Immune reconstitution syndrome following HAART in human immunodeficiency virus (HIV)-infected patients is characterized by inflammatory worsening of organ functions despite improvement in HIV surrogate markers of HIV infection. We describe a patient with miliary tuberculosis and urinary shedding of acid fast bacilli who developed acute renal failure 8 weeks after initiation of antituberculosis therapy and 6 weeks after initiation of HAART. The diagnostic workup and further course of disease implicated immune reconstitution syndrome as the cause of acute renal failur

Battegay, Manuel

Dickenmann, Michael

Glatz-Krieger, Katharina

Hirsch, Hans H.

Jehle, Andreas W.

Khanna, Nina

Sigle, Jörg-Peter

Steiger, Jürg

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e32 • CID 2004:38 (15 February) • BRIEF REPORTB R I E F R E P O R TAcute Renal Failure on ImmuneReconstitution in an HIV-PositivePatient with Miliary TuberculosisAndreas W. Jehle,1 Nina Khanna,2 Jo¨rg-Peter Sigle,2 KatharinaGlatz-Krieger,3 Manuel Battegay,2 Ju¨rg Steiger,1 Michael Dickenmann,1and Hans H. Hirsch2,4Divisions of 1Transplantation Immunology and Nephrology and 2InfectiousDiseases, and Institutes for 3Pathology and 4Medical Microbiology, UniversityHospitals Basel, SwitzerlandImmune reconstitution syndrome following HAART in hu-man immunodeficiency virus (HIV)–infected patients ischaracterized by inflammatory worsening of organ functionsdespite improvement in HIV surrogate markers of HIV in-fection. We describe a patient with miliary tuberculosis andurinary shedding of acid fast bacilli who developed acuterenal failure 8 weeks after initiation of antituberculosis ther-apy and 6 weeks after initiation of HAART. The diagnosticworkup and further course of disease implicated immunereconstitution syndrome as the cause of acute renal failure.Acute renal failure (ARF) is frequently encountered in patientswith HIV infection [1,2]. In a recent retrospective study of 92HIV-infected patients with ARF admitted to a nephrology unit[3], at least 10 different entities were diagnosed: hemolytic-uremic syndrome (in 35% of patients), acute tubular necrosis(in 26%), HIV-associated nephropathy (in 15%), acute inter-stitial nephritis (in 2%), obstructive renal failure due to lym-phoma and drug- and paraprotein-mediated causes (in 17%),and various forms of glomerulonephritis (in 4%). In contrastto ARF due to prerenal and postrenal causes, renal forms ofARF in HIV-infected patients are often related to HIV-mediatedviral or immunological disease, or to treatment-related toxicity,both of which have changed since the introduction of HAART[1–3].Case report. A 58-year-old male was hospitalized becauseof fever and weight loss of 110 kg in the 3 months prior toReceived 19 September 2003; accepted 3 November 2003; electronically published 30January 2004.Reprints or correspondence: Dr. Hans H. Hirsch, Division of Infectious Diseases, UniversityHospitals Basel, Petersgraben 4 CH-4031, Basel, Switzerland.Clinical Infectious Diseases 2004; 38:e32–5 2004 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2004/3804-00E2$15.00hospital admission. HIV infection (CD4 cell count, 69 cells/mL; virus load, 1,247,786 copies/mL) and miliary tuberculosiswas diagnosed. Acid-fast bacteria were seen in bronchoalveolarlavage fluid and in urine specimens. Mycobacterium tuberculosiswas identified by culture and specific PCR. The patient wasinitially treated with standard doses of 4 antituberculosis agents(isoniazid, rifampicin, pyrazinamid, and ethambutol). Primaryprophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX)3 times weekly was started. After 2 weeks, rifampicin was re-placed with rifabutin at a reduced dosage of 150 mg q.o.d., atthe time when HAART was initiated (zidovudine, lamivudine,and lopinavir/ritonavir) (figure 1). Drug-susceptibility testingof the Mycobacterium tuberculosis isolate revealed no resistance,and a 3-drug regimen consisting of isoniazid, pyrazinamid, andrifabutin was administered. The clinical condition improved,and the patient was referred to a rehabilitation clinic.However, after 2 months, ARF developed with rising serumcreatinine concentrations of 4.89 mg/dL (433 mmol/L), and thepatient was readmitted to the hospital. Overall, the clinicalstatus had improved. There was no fever, coughing, or lymph-adenopathy. Macrocytic hyperchromic anemia was found, witha hemoglobin concentration of 9 g/dL. The C-reactive proteinlevel measured 95 mg/L (normal range, !5 mg/L), increasingto 142 mg/L. The HIV load had