Severe tubulointerstitial nephritis: tracking tuberculosis even in the absence of renal granuloma

Severe tubulointerstitial nephritis: tracking tuberculosis even in the absence of renal granuloma Extra-pulmonary tuberculosis is frequently located in the kidneys and, in such cases, could be associated with a granulomatous interstitial nephritis. Granulomas are not always detected, especially in human immunodeficiency virus (HIV)-positive patients. We report here a case of tubulointerstitial nephritis without granulomas in an HIV-negative patient. Since all laboratory tests failed to isolate Mycobacterium tuberculosis in the kidney, a targeted biopsy guided by positron emission tomography–computed tomography was performed on a mediastinal node, revealing a positive culture. After 6 months of treatment, no recovery of the renal injury has been observed. Key words: chronic kidney disease, granuloma, positron emission tomography–computed tomography, QuantiFERON, tuber- culosis, tubulointerstitial nephritis Background Case report Urogenital tract is the second most common site for extra- A 41-year-old Congolese woman, living in France for 5 years, pulmonary tuberculosis (TB), accounting for one-quarter of was hospitalized for kidney injury. She had no medical history such cases [1]. According to the European Dialysis and except for six uncomplicated pregnancies. Two months after Transplant Association, only 0.65% of patients admitted for her last delivery, she noticed general sickness, loss of weight dialysis have TB as primary renal diagnosis [2]. Renal injury is and noctural fever. Physical examination was unremarkable. generally due to urinary tract scarring, and less commonly to Laboratory results were as follows: white cell 7  10 /L, with glomerulonephritis or secondary amyloidosis, but granuloma- lymphopenia 0.8  10 /L; microcytic anaemia 80 g/L; C-reactive tous interstitial nephritis could be the sole manifestation. protein 68.5 mg/L; serum creatinine (SCr) 457 mmol/L; estimated We report here a case of tubulointerstitial nephritis (TIN) glomerular filtration rate (eGFR) by chronic kidney disease- without granulomas in a human immunodeficiency virus epidemiology collaboration ( CKD-EPI) formula 10 mL/min/1.73 (HIV)-negative patient, which led to the diagnosis of dissemi- m . Renal ultrasonography was normal. Urinalysis revealed nated TB. low tubular proteinuria (0.6 g/g creatinine), sterile leucocyturia Received: August 2, 2017. Editorial decision: December 1, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 667 Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/667/4823423 by Ed 'DeepDyve' Gillespie user on 17 October 2018 668 | M. Delafosse et al. (250/mm ) and no haematuria. Renal biopsy showed diffuse culture on renal biopsy; two early morning urine cultures were active interstitial inflammation without granulomas (Figure 1). performed and gave negative results for Mycobacterium tuberculo- The first aetiological assessment was inconclusive: no drug sis (MTb). Positron emission tomography–computed tomogra- abuse (including over-the-counter medications), negative hepati- phy (PET/CT) showed uptakes in stomach, ileocecal valve and tis B, hepatitis C and human immunodeficiency viruses serolo- two mediastinal lymph nodes (Figure 2). A transbronchial gies, negative blood and urine cultures, normal chest X-ray, biopsy of one mediastinal node showed granuloma formations cardiac ultrasound and no immunologic antibodies with central necrosis, whereas PCR was negative for MTb. (antineutrophil cytoplasmic antibody, antinuclear antibody, anti- Finally, after 4 weeks, MTb grew in lymph node. Once cortico- RO/SSa and anti-La/SSb were negative). Complement was not therapy was decreased, a second QFT-TB assay was performed activated. Serum angiotensin-converting enzyme was normal. and the result was then positive. Six months later, fever and The patient was initially treated with IV methylprednisolone biological inflammation reduced, while renal function remained (500 mg/day for 3 days), followed by oral prednisolone (1 mg/kg/ at Stage 5 chronic kidney disease (CKD) (SCr 508 lmol/L, eGFR day), which was gradually tapered off. A first interferon gamma 2 8 mL/min/1.73 m ). A second kidney biopsy confirmed chronic release assay (IGRA), using QuantiFERON-TB Gold in Tube (QFT- lesions with atrophic tubules (Figure 3). TB) testing (Qiagen), was performed and considered indetermi- nate due to no reactivity in the mitogen control positive well. Due to a high suspicion of TB, antitubercular treatment was Discussion introduced 3 weeks later. TIN during TB infection is rare, but is characterized by the pres- As the fever persisted, investigations were intensified: ence of interstitial granulomas. To the authors’ best knowledge, ‘Ziehl–Neelsen’ staining, polymerase chain reaction (PCR) and this is the first reported case of TB-associated TIN without gran- ulomas in an HIV-negative patient; as for HIV-positive patients, inhibition of cell-mediated immunity during the post-partum period could explain the high risk of TB, and the lack of granulo- mas [3, 4]. In the face of ongoing migration, TB is probably an under- diagnosed cause of TIN, since MTb is rarely isolated. Urine cul- tures, ‘Ziehl–Neelsen’ staining and culture on renal biopsy mostly provide negative results [1]. Additionally, PCR has also shown poor sensitivity in paraffin-embedded extra-pulmonary samples (32% positive), probably associated with a low burden of mycobacteria [1, 5]. In extra-pulmonary TB cases, PET/CT can help perform tar- geted biopsies [6], as in the case of our patient. As previously published, an indeterminate IGRA test may be explained by high doses of glucocorticoids [7] or CKD [8]. Once the use of immunosuppressive drugs is reduced, the test result may turn positive, as noticed in our case. Therefore, the difficult diagnosis of TB entails many aetiologies for TIN, such as drug reaction, Fig. 1. Periodic acid–Schiff (PAS) staining (100 magnification): active interstitial infections and autoimmune diseases. inflammation with lymphocytes, histiocytes and polymorphonuclear leuco- Even in developed countries and in the absence of granu- cytes. Inset shows PAS staining (400 magnification): acute tubulitis without loma on renal biopsy, TB should be tracked in high-risk basement membrane thickening. Fig. 2. PET/CT. Axial image: hypermetabolic activity within subcarinal lymph node. Coronal image: hypermetabolic activity on ileocecal valve and two mediastinal lymph nodes. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/667/4823423 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Severe tubulointerstitial nephritis | 669 Gerinie ` re, MD, of the CHU Lyon Sud, for their help with patient recruitment and management. Funding Dr. Fouque reports personal fees from Amgen, personal fees from Fresenius Medical Care, personal fees from Sanofi, per- sonal fees from Vifor, personal fees from Fresenius Kabi, outside the submitted work. Other authors have nothing to disclose. Conflict of interest statement None declared. References Fig. 3. Periodic acid–Schiff (PAS) staining (100 magnification) chronic lesion 1. Chapagain A, Dobbie H, Sheaff M et al. Presentation, diagno- with atrophic tubules, ischaemic glomeruli and arteriolar thickening. Inset sis, and treatment outcome of tuberculous-mediated tubu- shows PAS staining (400 magnification) mild lymphocytic tubulitis. lointerstitial nephritis. Kidney Int 2011; 79: 671–677 2. Eastwood JB, Zaidi M, Maxwell JD et al. Tuberculosis as pri- populations, including immunosuppressed patients in the post- mary renal diagnosis in end-stage uremia. J Nephrol 1994; 7: partum period or with severe CKD. 290–293 Treatment of TIN caused by TB is based on a standard 6- 3. Zenner D, Kruijshaar ME, Andrews N et al. Risk of tuberculo- month antibiotic treatment, without ethambutol to avoid optic sis in pregnancy: a national, primary care-based cohort and neuritis [1]. Currently, the pathogenesis of TB-associated TIN is self-controlled case series study. Am J Respir Crit Care Med unknown. TIN might not be directly to bacterial invasion, but to 2012; 185: 779–784 indirect immunological mechanisms, and therefore the use of 4. Lawn SD, Bekker L-G, Miller RF. Immune reconstitution dis- corticosteroids could reduce interstitial fibrosis [9]. Shribman et ease associated with mycobacterial infections in HIV- al. report a case of miliary TB complicated by an immune com- infected individuals receiving antiretrovirals. Lancet Infect Dis plex nephritis, which could be in favour of an immunological 2005; 5: 361–373 process in TB-associated renal injury [10]. 