranous and membranoproliferativeglomerulonephritides, and as a result of infection.

In our case, renal functional impairment was alreadypresent at the initial presentation. However, the patient didnot require renal replacement therapy during the course ofhospitalization as she was not oliguric, so we preferred towait. She had nephrotic syndrome and uremia, consistentwith the cases reported in the literature. The patient also hadfever, cough, purulent sputum, constitutional symptoms,pulmonary infiltrates and nodules on imaging studies. Ourprimary concern was a pulmonary renal syndrome; however,serological disease markers were found to be negative. AfterARB were seen on expectorated sputum, a diagnosis ofpulmonary tuberculosis was established. ICCGwas thought tobe secondary to pulmonary tuberculosis infection. Ameliora-tion of kidney function with a four-drug anti-tuberculosisregimen further supported our initial diagnosis.

Additionally, a similar clinical and radiographical pictureof pulmonary tuberculosis may show non-tuberculosismycobacterium (NTM) infection. Chen et al. [28] reporteda single case of NTM infection associated with rapidlyprogressive glomerulonephritis. Pulmonary symptoms andrenal function steadily improved after initiation of anti-NTM therapy. Diagnosis of pulmonary NTM infection is

difficult. NTM are widely dispersed in our environment andthere are more than 20 species of NTM. Unlike tuberculosis,NTM are not spread from human to human. Clinical,radiographic, and microbiological criteria include pulmo-nary symptoms, radiographic opacities, nodular or cavitarypneumonia, or multifocal bronchiectasis with multiplesmall nodules and a thrice positive microbiological cultureof mycobacterium other than tuberculosis [29]. In ourpatient, three sputum cultures were negative for any formof tuberculosis.

When acute postinfectious glomerulonephritis developsand is related to tuberculosis, immune complex depositionalso occurs in the form of a granular pattern [5,6]. In ourcase, however, it was linear. At this point, we may arguethat our patient had anti-GBM antibody disease with cres-cent formation. The anti-GBM antibody test was negative,however, and the patient did not have pulmonary hemor-rhage. Furthermore, her kidney function amelioratedwithout plasmapheresis. This latter situation argues againstanti-GBM antibody disease, as it is unusual that sucha patient presenting with high serum creatinine wouldcompletely recover from renal dysfunction.

In conclusion, ICCG has rarely been reported in theliterature. It should be suspected in a patient with rapidly-deteriorating kidney function in the setting of pulmonary ordisseminated tuberculosis infection.

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