There are various causes of secondary nephrotic syndrome. Finding an underlying etiology in a case of nephrotic syndrome or subnephrotic range proteinuria can markedly alter the therapeutic options and disease course. We describe two cases of secondary nephrotic syndrome. The first case was a 22-year-old male with pulmonary tuberculosis with nephrotic syndrome secondary to renal amyloidosis, whereas the second case was a 17-year-old male with chronic hepatitis B-associated nephrotic syndrome. It is important, especially in developing countries, to be aware that tuberculosis and infections like hepatitis B, C, etc. continue to be part of the differential diagnosis of secondary nephrotic syndrome in adolescents and young adults.
Keywords: Chronic hepatitis B, minimal change nephropathy, pulmonary tuberculosis, renal amyloidosis, secondary nephrotic syndrome
Nephrotic syndrome is a kidney disease with heavy proteinuria (3 g/day or more), hypoalbuminemia, edema, and hypercholesterolemia. Nephrotic syndrome can be classified into primary and secondary nephrotic syndrome. Diseases that affect only the kidneys are called primary nephrotic syndrome. The glomeruli are usually the targets of these diseases. On the other hand, nephrotic syndrome caused by systemic diseases that also affect other parts of the body, are called secondary nephrotic syndrome. Secondary nephrotic syndrome may be due to several causes such as diabetes mellitus, systemic lupus erythematosus, juvenile idiopathic arthritis, familial Mediterranean fever More Details, and secondary renal amyloidosis. It is very important to detect the secondary causes for the therapeutic purposes, as many times treating the secondary causes usually resolves the renal pathology. Here we are presenting two interesting cases of secondary nephrotic syndrome.
Our first case was a 22-year-old boy, presented with history of gradual swelling of the whole body starting from abdomen, progressed to face and feet for 1 month, and dry cough with mild respiratory distress for 15 days. He had a history of pulmonary tuberculosis 10 months back for which he received antitubercular drug for only 2 months and discontinued therapy on his own. There was no rash, joint pain, hematuria, hemoptysis, sexual exposure, significant family history. On examination, he had blood pressure 100/70 mmHg, pulse 86/min, anasarca, mild pallor, and crepitations over right infraaxillary region of the chest. Examinations of other systems were within normal limits. Investigations revealed hemoglobin 11.4 gm%, triple-level cell 9000 with 75% neutrophils, erythrocyte sedimentation rate 48, fasting sugar 89 mg/dl, urea 25 mg/dl, creatinine 0.07 mg/dl, sodium 135 meq/l, potassium 4 meq/l, total protein/albumin 4.9/2.8, lipid profile – cholesterol, triglycerides, high-density lipoprotein 192/160/48. Sputum acid-fast bacillus positive, Mantoux 21 mm, urine routine – protein-3+, cast, crystal-nil. Urine protein (24-hour) was 4.5 g. Human immunodeficiency virus (HIV) negative, C3, C4-98/23. Ultrasonography of abdomen showed that right kidney was 11.7 × 5.09 cm and left was 11.7 × 6.3 cm. Both kidneys were edematous, bulky, and there was increased cortical thickness. There was mild right-sided pleural effusion. Hepatitis B surface antigen (HBsAg), anti-HCV, ANA were negative. Chest X-ray revealed bilateral upper lobe opacities with areas of breakdown [Figure 1]. His kidney biopsy revealed excess extracellular hyaline amorphous material (amyloid) occupying glomerular mesangium [Figure 2]. A potassium permanganate stain followed by Congo red staining revealed absence of apple-green birefringence on polarized light, suggestive of secondary amyloidosis. Anti-tubercular drugs were prescribed, to which he showed clinical improvement in 8 weeks.
Our second case was a 17-year-old boy from Mumbai, who presented to us with gradual swelling of whole body starting from face for 8 months with mild respiratory distress for one week. No history of fever, rash, joint pain, or any blood transfusion. On examination, he was found to have anasarca, tachypnea (respiratory rate 33/min), and blood pressure and pulse were 130/80 mmHg and 96/min, respectively. Respiratory system examination revealed evidence of pleural effusion on both side. There was no jaundice or organomegaly. Investigations revealed hemoglobin 11.9 gm/dl, triple-level cell 9600 (N-56, L-34, E-10), erythrocyte sedimentation rate 42 mm, platelet count 2.5 lakhs, fasting blood sugar 72 mg/dl, urea 19 mg/dl, creatinine 0.6 mg/dl, total protein/albumin/globulin was 3.3/1.2/2.1 gm/dl, bilirubin 0.9 mg/dl, glutamic pyruvic transaminase, 35U/L, glutamic oxaloacetic transamina, 38U/L, alkaline phosphatase 170 U/L, lipid profile – cholesterol 564, triglyceride 275, high-density lipoprotein 61. Sputum for acid-fast bacillus (2 days) negative, Mantoux test 3 mm, urine RE/ME Ph-6.4, alb-3+, RBC-occ, cast/crystal-nil, pus cells-2-4/hpf. Urinary protein (24-hour) 8 g, HIV 1 and 2 negative, C3-103, C4-33.6. Pleural fluid study – cell count 590, cell type N-30/L-70, protein 0.5, albumin 0.2, ADA 2.6 (ref <24), LDH 63 (serum LDH 353), Gram stain, ZN stain negative, pap study negtive. HBsAG positive, anti-HCV, HIV negative, ANA negative, hepatitis B e antigen (HBeAg) negative. HBV-DNA 1900 copies/ml. Ultrasonography of abdomen was normal except mild ascites. Kidney biopsy [Figure 3] was done; biopsied glomeruli were normal looking under light microscope, electron microscopy revealed denudation of epithelial foot processes in the glomeruli, absence of any electron dense deposits in the glomerular basement membrane, immunoperoxidase staining was negative for IgA, IgG, IgM, complements. Thus, a diagnosis of minimal change glomerulonephritis with nephrotic syndrome was made probably associated with hepatitis B. He was started with steroids (60 mg/m 2 /day) with lamivudine. He is presently under our follow-up at 6 weeks of commencement of therapy, patient is improving clinically. Proteinuria reduced to one plus, liver function test continues to be within normal limits, we hope him to continue to respond to therapy.