decreased by 4 log10, to 104copies/mL, and the CD4 cell count had increased to 82 cells/mL. Urine analysis showed mild proteinuria with a tubuloin-terstitial pattern (urine protein to creatinine concentration of53 mg/mmol, and ratios of a-1 microglobulin to creatinine andretinol-binding protein to creatinine increased by 31-fold and46-fold, respectively) in addition to few granular casts and fewleukocytes. Serial CT of the chest showed newly accentuatedpulmonary infiltrates. Bronchoscopy and bronchoalveolar lav-age were performed and revealed lymphocytosis, but yieldednegative results for a range of infectious agents, including My-cobacterium tuberculosis, Mycoplasma and Chlamydia species,cytomegalovirus, and bacterial pathogens. A renal biopsy wasperformed. Histologic examination showed severe, nondestruc-tive, granulomatous nephritis with interstitial infiltrates (figure2). Iimmunohistochemical analysis was negative for comple-ments C3 and C5b-9, fibrin, IgA, IgM, and IgG (not shown).The diagnosis of immune reconstitution syndrome withmanifestations in the lungs and kidneys was made 2 monthsafter initiation of HAART, which effectively suppressed HIVreplication and resulted in improved CD4 cell counts. Pred-nisone was administered at a dosage of 1 mg/kg for 2 weekswith a tapering dosage (figure 1). HAART was continued, butBRIEF REPORT • CID 2004:38 (15 February) • e33Figure 1. Time course of laboratory values and drug treatment in 2002 and 2003 for an HIV-infected patient with acute renal failure. Left Y-axis:Dotted line, Serum creatinine concentration, mmol/L; squares, C- reactive protein levels, mg/L ; and circles, CD4 cell counts, cells/mL. Right Y-axis:Triangles, HIV-1 viral load, log10/mL. The treatment administered is shown on top: zidovudine (AZT), lamivudine (3TC), lopinavir/ritonavir (LPV/r), stavudine(d4T), trimethoprim-sulfamethoxazole primary prophylaxis (TMP-SMX), isoniazid (INH), rifabutin (RFB), pyrazinamide (PZA), ethambutol (ETB), prednisolone(PRE, dosage in mg) and pentacarinate (PCT).stavudine was substituted for zidovudine because of anemia.TMP-SMX therapy was discontinued, and antituberculosistherapy was continued as a 2-drug regimen of isoniazid andrifabutin at the same dosages. C-reactive protein levels nor-malized and renal function improved, with serum creatinineconcentrations of ∼1.7 mg/dL (145 mmol/L) within 10 days(figure 1). Primary prophylaxis with pentacarinate was startedbut not tolerated, and TMP/SMX prophylaxis was reinitiatedand well tolerated. The CD4 cell count increased to 174 cells/mL but then decreased slightly, and the HIV load remainedundetectable (!20 copies/mL). After 1 year, the patient re-mained healthy while receiving HAART and TMP-SMX, andantituberculosis treatment could be discontinued.Discussion. The inflammatory syndrome elicited by im-proving immune response to mycobacterial antigens has beendescribed in patients with AIDS as early as 1992, at a time whenonly zidovudine was available for use against HIV [4]. Sincethe introduction of HAART, paradoxical clinical worsening isincreasingly reported, most likely reflecting the more efficientimmune recovery. The immune responses were directed againsta range of antigens derived from infectious agents, such ascytomegalovirus, hepatitis viruses, Histoplasma species, poly-omaviruses JC and BK, and Cryptococcus neoformans [5–7], butalso from noninfectious antigens [8, 6]. The latter observationsupports the notion that the primary pathogenic element ofimmune reconstitution syndrome is a severe inflammatory re-sponse directed against antigens but not necessarily against on-going infections. However, this distinction may be difficult tomake at times. Apart from frequent manifestations in lungs[9–11], immune reconstitution syndrome directed against M.tuberculosis may affect the lymph nodes, CNS, liver, testicles,and gut [12–14]. In our patient, ARF occurred concurrentlywith radiologically documented signs of pulmonary worseningand increasing levels of C-reactive protein, and cultures re-mained negative for M. tuberculosis . The main differential di-agnosis of ARF in our patient included drug toxicity caused byTMP-SMX and/or ritonavir. However, in contrast to previousreports, the ritonavir dosage was set as required for “boosting”protease inhibitor activity, and this therapy was safely continuedfor our patient. Similarly, TMP-SMX prophylaxis was safelyreintroduced (figure 1). Ethambutol might represent be a rarecause of interstitial nephritis, and this cause cannot be ruledout with