Acute Interstitial Nephritis in Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

IntroductionAcute kidney injury (AKI) in hospitalized individuals is associated with increased length of hospitalization and mortality.1Vachiat A.I. Musenge E. Wadee S. Naicker S. Renal failure in HIV-positive patients—a South African experience.Clin Kidney J. 2013; 6: 584-594https://doi.org/10.1093/ckj/sft128Crossref PubMed Scopus (19) Google Scholar,2Izzedine H. Baumelou A. Deray G. Acute renal failure in HIV patients.Nephrol Dial Transplant. 2007; 22: 2757-2762https://doi.org/10.1093/ndt/gfm404Crossref PubMed Scopus (27) Google Scholar The high burden of HIV infection in South Africa (adult prevalence rate of 19.1%)3UNAIDSUNAIDS report on the global AIDS epidemic.UNAIDS. 2020; https://aids2020.unaids.org/reportDate accessed: October 6, 2021Google Scholar may be complicated by AKI, where HIV-infected patients have an increased incidence of AKI compared with HIV-uninfected patients.2Izzedine H. Baumelou A. Deray G. Acute renal failure in HIV patients.Nephrol Dial Transplant. 2007; 22: 2757-2762https://doi.org/10.1093/ndt/gfm404Crossref PubMed Scopus (27) Google Scholar HIV infection and AKI in South Africa are likely further complicated by the high burden of tuberculosis (TB) (615 per 100,000 population).4World Health OrganizationGlobal tuberculosis report 2020: executive summary. World Health Organization.https://www.who.int/publications-detail-redirect/9789240013131Date accessed: October 6, 2021Google Scholar In a South African cohort, 26% of HIV-infected patients presenting with AKI were coinfected with TB compared with 2% in the uninfected group.1Vachiat A.I. Musenge E. Wadee S. Naicker S. Renal failure in HIV-positive patients—a South African experience.Clin Kidney J. 2013; 6: 584-594https://doi.org/10.1093/ckj/sft128Crossref PubMed Scopus (19) Google Scholar The high HIV-TB coinfection rates in South Africa (58% among incident TB cases)4World Health OrganizationGlobal tuberculosis report 2020: executive summary. World Health Organization.https://www.who.int/publications-detail-redirect/9789240013131Date accessed: October 6, 2021Google Scholar increase the risk of disseminated TB, including urogenital TB.5Shafer R.W. Kim D.S. Weiss J.P. Quale J.M. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection.Medicine (Baltimore). 1991; 70: 384-397https://doi.org/10.1097/00005792-199111000-00004Crossref PubMed Scopus (298) Google ScholarTB-immune reconstitution inflammatory syndrome (TB-IRIS) contributes to 87% of deaths in the first 3 months after combination antiretroviral therapy (cART) initiation in South Africa.6Murdoch D.M. Venter W.D. Feldman C. Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study.AIDS. 2008; 22: 601-610https://doi.org/10.1097/QAD.0b013e3282f4a607Crossref PubMed Scopus (243) Google Scholar In HIV-infected patients with recently or undiagnosed TB, Mycobacterium tuberculosis (MTB) infection and IRIS can manifest as AKI directly, as seen in urogenital TB, or indirectly, as seen in IRIS. Urogenital TB is a chronic infection of the kidneys, urinary tract, and genital tract by MTB, with the kidneys the primary infection site.7Figueiredo A.A. Lucon A.M. Urogenital tuberculosis: update and review of 8961 cases from the world literature.Rev Urol. 2008; 10: 207-217PubMed Google Scholar Diagnosis is often delayed owing to nonspecific symptoms, insidious progression, and lack of physician awareness.7Figueiredo A.A. Lucon A.M. Urogenital tuberculosis: update and review of 8961 cases from the world literature.Rev Urol. 2008; 10: 207-217PubMed Google Scholar Urogenital TB in HIV-infected individuals may manifest dramatically as IRIS, a complication of cART with inflammatory-mediated organ dysfunction secondary to the restoration of a pathogen-specific immune response.8Izzedine H. Brocheriou I. Martinez V. Deray G. Immune reconstitution inflammatory syndrome and acute granulomatous interstitial nephritis.AIDS. 2007; 21: 534-535https://doi.org/10.1097/QAD.0b013e32802c7bceCrossref PubMed Scopus (13) Google Scholar,9Salliot C. Guichard I. Daugas E. Lagrange M. Verine J. Molina J.M. Acute kidney disease due to immune reconstitution inflammatory syndrome in an HIV-infected patient with tuberculosis.J Int Assoc Phys AIDS Care (Chic). 