Acute Renal Injury in a 14-year-old With HIV/AIDS and Tuberculosis

A 14-year-old male, who had immigrated to the United States from sub-Saharan Africa 7 years ago and was recently diagnosed with HIV/AIDS and disseminated tuberculosis, presented with a rapidly rising serum creatinine of unknown etiology. He had initially presented to our institution approximately 1 month before with 2 months of fever, general malaise, abdominal pain, a 23-pound weight loss and 4 months of cough. He was diagnosed with HIV/ AIDS and found to have an initial absolute CD4+ T-lymphocyte count of 227 cells/μL (16.8%) and an HIV RNA level of 734,709 copies/mL. At that time, computed tomography scan of his chest, abdomen and pelvis demonstrated extensive necrotic adenopathy in his bilateral neck and axilla, as well as multiple sites within his thorax and abdomen, along with diffuse miliary pulmonary nodules with ground glass opacification and several small, hypodense splenic lesions. Biopsies of a left neck lymph node and a right lower lung pulmonary nodule showed extensive granulomatous lymphadenitis and a granulomatous pneumonia, respectively, both with rare acid-fast bacilli. In addition, several sputum samples and a broncheoalveolar lavage sample grew Mycobacterium tuberculosis. Consequently, the patient was started on tuberculosis therapy consisting of rifampin, isoniazid, pyrazinamide and ethambutol. Two weeks after initiating tuberculosis therapy and 2 weeks before the current presentation, antiretroviral therapy with lamivudine, zidovudine and efavirenz was also initiated, but 4 days later, the regimen was transitioned to efavirenz, emtricitabine and tenofovir (as 1 pill daily; Atripla) for ease of administration. Of note, before the start of antiretroviral therapy, a renal ultrasound revealed normal kidney size and echogenicity with no signs of renal abnormalities, and the patient had a normal serum creatinine (0.4 mg/dL) and urinalysis. At the time of initial discharge from our hospital, the patient was afebrile without abdominal pain and was noted to have a marked decrease in his peripheral lymphadenopathy.

Approximately 2 weeks after initiating antiretroviral therapy, he developed daily low-grade fevers, diffuse abdominal pain and increasing peripheral lymphadenopathy. Screening laboratory studies were suggestive of acute kidney injury with a blood urea nitrogen of 62 mg/dL (7–18 mg/ dL), creatinine of 4.9 mg/dL (0.3–0.8 mg/ dL), bicarbonate of 15 mmol/L (20–26 mmol/L) and phosphorus of 6.5 mg/dL (2.4–5.4 mg/dL), but normal potassium of 4.3 mmol/L (3.8–5.4 mmol/L). Other laboratory findings showed systemic inflammation with a C-reactive protein of 8.1 mg/dL (0–0.9 mg/dL), erythrocyte sedimentation rate of 137 mm/hr (0–2 mm/hr) and a lactate dehydrogenase of 1131 U/L (360–730 U/L). His absolute CD4+ T-lymphocyte count had increased to 812 cells/μL, and his HIV RNA level had decreased to 269 copies/mL.

The patient was admitted to the nephrology service of our hospital for further evaluation of his acute kidney injury. He reported ongoing fevers, nonbloody, nonbilious emesis and diffuse abdominal pain, but denied diarrhea, respiratory distress or urinary complaints and reported a normal urine output. He and his family denied use of any nonprescription medicines or herbal remedies. He had a temperature of 36.7°C, heart rate of 92 beats per minute, respiratory rate of 20 breaths per minute, blood pressure of 106/72 mm Hg and oxygen saturation of 99% breathing room air. His examination was significant for a thin male in no acute distress with oral thrush, a distended abdomen with diffuse tenderness greatest in the right upper quadrant, and mild hepatomegaly. The remainder of his physical and neurological examination was normal. An abdominal ultrasound showed bilateral kidney enlargement (12 cm on the right and 12.6 cm on the left) with increased cortical echogenicity but no hydronephrosis and relative preservation of the corticomedullary differentiation. Renal doppler studies were normal. Abdominal ultrasound also demonstrated hepatosplenomegaly and diffuse lymphadenopathy, particularly within the porta hepatis, in the retroperitoneum around the aorta, and adjacent to the right and left renal hilum. A renal biopsy was performed on the second day of admission.