5. Alvarado-Esquivel C, Garcı ´a-Corral N, Carrero-Dominguez D Due to the poor renal prognosis, diagnosis must be done as et al. Molecular analysis of mycobacterium isolates from early as possible, preferably when eGFR is >15 mL/min. Indeed, extrapulmonary specimens obtained from patients in two-thirds of patients presenting with an eGFR<15 mL/min Mexico. BMC Clin Pathol 2009; 9: 1 need to start a renal replacement therapy within 12 months 6. Ankrah AO, van der Werf TS, de Vries EFJ et al. PET/CT imag- after diagnosis [1]. ing of mycobacterium tuberculosis infection. Clin Transl Imaging 2016; 4: 131–144 Conclusion 7. Calabrese C, Overman RA, Dusetzina SB et al. Evaluating indeterminate interferon-c-release assay results in patients TB remains an underdiagnosed cause of severe TIN, especially with chronic inflammatory diseases receiving immunosup- in the lack of granulomas on renal biopsy, leading to a delay of pressive therapy. Arthritis Care Res 2015; 67: 1063–1069 specific treatment and a poor renal outcome. Physicians should 8. Jeong SJ, Han SH, Kim CO et al. Predictive factors for indeter- be advised to hunt down TB in high-risk populations or in cases minate result on the QuantiFERON test in an intermediate where there is a lack of corticotherapy response. When there is tuberculosis-burden country. J Infect 2011; 62: 347–354 no evidence of pulmonary disease, PET/CT imaging could help 9. Eastwood JB, Corbishley CM, Grange JM. Tuberculosis and in making the diagnosis. tubulointerstitial nephritis: an intriguing puzzle. Kidney Int 2011; 79: 579–581 Acknowledgements 10. Shribman JH, Eastwood JB, Uff J. Immune complex nephritis The authors would like to thank the members of complicating miliary tuberculosis. Br Med J (Clin Res Ed) 1983; Nephrology Department, Claire Grange, MD and Laurence 287: 1593–1594 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Severe tubulointerstitial nephritis: tracking tuberculosis even in the absence of renal granuloma

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Abstract

Extra-pulmonary tuberculosis is frequently located in the kidneys and, in such cases, could be associated with a granulomatous interstitial nephritis. Granulomas are not always detected, especially in human immunodeficiency virus (HIV)-positive patients. We report here a case of tubulointerstitial nephritis without granulomas in an HIV-negative patient. Since all laboratory tests failed to isolate Mycobacterium tuberculosis in the kidney, a targeted biopsy guided by positron emission tomography–computed tomography was performed on a mediastinal node, revealing a positive culture. After 6 months of treatment, no recovery of the renal injury has been observed. Key words: chronic kidney disease, granuloma, positron emission tomography–computed tomography, QuantiFERON, tuber- culosis, tubulointerstitial nephritis Background Case report Urogenital tract is the second most common site for extra- A 41-year-old Congolese woman, living in France for 5 years, pulmonary tuberculosis (TB), accounting for one-quarter of was hospitalized for kidney injury. She had no medical history such cases [1]. According to the European Dialysis and except for six uncomplicated pregnancies. Two months after Transplant Association, only 0.65% of patients admitted for her last delivery, she noticed general sickness, loss of weight dialysis have TB as primary renal diagnosis [2]. Renal injury is and noctural fever. Physical examination was unremarkable. generally due to urinary tract scarring, and less commonly to Laboratory results were as follows: white cell 7  10 /L, with glomerulonephritis or secondary amyloidosis, but granuloma- lymphopenia 0.8  10 /L; microcytic anaemia 80 g/L; C-reactive tous interstitial nephritis could be the sole manifestation. protein 68.5 mg/L; serum creatinine (SCr) 457 mmol/L; estimated We report here a case of tubulointerstitial nephritis (TIN) glomerular filtration rate (eGFR) by chronic kidney disease- without granulomas in a human immunodeficiency