2008; 7: 178-181https://doi.org/10.1177/1545109708320683Crossref PubMed Scopus (22) Google Scholar,S1–S3 Acute interstitial nephritis in TB-IRIS has been rarely described in the literature and previously never reported in Africa.9Salliot C. Guichard I. Daugas E. Lagrange M. Verine J. Molina J.M. Acute kidney disease due to immune reconstitution inflammatory syndrome in an HIV-infected patient with tuberculosis.J Int Assoc Phys AIDS Care (Chic). 2008; 7: 178-181https://doi.org/10.1177/1545109708320683Crossref PubMed Scopus (22) Google Scholar We present 8 patients with HIV-TB coinfection who presented with IRIS and AKI secondary to TB-IRIS in Johannesburg, South Africa, the largest case series to date.Case PresentationAll 8 patients lived within the greater Johannesburg area and presented for hospital admission from October 1, 2013, to January 31, 2015. Seven patients were evaluated at Helen Joseph Hospital, with 1 case admitted to Charlotte Maxeke Johannesburg Academic Hospital. All patients presented for hospital admission within 3 months of cART initiation (median [interquartile range (IQR)] = 27 [17–49] days). The median (IQR) age was 36 (36–38) years, and 5 patients (62.5%) were male. All were initiated on tenofovir, emtricitabine, and efavirenz as a fixed-dose combination tablet. At initiation of treatment, 7 patients had normal serum creatinine with a normal estimated glomerular filtration rate. One patient had an estimated glomerular filtration rate between 30 and 40 ml/min per 1.73 m2. The median (IQR) baseline CD4 T-cell (CD4) count was 38 (23–69) cells/mm3 (Table 1).Table 1Demographics, laboratory, and kidney biopsy results of the patientsCase number12345678SexMaleMaleMaleMaleFemaleFemaleMaleFemaleAge3937333644363636Original CD4 (cells/mm3)962360292394472Admission CD4 (cells/mm3)1641297471Not done2033274Days on cART regimen2769421726148114Admission viral load (copies/ml)193111,449Not done72,087<40Not doneNot done26CRP (mg/l)8925720424516048100129Baseline creatinine (μmol/l)82577554911749060Baseline creatinine (mg/dl)0.930.650.850.611.031.971.020.68Admission creatinine (μmol/l)11361182137010972169821429264Admission creatinine (mg/dl)12.8513.3715.5012.4124.549.294.852.99Urine PCR (g/mmol creatinine)0.6210.080.4670.1610.3130.250.09Not doneUrine leucocytes90,000600063,00013,0003000750,00010,8004,000Urine erythrocytes90,000043,000400010000216,000scantyUrine cultureE coliNilNilNilNilC. freundiiE. coliNilUrine LAM+Not done−−Not doneNot doneNot doneNot doneSputum Xpert MTB/RIF++−++++−Bone marrowMTBNot doneNot doneMTBNot doneNot doneNot doneNot doneTB blood culture−Not doneMTBMTBMACNot done−Not doneFNA:TB cultureNot doneNot doneNot doneNot doneNot doneNot done+Not doneKidney biopsyGINNot doneNot doneNot doneNot doneINGINGINAFB +TB-IRISParadoxicalParadoxicalParadoxicalParadoxicalUnmaskingParadoxicalParadoxicalUnmaskingCorticosteroidsYesYesYesYesYesYesNoNoOutcomeNKFNKFNKFNKFNKFNKFDemisedLost to F/UAFB, acid-fast bacilli on Ziehl-Neelsen staining; C. freundii, Citrobacter freundii; cART, combined antiretroviral therapy; CRP, C-reactive-reactive protein; E. coli, Escherichia coli; F/U, follow-up; FNA, fine needle aspirate; GIN, granulomatous interstitial nephritis; IN, interstitial nephritis; MTB, Mycobacterium tuberculosis; NKF, normal kidney function; TB-IRIS, tuberculosis-immune reconstitution inflammatory syndrome; urine LAM, urine lipoarabinomannan test; urine PCR, urine protein-to-creatinine ratio. Open table in a new tab All patients