Denouement

The renal biopsy revealed mild to moderate interstitial nephritis with poorly formed granulomas (Fig. 1). No acid-fast bacillus were identified on smear, and there was no evidence of acute tubular necrosis (ATN) or eosinophilia to suggest an allergic reaction to drugs. Acid-fast bacillus culture and polymerase chain reaction for Mycobacterium tuberculosis were not performed on the kidney biopsy. However, based on his known diagnosis of disseminated tuberculosis (TB), acute bilateral kidney enlargement with renal granulomas and recent initiation of antiretroviral therapy (ART), the patient was diagnosed with paradoxical TB-associated immune reconstitution inflammatory syndrome (TB IRIS) as the likely cause of his acute kidney injury (AKI).

Figure 1.

Photomicrograph of renal biopsy showing focal interstitial nephritis (A, 400x) and early granuloma formation (B, black arrow, 600x).

Although the development of ART has revolutionized the treatment of HIV/AIDS, this success has brought new challenges to HIV/AIDS patient management. One of the most important is the IRIS, which has emerged as a major cause of morbidity and mortality in patients with HIV/AIDS.¹ IRIS develops as a result of the robust immunological recovery in HIV/AIDS patients with advanced immunologic suppression who are initiated on effective ART. IRIS often occurs in patients with an underlying opportunistic infection, most commonly TB, Cytomegalovirus or Cryptococcus, but also with other disease processes that cause immunosuppression, such as malignancy and autoimmune syndromes.¹ After ART initiation in patients with HIV/AIDS, IRIS manifests as an exaggerated and dysregulated immune response against opportunistic pathogen-specific antigens.² TB IRIS has been further characterized into “unmasking” TB IRIS, where ART and the associated immunopathological host response uncover a previously subclinical TB infection, and “paradoxical” TB IRIS, where patients on appropriate TB treatment manifest new or worsening signs and symptoms as the reconstituting immune system reacts to antigens present in host tissue, as was likely the case with our patient.² Both forms of TB IRIS typically present within 3 months of ART initiation.²

TB IRIS occurs in between 11% and 45% of adults and up to 20% of children with TB/HIV coinfection who initiate ART, although the incidence in pediatric patients has not been as well characterized.^3,4 Although the immune destruction from TB IRIS often occurs at the primary site of opportunistic infection, it may also occur in organs not previously known to be affected. Kidney involvement is rare but has been reported in several adult patients, typically manifesting as interstitial nephritis with or without granuloma formation.^5-7 ART initiation time in these previously described patients with TB IRIS ranged from 14 weeks before the start of TB therapy to 6 weeks after therapy initiation. All 6 adult patients had an initial CD4+ T lymphocyte count of less than 100 cells/μL with an initial HIV RNA count ranging from 56,732 to 3,162,277 copies/mL. Symptoms of IRIS along with signs of AKI occurred between 4 days and 4 months after ART initiation in these patients, and they all responded well to prednisone therapy with a decrease in their clinical symptoms and normalization of their serum creatinine levels. However, to our knowledge, AKI associated with paradoxical TB IRIS has not been previously reported as a complication of HIV/AIDS and ART in the pediatric population.

Specific aspects of our patient’s clinical course put him at increased risk of developing paradoxical TB IRIS. These include his diffuse burden of opportunistic infection at time of diagnosis and ART initiation, relatively low baseline CD4+ T lymphocyte count, initiation of ART shortly after initiation of TB therapy, rapid HIV viral suppression and robust immunologic recovery with ART and high levels of systemic inflammation before starting ART (erythrocyte sedimentation rate of 150 mm/hr and C-reactive protein of 5.5 mg/dL).^2,3