Nephrotic syndrome represents a constellation of symptoms including hyperalbuminuria, hypoalbuminemia, edema formation, hypercholesterolemia, hypertension, hypercoagulopathy, and increased infection risk. The glomerular diseases that cause nephrotic syndrome generally can be divided into primary and secondary etiologies. By definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney.
In the diagnostic approach to adolescents and young adults, secondary causes of nephrotic syndrome must first be excluded. Important secondary causes include Henoch-Schönlein nephritis, lupus nephritis, secondary renal amyloidosis, and infection-associated nephropathies, especially hepatitis B in this region. Hepatitis B is associated with membranous nephropathy, whereas hepatitis C is associated with cryoglobulinemic glomerulonephritis or membranoproliferative glomerulonephritis, where as HIV and parvovirus are associated with focal segmental glomerulosclerosis.
Our first case is a classic example of secondary renal amyloidosis associated with pulmonary tuberculosis. Primary amyloidosis occurs rarely in adolescents. Most cases of secondary amyloidosis described in adolescents and children are secondary to juvenile idiopathic arthritis  and familial Mediterranean fever.  Other reported etiologies in children include tuberculosis, , and Hodgkin disease.  The association of tuberculosis with amyloidosis is fairly common in adults (3.6-50%), but only infrequently reported in children. , Tank et al.,  described a 12-year-old girl with disseminated tuberculosis and amyloidosis who did not respond to anti-tubercular therapy, while Ozkaya et al.,  have described a 13-year-old girl with Down syndrome who had pulmonary tuberculosis-related renal amyloidosis. Renal amyloidosis is diagnosed by demonstration of amyloid on renal biopsy. In contrast to primary amyloidosis, the apple-green birefringence is abolished in secondary amyloidosis if the specimen is treated with potassium permanganate before Congo red stain.  Management of secondary amyloidosis involves treatment of underlying cause, as remission has been reported following treatment of the underlying disorder.  The case described by us had clinical improvement following treatment of tuberculosis. This is in conformity with the observations of some authors. ,
Our second case reported here is hepatitis B virus-associated nephrotic syndrome. He was completely asymptomatic with regard to hepatitis B and presented in an atypical pattern with nephrotic syndrome. A variety of glomerulonephritis have been reported in patients with chronic hepatitis B. Hepatitis B-associated glomerulonephritis (HBV-GN) is immune complex mediated although most patients do not have evidence of circulating immune complexes. Thus, glomerular in situ immune complex formation and deposition is the probable mechanism. The most common histologic pattern of B virus associated-glomerulonephritis is membranous in children and adolescents  and membranoproliferative in adults.  The association of minimal change nephropathy with chronic hepatitis B is rarely reported in adults,  though it is not uncommon in pediatric population. The most common serological pattern in such patients is positivity for HBsAg and HBeAg.  In our case, HBeAg was negative.
In this case, there was no indication to start therapy with antivirals (e.g., lamivudine) with regard to his hepatitis B, since his liver enzymes were normal and HBV-DNA load was not very high. However, there was a potential threat of activation of chronic hepatitis with use of steroids in this situation.
Antiviral drugs have been recommended for treatment of HBV-GN because they can inhibit HBV replication and reduce proteinuria. ,, The use of prednisone alone has been reported to cause a significant increase in the levels of HBeAg and HBV-DNA.  One Meta-analysis of combined therapy for adult HBV-GN showed that combined antiviral and immunosuppressant therapy can improve the proteinuria in HBV-GN patients without altering HBV replication or damaging liver and renal functions. 
So, we started corticosteroids (60 mg/m 2 /day) along with oral lamivudine (100 mg OD) in our patient. He is improving clinically at the end of 4 weeks; edema reduced, proteinuria reduced to one plus and liver function test reports remain within normal limits. Although it is too early to predict his outcome, we expect better results and complete remission.
We thus suggest that all patients with nephrotic syndrome or subnephrotic proteinuria should be screened for underlying secondary eitiologies which might alter the therapeutic options and prognosis of the patient.
Source of Support: None, Conflict of Interest: None
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