presented with nonspecific clinical symptoms such as dyspnea, generalized body weakness and vomiting. Three patients were encephalopathic, and 6 patients had a severe high anion gap metabolic acidosis. Physical examination was unremarkable in all but 1 patient, who demonstrated cervical, axillary, and inguinal lymphadenopathy. All patients were afebrile with normal urine output on presentation.On admission, laboratory investigation in all patients revealed normocytic, normochromic anemia, elevated alkaline phosphatase and gamma glutamyl transpeptidase, elevated C-reactive protein (median [IQR] 160 [115–225] mg/l), and estimated glomerular filtration rate <20 ml/min per 1.73 m2. The median (IQR) CD4 count was 74 (73–147) cells/mm3. Three patients had hyperkalemia. All patients had a normal serum calcium and phosphate. No patient had glycosuria. Five patients had sterile pyuria on admission. Three patients had bacterial urinary tract infections diagnosed by urine culture on admission. After appropriate antibiotics, patients had sterile urine cultures, but the pyuria persisted. All patients were proteinuric, with 3 demonstrating nephrotic range proteinuria.Pulmonary TB was confirmed via positive Xpert MTB/RIF on sputum in 6 patients. Of the remaining 2 patients, 1 grew MTB on blood culture, while the other demonstrated granulomata with acid-fast bacilli on kidney biopsy. Three patients had culture-confirmed disseminated TB. Six patients were diagnosed with paradoxical TB-IRIS, and 2 were diagnosed with unmasking TB-IRIS. All patients were diagnosed with TB-IRIS by the primary management team based on their clinical presentation, inflammatory markers, change in HIV viral load, change in CD4 count, and a positive laboratory diagnosis of MTB.Four patients had kidney biopsies performed, with 3 biopsies revealing a granulomatous interstitial nephritis (Figure 1). Of those, 1 was positive for acid-fast bacilli on Ziehl-Neelsen stain. The fourth biopsy revealed an interstitial nephritis. None had histologic findings of tenofovir-induced nephrotoxicity.All patients were supported with i.v. fluids on admission. Antiretrovirals were continued in all 8 patients; however, tenofovir was replaced with another nucleoside reverse-transcriptase inhibitor in all patients. A total of 5 patients required acute hemodialysis for <1 week because of uremic encephalopathy and refractory hyperkalemia. Six patients were initiated on prednisone (1 mg/kg/d) on diagnosis of TB-IRIS. Two patients did not receive corticosteroids. The first was diagnosed with urogenital TB-IRIS on kidney biopsy and did not return for clinical follow-up. Unfortunately, the second patient died from complications of hyperkalemia. An autopsy was not authorized. Among the 6 patients receiving corticosteroids, 5 had normal kidney function before hospital discharge, and the sixth had normalized within 3 months of discharge.DiscussionWe have described 8 patients with AKI in the setting of TB-IRIS, of which all 4 with biopsies had evidence of interstitial nephritis, and 3 of these 4 had evidence suggestive of urogenital TB. The incidence of urogenital TB and AKI secondary to TB-IRIS of the kidney in HIV coinfected patients is rarely described, particularly in Africa. Five previous cases, 4 adult and 1 pediatric case, have been published, all from low HIV-TB coinfection settings.8Izzedine H. Brocheriou I. Martinez V. Deray G. Immune reconstitution inflammatory syndrome and acute granulomatous interstitial nephritis.AIDS. 2007; 21: 534-535https://doi.org/10.1097/QAD.0b013e32802c7bceCrossref PubMed Scopus (13) Google Scholar,9Salliot C. Guichard I. Daugas E. Lagrange M. Verine J. Molina J.M. Acute kidney disease due to immune reconstitution inflammatory syndrome in an HIV-infected patient with tuberculosis.J Int Assoc Phys AIDS Care (Chic). 