virus epidemiology collaboration ( CKD-EPI) formula 10 mL/min/1.73 (HIV)-negative patient, which led to the diagnosis of dissemi- m . Renal ultrasonography was normal. Urinalysis revealed nated TB. low tubular proteinuria (0.6 g/g creatinine), sterile leucocyturia Received: August 2, 2017. Editorial decision: December 1, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 667 Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/667/4823423 by Ed 'DeepDyve' Gillespie user on 17 October 2018 668 | M. Delafosse et al. (250/mm ) and no haematuria. Renal biopsy showed diffuse culture on renal biopsy; two early morning urine cultures were active interstitial inflammation without granulomas (Figure 1). performed and gave negative results for Mycobacterium tuberculo- The first aetiological assessment was inconclusive: no drug sis (MTb). Positron emission tomography–computed tomogra- abuse (including over-the-counter medications), negative hepati- phy (PET/CT) showed uptakes in stomach, ileocecal valve and tis B, hepatitis C and human immunodeficiency viruses serolo- two mediastinal lymph nodes (Figure 2). A transbronchial gies, negative blood and urine cultures, normal chest X-ray, biopsy of one mediastinal node showed granuloma formations cardiac ultrasound and no immunologic antibodies with central necrosis, whereas PCR was negative for MTb. (antineutrophil cytoplasmic antibody, antinuclear antibody, anti- Finally, after 4 weeks, MTb grew in lymph node. Once cortico- RO/SSa and anti-La/SSb were negative). Complement was not therapy was decreased, a second QFT-TB assay was performed activated. Serum angiotensin-converting enzyme was normal. and the result was then positive. Six months later, fever and The patient was initially treated with IV methylprednisolone biological inflammation reduced, while renal function remained (500 mg/day for 3 days), followed by oral prednisolone (1 mg/kg/ at Stage 5 chronic kidney disease (CKD) (SCr 508 lmol/L, eGFR day), which was gradually tapered off. A first interferon gamma 2 8 mL/min/1.73 m ). A second kidney biopsy confirmed chronic release assay (IGRA), using QuantiFERON-TB Gold in Tube (QFT- lesions with atrophic tubules (Figure 3). TB) testing (Qiagen), was performed and considered indetermi- nate due to no reactivity in the mitogen control positive well. Due to a high suspicion of TB, antitubercular treatment was Discussion introduced 3 weeks later. TIN during TB infection is rare, but is characterized by the pres- As the fever persisted, investigations were intensified: ence of interstitial granulomas. To the authors’ best knowledge, ‘Ziehl–Neelsen’ staining, polymerase chain reaction (PCR) and this is the first reported case of TB-associated TIN without gran- ulomas in an HIV-negative patient; as for HIV-positive patients, inhibition of cell-mediated immunity during the post-partum period could explain the high risk of TB, and the lack of granulo- mas [3, 4]. In the face of ongoing migration, TB is probably an under- diagnosed cause of TIN, since MTb is rarely isolated. Urine cul- tures, ‘Ziehl–Neelsen’ staining and culture on renal biopsy mostly provide negative results [1]. Additionally, PCR has also shown poor sensitivity in paraffin-embedded extra-pulmonary samples (32% positive), probably associated with a low burden of mycobacteria [1, 5]. In extra-pulmonary TB cases, PET/CT can help perform tar- geted biopsies [6], as in the case of our patient. As previously published, an indeterminate IGRA test may be explained by high doses of glucocorticoids [7] or CKD [8]. Once the use of immunosuppressive drugs is reduced, the test result may turn positive, as noticed in our case. Therefore, the difficult diagnosis of TB entails many aetiologies for TIN, such as drug reaction, Fig. 1. Periodic acid–Schiff (PAS) staining (100 magnification): active interstitial infections and autoimmune diseases. inflammation with lymphocytes, histiocytes and polymorphonuclear leuco- Even in developed countries and in the absence of granu- cytes. Inset shows PAS staining (400 magnification): acute tubulitis without loma on renal biopsy, TB should be tracked in high-risk basement membrane thickening. Fig. 2. PET/CT. Axial image: hypermetabolic activity within subcarinal lymph node. Coronal image: hypermetabolic activity on ileocecal valve and two mediastinal lymph nodes. