Hematuria and proteinuria in a 14-year-old boy on anti-tubercular treatment: Answers

Considering the findings of prolonged fever with cervical lymphadenitis, FNAC showing granulomatous lymphadenitis and good clinical response to anti-tubercular treatment (ATT), the diagnosis of tubercular lymphadenitis in this child was of reasonable certainty, especially in the Indian scenario, where tuberculosis is endemic. The child developed periorbital puffiness, pedal edema, and bilateral non-palpable purpuric lesions in the lower limbs, 4 weeks following anti-tubercular treatment (ATT) after an initial period of clinical improvement to ATT in the form of weight gain and defervescence.

His laboratory investigations included nephrotic range proteinuria, hematuria, hypocomplementemia, low eGFR, and features consistent with leucocytoclastic vasculitis on skin biopsy. With the above constellation of findings, possibilities considered in the index patient were infection-related glomerulonephritis (IRGN), infection-associated membranoproliferative glomerulonephritis (MPGN), drug-induced lupus (DIL) erythematosus, renal amyloidosis, and tubercular pyelonephritis.

In the presence of hypocomplementemia and hematuria, and in the setting of a recent infection, it is reasonable to suspect IRGN and MPGN, both of which can be incited by an infection [1]. There is significant overlap in the clinical features of the two, and distinction of early MPGN from IRGN can be difficult even on light microscopy [2]. The presence of full house immune positivity instead of isolated IgG and C3 deposits in our case, however, diminished the possibility of IRGN and MPGN. Tuberculosis is still the most common cause of secondary renal amyloidosis in developing countries like India [3], the most consistent features being proteinuria and pedal edema, the presence of which in any tuberculosis patient should make one suspect the possibility of this life-threatening complication. The possibility of renal amyloidosis was however ruled out in the absence of amorphous deposits in glomeruli on kidney biopsy and negative amyloid staining. Tubercular pyelonephritis can also be suspected in the presence of proteinuria and hematuria, with a rare probability of dissemination of tubercular infection to the renal pelvis. However, the absence of fever and pyuria on urinalysis precluded this possibility. After excluding aforementioned differential diagnosis, DIL was considered as the most likely explanation for the child’s clinical presentation. DIL is a condition wherein, secondary to exposure to a drug (usually about 4 weeks later), a patient develops systemic lupus erythematosus (SLE)-like features in the absence of pre-existing lupus [4]. In the index child, isoniazid was the suspected offending drug. Causality assessments were done using World Health Organisation Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (WHO-UMC) criteria [5] and Naranjo’s probability scale [6] to determine the likelihood that isoniazid caused the suspected adverse drug reaction (ADR) of DIL. According to the WHO-UMC causality assessment criteria, an association between the reaction and the drug was probable and Naranjo’s ADR score was 6 (probable) [5, 6]. Laboratory evaluation, especially that of auto-antibodies, further reaffirmed the diagnosis. In our index case, ANA was positive, with negative anti-dsDNA titers and strongly positive anti-histone antibody titers. Kidney biopsy was performed. Light microscopy showed diffuse proliferative glomerulonephritis with crescents (Fig. 1). On immunofluorescence, there was a full house positivity with diffuse granular deposits of IgG, IgA, IgM, C3, C1q, kappa, and lambda (Fig. 2). Therefore, the histopathological features were consistent with class 4 lupus nephritis. In the clinical setting of onset of symptoms of SLE after a considerable duration of exposure to the suspected offending drug, probable causal association on the assessment scales, significant levels of antibodies against ANA, strongly positive anti-histone antibody titers, and skin lesions which disappeared with the discontinuation of the offending drug, a diagnosis of drug-induced lupus nephritis was made, and attributed to isoniazid, one of the rare instances where a drug for cure can lead to serious adverse effects. The rarity of the condition, with the incidence of isoniazid-induced lupus-like syndrome being less than 1%, posed a diagnostic challenge in this case [7]. Isoniazid has been implicated as a definite cause for DIL, and rifampin has been mentioned as a probable cause [8].

DIL presents with a clinical picture of pupura or erythema nodosum, joint pain, hematuria, and proteinuria in a patient on this drug for a considerable amount of time. For a long time, the plausible mechanism proposed for the immunogenicity of isoniazid was the haptenization of the drug, where binding of a small molecule to a macromolecule renders it immunogenic. It has been shown that at least one-fifth of patients treated with isoniazid for more than 6 months can develop anti-nuclear antibodies [8]. Later, it was shown that there is oxidation of isoniazid by leucocytes to form a metabolite known as isonicotinic acid. These reactive intermediates have been postulated to trigger T-cell autoreactivity and inhibit the activation of C3 by the classical complement pathway which in turn hinders the clearance of immune complexes, culminating in DIL [9]. Environmental exposures and host characteristics like slow acetylators further modulate the incidence and severity of isoniazid-induced idiosyncratic reactions by increasing the concentration of intermediate metabolites [10].