A Young Female with Fever and Proteinuria

BACKGROUND

Lupus patients are immunocompromised either due to disease activity or due to immunosuppressive treatment. Lupus nephritis is an additional risk factor for TB as these patients are usually treated with higher doses of immunosuppression. This is the first report describing concomitant proliferative lupus nephritis with tubercular granulomatous tubulointerstitial nephritis (GIN) in a lupus patient with disseminated TB and the challenges faced during the diagnosis and management.

CASE DESCRIPTION

A 29-year-old lady with no known comorbidities or renal disease presented with a history of intermittent fever, photosensitivity, and joint pain for one year. She also had easy fatigability and progressively increasing exertional shortness of breath for six months. She had decreased appetite and weight loss of 15 kg during the last one year. There was shortness of breath on exertion for 6 months, which gradually increased for one month. There was no history of cough or chest pain. She had two first-trimester abortions.

On examination, she had tachypnea (respiratory rate: 28/minute) and tachycardia (pulse rate: 140/minute) with normal blood pressure at presentation. There was severe pallor, and generalized lymphadenopathy involving cervical, axillary, and epitrochlear nodes. Her body mass index was 19.2 kg/m². Investigations showed hemoglobin of 6.2 g/dL, normochromic and normocytic erythrocytes with a corrected reticulocyte count of 1.2% and negative hemolytic workup. Serum creatinine was 0.9 mg/dL, and serum albumin was 1.86 g/dL with a 24-hour urine protein excretion of 1.052 g/day. Urine dipstick was positive for albumin (1+), and microscopy was suggestive of 6–8 erythrocytes/high-power field, but no casts. Her Mantoux test was negative. Antinuclear antibody was 3+ with diffuse pattern on indirect immunofluorescence with positive anti-dsDNA (>379 IU/mL), and low C3 (21.6 mg/dL) and C4 (2.98 mg/dL) values. A renal ultrasound revealed normal-sized kidneys and normal echogenicity. A renal biopsy was done for possibility of lupus nephritis. Light microscopy details are shown in Figure 1.

The kidney biopsy consisted of 7 glomeruli, 3 out of which were noted for mesangial expansion and endocapillary proliferation, with 2 having hyaline thrombi (Fig. 1). Multiple epithelioid cell granulomas with Langhan’s giant cells and large areas of necrosis were seen in the interstitium causing destruction of tubules (Fig. 2). There were no eosinophils, or interstitial fibrosis noted. There was evidence of vasculitis in smaller arteries seen. The immunofluorescence analysis revealed intense (3+) positivity for antisera specific for IgG, IgA, IgM, C3, C1q, κ, and λ light chains in subendothelium and mesangium, denoting full-house staining pattern (Fig. 3). Extraglomerular deposits for IgG, IgA, kappa, and lambda were noted along the blood vessels. The diagnosis was confirmed to be lupus nephritis-class III (A) with evidence of vasculitis and necrotizing interstitial granulomas. Although acid-fast bacilli (AFB) stain was negative, mycobacterial protein was detected using multiplex polymerase chain reaction (PCR) in kidney tissue (Fig. 3: inset). There was evidence of disseminated tuberculosis in the form of bilateral lung consolidation with cavity formation, peritoneal enhancement with ascites, and retroperitoneal lymphadenopathy in the contrast enhanced computed tomography (CECT) of chest and abdomen. CT guided lung biopsy revealed interstitial epithelioid granulomas with multinucleated giant cells, and caseous necrosis and stain for AFB was positive, confirming the diagnosis of tuberculosis (Fig. 4). Patient was diagnosed with systemic lupus erythematosus (SLE) with renal and hematological involvement with disseminated tuberculosis and was started on corticosteroids (1 mg/kg/day) with antituberculous treatment. Mycophenolate mofetil (MMF) at the dose of 2 g per day was introduced after initial 1 month of antituberculous therapy for underlying lupus nephritis. After 6 months of follow-up, patient achieved complete remission in proteinuria with normal renal function.

DISCUSSION

Systemic lupus erythematosus and TB infection are known to interact and mimic each other clinically, often leading to delayed diagnosis of active TB infection in such patients. The incidence and severity of TB are higher in lupus patients, specifically in endemic countries, which is attributable to the defective immunity in SLE patients and higher exposure to infection.¹ Tuberculosis can, in turn, act as a trigger for SLE owing to shared antigens between Mycobacterium tuberculosis and autoantigens in patients.² Lupus patients with TB are also at increased risk of dissemination.² Our patient presented with disseminated tuberculosis with first presentation of active SLE simultaneously. She was found to have proliferative lupus nephritis with interstitial necrotizing granulomas. Granulomatous tubulointerstitial nephritis is a rare entity comprising only 0.5–0.9% of all renal biopsies.^3,4 Whereas the commonest cause worldwide is drugs,⁵ TB was reported as the most common etiology in the Indian subcontinent.⁴ Furthermore, SLE has also been described as a cause of GIN.⁴ Joss et al.³ found the poor role of histological features to discriminate against various causes of GIN. Moreover, definitive diagnosis of tuberculous GIN is often difficult with conventional methods such as urine culture or stain for AFB and caseous necrosis in the granulomas. Use of molecular methods such as multiplex PCR for mycobacterial protein in kidney tissue has been shown to yield positive results in tuberculous GIN earlier.⁶ Our patient was confirmed to have TB as the cause of granulomas based on positive multiplex PCR for Mycobacterium tuberculosis in kidney tissue. Glucocorticoids independently increase the risk for developing TB⁷ and also cause overwhelming disease in those affected with TB, if given without antituberculous therapy. Nevertheless, in conjunction with antituberculous therapy, glucocorticoids lead to beneficial effects in certain forms of TB. While common guidelines do not specifically recommend corticosteroids in treating tuberculous GIN, treatment usually comprises of antituberculous therapy with or without steroids. Whereas some advocate a combination of corticosteroids with antituberculous drugs,⁸ others do not.⁴ We have used corticosteroid with antituberculous drugs and gradually added MMF in our patient with good control of both TB infection and SLE activity.

CONCLUSION

A patient with an initial diagnosis of SLE can have also harbor TB at the same time. Molecular methods help in appropriate diagnosis of renal tuberculous granulomas. Whenever present, watchful observation, and treatment with steroids and ATT in the initial phase followed by an escalation of immunosuppression later might help treat both the disease entities.

REFERENCES

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8. Chapagain A, Dobbie H, Sheaff M, et al. Presentation, diagnosis, and treatment outcome of tuberculous-mediated tubulointerstitial nephritis. Kidney Int 2011;79(6):671–677. DOI: 10.1038/ki.2010.482.