certainty. However, there were no signs of neuraltoxicity or optic neuritis in our patient.The initial identification of M. tuberculosis in the urine in-dicated a disseminated infection that involved the kidneys. Theidentification of ARF with granulomatous inflammation by re-nal biopsy concurrent with systemic inflammatory signs andparadoxical worsening of pulmonary infiltrates supports thediagnosis of immune reconstitution syndrome, despite onlye34 • CID 2004:38 (15 February) • BRIEF REPORTFigure 2. Micrographs of a renal biopsy specimen showing granulomatous nephritis ( top, hematoxilin-eosin stain; original magnification 5) withnonnecrotizing epitheloid granuloma and faint fibrosis (bottom, sirius stain; original magnification 200).modest increases in the CD4 cell count in the peripheral blood.It is remarkable that immune reconstitution syndrome has beenobserved in HIV-infected patients with substantially lesser in-creases in CD4 cell counts in the peripheral blood [5]. Thepathophysiology of the immune reconstitution syndrome is stillincompletely understood, but host- and antigen-specific factorsmay play a role, in addition to specific CD4 cell responses and,possibly, CD4 cell redistribution in tissue. However, the in-creasing incidence of immune reconstitution syndrome follow-ing the introduction of HAART suggests that suppression ofHIV replication is a significant, but not a sufficient, factor. Inour patient, a substantial decrease in HIV load (4 log10) wasnoted within only 6 weeks. In summary, immune reconsti-tution syndrome should be considered as a cause of ARF afterinitiation of HAART in patients who have AIDS and renallydisseminated antigens, as documented here for miliarytuberculosis.References1. Kimmel PL, Barisoni L, Kopp JB. Pathogenesis and treatment of HIV-associated renal diseases: lessons from clinical and animal studies, mo-lecular pathologic correlations, and genetic investigations. Ann InternMed 2003; 139:214–26.2. Perazella MA. Acute renal failure in HIV-infected patients: a briefreview of common causes. Am J Med Sci 2000; 319:385–91.3. Peraldi MN, Maslo C, Akposso K, et al. Acute renal failure in theBRIEF REPORT • CID 2004:38 (15 February) • e35course of HIV infection: a single-institution retrospective study ofninety-two patients and sixty renal biopsies. Nephrol Dial Transplant1999; 14:1578–85.4. French MA, Mallal SA, Dawkins RL. Zidovudine-induced restorationof cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients. AIDS 1992; 6:1293–7.5. Cheng VC, Yuen KY, Chan WM, et al. Immunorestitution diseaseinvolving the innate and adaptive response. Clin Infect Dis 2000; 30:882–92.6. DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactionsin HIV-1-infected persons after initiation of highly active antiretroviraltherapy. Ann Intern Med 2000; 133:447–54.7. Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis 2003; 3:611–23.8. Silvestre JF, Albares MP, Ramon R, Botella R. Cutaneous intoleranceto tattoos in a patient with human immunodeficiency virus: a mani-festation of the immune restoration syndrome. Arch Dermatol 2001;137:669–70.9. Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonaryTB. Chest 1998; 114:933–6.10. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical wors-ening of tuberculosis following antiretroviral therapy in patients withAIDS. Am J Respir Crit Care Med 1998; 158:157–61.11. Fishman JE, Saraf-Lavi E, Narita M, et al. Pulmonary tuberculosis inAIDS patients: transient chest radiographic worsening after initiationof antiretroviral therapy. AJR Am J Roentgenol 2000; 174:43–9.12. Crump JA, Tyrer MJ, Lloyd-Owen SJ, et al. Military tuberculosis withparadoxical expansion of intracranial tuberculomas complicating hu-man immunodeficiency virus infection in a patient receiving highlyactive antiretroviral therapy. Clin Infect Dis 1998; 26:1008–9.13. Guex AC, Bucher HC, Demartines N, et al. Inflammatory bowel per-foration during immune restoration after one year of antiretroviral andantituberculous therapy in an HIV-1-infected patient: report of a case.Dis Colon Rectum 2002; 45:977–8.14. Furrer H, Malinverni R. Systemic inflammatory reaction after startinghighly active antiretroviral therapy in AIDS patients treated for extra-pulmonary tuberculosis. Am J Med 1999; 106:371–2.

Acute Renal Failure on Immune Reconstitution in an HIV-Positive Patient with Miliary Tuberculosis

Acute Renal Failure on Immune Reconstitution in an HIV-Positive Patient with Miliary Tuberculosis

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