2008; 7: 178-181https://doi.org/10.1177/1545109708320683Crossref PubMed Scopus (22) Google Scholar,S1–S3 There was a male predominance (80%), with a mean age of 41 years. The time from initiation of cART to presentation varied in a similar distribution to our patients but with a slightly longer median of 39 days. The CD4 count for all 4 adult patients was <100 cells/mm3 at initiation, and the pediatric case had a CD4 count of 227 cells/mm3. The pediatric patient and 1 adult patient had a previous diagnosis of TB and presented as a paradoxical IRIS. A total of 3 patients were on a tenofovir-based regimen, and the remainder were on zidovudine, lamivudine, and lopinavir/ritonavir. One patient had MTB identified on urine culture. Four patients had a granulomatous interstitial nephritis on kidney biopsy, and 1 patient had an interstitial nephritis, similar to our patients. Only 1 patient had their cART stopped, and all had a good clinical response after they were initiated on prednisone 1mg/kg/d for a few weeks followed by a tapering dose. All had normal kidney function a year later.All of our cases as well as the 3 published patients,9Salliot C. Guichard I. Daugas E. Lagrange M. Verine J. Molina J.M. Acute kidney disease due to immune reconstitution inflammatory syndrome in an HIV-infected patient with tuberculosis.J Int Assoc Phys AIDS Care (Chic). 2008; 7: 178-181https://doi.org/10.1177/1545109708320683Crossref PubMed Scopus (22) Google Scholar,S2,S3 who had been initiated on tenofovir, had tenofovir nephrotoxicity excluded as a cause for the AKI. None had clinical features of a proximal tubulopathy associated with Fanconi syndrome nor any histologic features of tenofovir-associated nephrotoxicity on kidney biopsy.Whereas the previous cases have been published as unusual or rare events, our collection of cases suggest this may be occurring more frequently in South Africa. In a South African study characterizing causes of death on antiretroviral therapy, 87% of deaths were due to mycobacterial infections, mainly MTB, in the early cART (7–90 days) death group—with 85% of those cases diagnosed postmortem as having TB-IRIS. Of those, 46% were found to have granulomatous inflammation of the kidney, and 31% had antemortem kidney failure.S4Urogenital TB presents significant diagnostic challenges. Of patients with granulomatous inflammation on kidney biopsy, in the aforementioned autopsy study, mycobacterial infection was not clinically suspected in 67% of patients at the time of death.S4 Currently, diagnosis is based on identification of acid-fast bacilli in the urine through Ziehl-Neelsen staining or mycobacterial culture, both of which have limited sensitivity.7Figueiredo A.A. Lucon A.M. Urogenital tuberculosis: update and review of 8961 cases from the world literature.Rev Urol. 2008; 10: 207-217PubMed Google Scholar Urine culture is particularly hindered by a long turnaround time and a wide variation in sensitivity due to sporadic bacilluria.7Figueiredo A.A. Lucon A.M. Urogenital tuberculosis: update and review of 8961 cases from the world literature.Rev Urol. 2008; 10: 207-217PubMed Google Scholar Urine polymerase chain reaction techniques appear to be promising; however, there is marked variation in the sensitivity, which appears to be affected by sporadic bacilluria. Thus, multiple samples or a 24-hour urine collection may improve diagnosis.S5 Kidney biopsy may assist with diagnosis. Typical biopsy findings demonstrate a tubulointerstitial nephritis and granuloma formation with or without the presence of acid-fast bacilli.S6Diffuse interstitial nephritis has been described as a separate entity of urogenital TB.S7 These cases differ from the typical presentation of urogenital TB as voiding symptoms and radiographical changes are not present and the bacillus can rarely be found in the urine.S7 The difficulty in proving definite kidney parenchymal TB infection is further complicated in immunodeficient