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/667/4823423 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Severe tubulointerstitial nephritis | 669 Gerinie ` re, MD, of the CHU Lyon Sud, for their help with patient recruitment and management. Funding Dr. Fouque reports personal fees from Amgen, personal fees from Fresenius Medical Care, personal fees from Sanofi, per- sonal fees from Vifor, personal fees from Fresenius Kabi, outside the submitted work. Other authors have nothing to disclose. Conflict of interest statement None declared. References Fig. 3. Periodic acid–Schiff (PAS) staining (100 magnification) chronic lesion 1. Chapagain A, Dobbie H, Sheaff M et al. Presentation, diagno- with atrophic tubules, ischaemic glomeruli and arteriolar thickening. Inset sis, and treatment outcome of tuberculous-mediated tubu- shows PAS staining (400 magnification) mild lymphocytic tubulitis. lointerstitial nephritis. Kidney Int 2011; 79: 671–677 2. Eastwood JB, Zaidi M, Maxwell JD et al. Tuberculosis as pri- populations, including immunosuppressed patients in the post- mary renal diagnosis in end-stage uremia. J Nephrol 1994; 7: partum period or with severe CKD. 290–293 Treatment of TIN caused by TB is based on a standard 6- 3. Zenner D, Kruijshaar ME, Andrews N et al. Risk of tuberculo- month antibiotic treatment, without ethambutol to avoid optic sis in pregnancy: a national, primary care-based cohort and neuritis [1]. Currently, the pathogenesis of TB-associated TIN is self-controlled case series study. Am J Respir Crit Care Med unknown. TIN might not be directly to bacterial invasion, but to 2012; 185: 779–784 indirect immunological mechanisms, and therefore the use of 4. Lawn SD, Bekker L-G, Miller RF. Immune reconstitution dis- corticosteroids could reduce interstitial fibrosis [9]. Shribman et ease associated with mycobacterial infections in HIV- al. report a case of miliary TB complicated by an immune com- infected individuals receiving antiretrovirals. Lancet Infect Dis plex nephritis, which could be in favour of an immunological 2005; 5: 361–373 process in TB-associated renal injury [10]. 5. Alvarado-Esquivel C, Garcı ´a-Corral N, Carrero-Dominguez D Due to the poor renal prognosis, diagnosis must be done as et al. Molecular analysis of mycobacterium isolates from early as possible, preferably when eGFR is >15 mL/min. Indeed, extrapulmonary specimens obtained from patients in two-thirds of patients presenting with an eGFR<15 mL/min Mexico. BMC Clin Pathol 2009; 9: 1 need to start a renal replacement therapy within 12 months 6. Ankrah AO, van der Werf TS, de Vries EFJ et al. PET/CT imag- after diagnosis [1]. ing of mycobacterium tuberculosis infection. Clin Transl Imaging 2016; 4: 131–144 Conclusion 7. Calabrese C, Overman RA, Dusetzina SB et al. Evaluating indeterminate interferon-c-release assay results in patients TB remains an underdiagnosed cause of severe TIN, especially with chronic inflammatory diseases receiving immunosup- in the lack of granulomas on renal biopsy, leading to a delay of pressive therapy. Arthritis Care Res 2015; 67: 1063–1069 specific treatment and a poor renal outcome. Physicians should 8. Jeong SJ, Han SH, Kim CO et al. Predictive factors for indeter- be advised to hunt down TB in high-risk populations or in cases minate result on the QuantiFERON test in an intermediate where there is a lack of corticotherapy response. When there is tuberculosis-burden country. J Infect 2011; 62: 347–354 no evidence of pulmonary disease, PET/CT imaging could help 9. Eastwood JB, Corbishley CM, Grange JM. Tuberculosis and in making the diagnosis. tubulointerstitial nephritis: an intriguing puzzle. Kidney Int 2011; 79: 579–581 Acknowledgements 10. Shribman JH, Eastwood JB, Uff J. Immune complex nephritis The authors would like to thank the members of complicating miliary tuberculosis. Br Med J (Clin Res Ed) 1983; Nephrology Department, Claire Grange, MD and Laurence 287: 1593–1594

Journal

Clinical Kidney JournalOxford University Press

Published: Oct 1, 2018

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