Although IRIS is the most likely cause of AKI in our patient, tenofovirinduced nephrotoxicity was also considered. Tenofovir therapy, which our patient had started 10 days before his AKI, has been associated with a wide array of renal abnormalities, including ATN, Fanconi syndrome and nephrogenic diabetes insipidus, but nephrotoxicity usually occurs after many months of therapy.⁸ Furthermore, his urinalysis on admission did not show evidence of the proximal tubulopathy seen in Fanconi’s syndrome (ie, glycosuria) or the pigmented granular casts seen with ATN. His laboratory findings were also not consistent with nephrogenic diabetes insipidus.⁸ Finally, his renal biopsy did not show ATN or the distinct eosinophilic proximal tubular inclusions previously described with tenofovir-induced nephrotoxicity. Given our patient’s disseminated TB, increasing renal size shortly after initiation of ART, robust immune recovery with ART initiation and granuloma formation and interstitial nephritis seen on renal biopsy, it is most likely that his AKI was induced by a paradoxical TB IRIS triggered by a large mycobacterial antigen load in his kidneys.

There is limited evidence to guide the treatment of IRIS.^9,10 However, systemic corticosteroids have been prospectively studied in the treatment of paradoxical TB IRIS and have been shown to significantly improve symptoms and decrease morbidity.¹¹ Accordingly, in the 6 previously reported cases of TB IRIS-induced AKI in adults, all patients received steroids for 3 to 6 months, resulting in complete recovery of their baseline renal function.^5-7 Prednisone was initiated by our patient’s HIV specialist on the day before his hospital admission due to his clinical signs/symptoms suggestive of IRIS, and the dose was increased to 1 mg/kg given twice daily upon admission to our hospital. His kidney function rapidly improved, with his serum creatinine falling to 1.8 mg/dL within 1 week and to normal within 2 weeks and subsequently remaining normal during his steroid wean. Of note, his ART was also transitioned on admission to a regimen without tenofovir due to initial consideration of tenofovir nephrotoxicity contributing to his AKI.

Our patient’s presentation and clinical course underscore the challenges of ART initiation in patients with HIV/AIDS who present with advanced immunosuppression and disseminated opportunistic infections. Prompt treatment of the opportunistic infection is often imperative, but early initiation of ART comes with an increased risk of IRIS, of adverse events due to drug–drug interactions, and of treatment nonadherence from the resulting pill burden.^12-14 For HIV/AIDS patients with TB, the optimal timing of ART initiation is an area of active investigation.^12-14 Recent evidence from multiple adult studies published since 2011 suggests that early initiation of ART after the start of pulmonary TB therapy (within 2 to 4 weeks) is beneficial for patients with severe immunosuppression (CD4+ T lymphocyte counts<50 cells/μL), resulting in prolonged AIDS-free survival for this subset of patients.^12-14 One of these studies also reported a survival benefit with initiation of ART within 2 weeks (versus after 8 weeks) in patients with TB and CD4+ T lymphocyte counts <200 cells/μL, although more than 70% of trial participants had a CD4+ T lymphocyte count of <50 cells/μL.¹³ These data have led to updated national treatment guidelines for adults and adolescents, which now recommend that the most severely immunosuppressed patients (CD4+ T lymphocyte counts <50 cells/μL) initiate ART within 2 weeks of starting TB treatment.¹⁵ For patients with CD4+ T lymphocyte counts ≥50 cells/μL (in particular, 50–200 cells/μL) and clinical disease of major severity, ART should be initiated within 2 to 4 weeks of starting anti-TB therapy.¹⁵ For patients with CD4+ T lymphocyte count of ≥50 cells/μL without severe clinical disease, ART may be delayed beyond 2 to 4 weeks but should be started within 8 to 12 weeks of the onset of TB therapy.¹⁵ Although these national guidelines have begun to address the optimal timing of ART in adults and adolescents with HIV and TB coinfection, the level of clinical evidence and expert opinion guiding the optimal timing of ART initiation during TB therapy for patients with less severe immunosuppression (especially those with CD4+ T lymphocyte counts >200 cells/μL), for patients with extrapulmonary TB and for pediatric patients is more limited and await further prospective, randomized assessment.