patients as granulomas tend to be diffuse and poorly formed with infrequent caseous necrosis.S6 On some biopsies, the only finding is a tubulo-interstitial nephritis.S6 In this setting, it is suggested that kidney dysfunction is from both infection and immunologic kidney injury, and the diagnosis is confirmed if the kidney function starts to improve with a combination of anti–TB treatment and corticosteroids.S6To accurately reflect the pathophysiological spectrum of kidney injury in these patients, we propose the term TB-IRIS interstitial nephritis (TIIN). Autopsy studies suggest that TIIN may be common in high-burden HIV-TB coinfection settings, such as South Africa. This diagnosis encompasses urogenital TB in the setting of TB-IRIS and TB-IRIS where urogenital TB has not been definitively diagnosed. TIIN should be considered in all HIV-infected patients who have recently been initiated on cART in high-burden TB settings when presenting with a sudden deterioration in kidney function—regardless of the cART regimen that was initiated. TIIN treatment (TB treatment, i.v. fluids, and systemic corticosteroids) is widely accessible in South Africa, and normalization of kidney dysfunction is common when TIIN is diagnosed in a timely manner.ConclusionClinicians, especially those in high prevalence HIV-TB coinfection settings, should identify patients at risk for TB-IRIS and TIIN and actively monitor their kidney function—predominantly in the first 4 months after cART initiation. Guidance or guidelines for diagnosis of TIIN are needed, and improved diagnostic testing for urogenital TB will be critical. Further studies should clarify whether kidney dysfunction is due to infection, immunologic injury, or a combination and assess diagnostics, incidence, appropriate management, and longitudinal outcomes of TIIN. The main teaching points are found in Table 2.Table 2Teaching points1TIIN should be considered in HIV-infected patients recently initiated on cART who present with a sudden deterioration in kidney function.2TIIN has nonspecific symptoms and is difficult to diagnose.3Kidney biopsy may reveal a diffuse interstitial nephritis with or without granuloma formation.4TIIN treatment is widely accessible and consists of antituberculosis treatment and systemic corticosteroids.5Normalization of kidney dysfunction is common when TIIN is diagnosed and treated in a timely manner.cART, combined antiretroviral therapy; TIIN, tuberculosis-immune reconstitution inflammatory syndrome interstitial nephritis. Open table in a new tab DisclosureAll the authors declared no competing interests.Patient ConsentThis was a retrospective record review, and it was not possible to contact the patients. Ethics approval for the study was obtained from the University of the Witwatersrand Human Research Ethics Committee (Medical), clearance certificate number M150264. IntroductionAcute kidney injury (AKI) in hospitalized individuals is associated with increased length of hospitalization and mortality.1Vachiat A.I. Musenge E. Wadee S. Naicker S. Renal failure in HIV-positive patients—a South African experience.Clin Kidney J. 2013; 6: 584-594https://doi.org/10.1093/ckj/sft128Crossref PubMed Scopus (19) Google Scholar,2Izzedine H. Baumelou A. Deray G. Acute renal failure in HIV patients.Nephrol Dial Transplant. 2007; 22: 2757-2762https://doi.org/10.1093/ndt/gfm404Crossref PubMed Scopus (27) Google Scholar The high burden of HIV infection in South Africa (adult prevalence rate of 19.1%)3UNAIDSUNAIDS report on the global AIDS epidemic.UNAIDS. 2020; https://aids2020.unaids.org/reportDate accessed: October 6, 2021Google Scholar may be complicated by AKI, where HIV-infected patients have an increased incidence of AKI compared with HIV-uninfected patients.2Izzedine H. Baumelou A. Deray G. Acute renal failure in HIV patients.Nephrol Dial Transplant. 2007; 22: 2757-2762https://doi.org/10.1093/ndt/gfm404Crossref PubMed Scopus (27) Google Scholar HIV infection and AKI in South Africa are likely further complicated by the high burden of tuberculosis (TB) (615 per 100,000 population).4World Health OrganizationGlobal tuberculosis report 2020: executive summary. World Health Organization.https://www.who.int/publications-detail-redirect/9789240013131Date accessed: October 6, 2021Google Scholar In a South African cohort, 26% of HIV-infected patients presenting with AKI were coinfected with TB compared with 2% in the uninfected group.1Vachiat A.I. Musenge E. Wadee S. Naicker S. Renal failure in HIV-positive patients—a South African experience.Clin Kidney J. 2013; 6: 584-594https://doi.org/10.1093/ckj/sft128Crossref PubMed Scopus (19) Google Scholar The high HIV-TB coinfection rates in South Africa (58% among incident TB cases)4World Health OrganizationGlobal tuberculosis report 2020: executive summary. World Health Organization.https://www.who.int/publications-detail-redirect/9789240013131Date accessed: October 6, 2021Google Scholar increase the risk of disseminated TB, including urogenital TB.5Shafer R.W. Kim D.S. Weiss J.P. Quale J.M. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection.Medicine (Baltimore). 1991; 70: 384-397https://doi.org/10.1097/00005792-199111000-00004Crossref PubMed Scopus (298) Google ScholarTB-immune reconstitution inflammatory syndrome (TB-IRIS) contributes to 87% of deaths in the first 3 months after combination antiretroviral therapy (cART) initiation in South Africa.6Murdoch D.M. Venter W.D. Feldman C. Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study.AIDS. 2008; 22: 601-610https://doi.org/10.1097/QAD.0b013e3282f4a607Crossref PubMed Scopus (243) Google Scholar In HIV-infected patients with recently or undiagnosed TB, Mycobacterium tuberculosis (MTB) infection and IRIS can manifest as AKI directly, as seen in urogenital TB, or indirectly, as seen in IRIS. Urogenital TB is a chronic infection of the kidneys, urinary tract, and genital tract by MTB, with the kidneys the primary infection site.7Figueiredo A.A. Lucon A.M. Urogenital tuberculosis: update and review of 8961 cases from the world literature.Rev Urol. 2008; 10: 207-217PubMed Google Scholar Diagnosis is often delayed owing to nonspecific symptoms, insidious progression, and lack of physician awareness.7Figueiredo A.A. Lucon A.M. Urogenital tuberculosis: update and review of 8961 cases from the world literature.Rev Urol. 2008; 10: 207-217PubMed Google Scholar Urogenital TB in HIV-infected individuals may manifest dramatically as IRIS, a complication of cART with inflammatory-mediated organ dysfunction secondary to the restoration of a pathogen-specific immune response.8Izzedine H. Brocheriou I. Martinez V. Deray G. Immune reconstitution inflammatory syndrome and acute granulomatous interstitial nephritis.AIDS. 2007; 21: 534-535https://doi.org/10.1097/QAD.0b013e32802c7bceCrossref PubMed Scopus (13) Google Scholar,9Salliot C. Guichard I. Daugas E. Lagrange M. Verine J. Molina J.M. Acute kidney disease due to immune reconstitution inflammatory syndrome in an HIV-infected patient with tuberculosis.J Int Assoc Phys AIDS Care (Chic). 2008; 7: 178-181https://doi.org/10.1177/1545109708320683Crossref PubMed Scopus (22) Google Scholar,S1–S3 Acute interstitial nephritis in TB-IRIS has been rarely described in the literature and previously never reported in Africa.9Salliot C. Guichard I. Daugas E. Lagrange M. Verine J. Molina J.M. Acute kidney disease due to immune reconstitution inflammatory syndrome in an HIV-infected patient with tuberculosis.J Int Assoc Phys AIDS Care (Chic). 2008; 7: 178-181https://doi.org/10.1177/1545109708320683Crossref PubMed Scopus (22) Google Scholar We present 8 patients with HIV-TB coinfection who presented with IRIS and AKI secondary to TB-IRIS in Johannesburg, South Africa, the largest case series to date.