Rare case of post-varicella membranoproliferative glomerulonephritis presenting with massive proteinuria

Abstract

Chicken pox caused by varicella zoster virus is usually a self-limiting disease causing rare life-threatening complications. Involvement of the kidneys is infrequent during the course of the illness. Literature shows rare reports of acute glomerulonephritis following varicella infection. We report a case of 16-year-old boy presenting with anasarca with characteristic healed rashes of chicken pox. His urinalysis revealed a ‘massive’ nephrotic range proteinuria (16 g/24 hours), gross hematuria and pyuria. A percutaneous renal biopsy showed membranoproliferative glomerulonephritis. Most cases of post-varicella glomerulonephritis have been described in children, massive proteinuria of this range in an immunocompetent adolescent, being an extremely rare entity. Acute proliferative glomerulonephritis in such cases is usually an immune complex hypocomplementaemic glomerulonephritis in response to the zoster infection. Proteinuria in most patients is benign and self-limiting with few fatal reports of crescentic glomerulonephritis progressing to acute renal failure.

Background

Chicken pox caused by human herpesvirus 3, varicella zoster virus is a common infection among children and adolescents. The association of renal disease and varicella was first described by Henoch in the year 1884.¹ With an incidence of 0.12%–19%, renal involvement in varicella is rare.² The onset of glomerulonephritis can be either prior to or with the appearance of varicella rash or after a latent period of 7–14 days.³ Varicella-induced glomerulonephritis generally resembles post-streptococcal glomerulonephritis and a complete recovery with benign clinical course is the rule. Acute proliferative glomerulonephritis is an immune complex mediated hypocomplementaemic glomerulonephritis in response to infection by the virus—clinically presenting as a nephritic or a nephrotic syndrome.⁴ Proteinuria in most reported cases is mild to moderate.⁵ Here we report an atypical case of post-varicella glomerulonephritis presenting with ‘massive’ nephrotic range proteinuria.

Case presentation

A 16-year-old boy from the Indian state of Uttar Pradesh presented to us with a 5-day history of periorbital puffiness and swelling of both feet. He had an episode of high-grade fever around 15 days ago and subsequent papulo-vesicular eruptions which was diagnosed by family physician as chicken pox. He denied having fever, sore throat, prior hospitalisation, drug intake, dysuria, dyspnoea or oliguria on admission.

On examination, the boy was conscious, afebrile (oral temperature 37.1°C) with hypopigmented macules and few crusted vesicles all over the trunk and upper extremities (figure 1). Bilateral pitting pedal oedema was present. Blood pressure recorded in upper extremity was 130/90 mm Hg, chest auscultation revealed bilateral equal air entry and no crepitations. Abdomen was soft, non-tender; examination of cardiovascular system was normal.

Figure 1.

Diffuse healed (post-varicella) hypopigmented macular lesions over trunk.

Investigations

Blood investigations revealed a normal haemoglobin (137 g/L), total leucocyte count (12.7×10⁹/L), random blood glucose (96 mg/dL) and electrolytes (sodium 139 meq/L, potassium 4.8 meq/L), but deranged renal function tests (urea 151 mg/dL, creatinine 1.4 mg/dL, creatinine clearance 45.5 mL/min/1.73 m²), profound hypoalbuminemia (serum protein 5.7 g/dL, serum albumin 2.5g/dL) and dyslipidemia (serum cholesterol 269.44 mg/dL, triglycerides 238.69 mg/dL, low density lipoprotein cholesterol 205 mg/dL). Urinalysis showed acidic, sterile (by culture) urine with a specific gravity of 1.020, 4+proteinuria (24 hours urinary protein 16.6 g), pyuria (8–10 pus cells/hpf) and a large number of red blood cells. No casts or crystals were present in urine. Bilateral bulky kidneys with attenuated cortico-medullary differentiation were the findings on abdominal ultrasound. Serum IgM varicella was positive (qualitative) and antistreptolysin-O titre was negative. Throat swab did not reveal growth of pathogenic organisms. Serum markers for hepatitis B, hepatitis C and HIV were negative. Complement assay showed a decreased C3 level (38.1 mg/dL) and a normal C4 level (22.2 mg/dL). C-reactive protein was mildly elevated 12 mg/dL (day 2 of admission) which declined to 0.5 mg/dL (day 14) (figure 2).

Figure 2.

Schematic figure showing clinical course of the patient.

A percutaneous renal biopsy was done on day 14 of admission which showed diffuse thickening and splitting of basement membranes with endocapillary and mesangial hypercellularity, mild neutrophilic infiltrate with two glomeruli showing circumferential cellular crescents on histopathology (figures 3 and 4). Coarse granular deposits of IgG (+++), C3 and IgA (++) were found along the glomerular basement membrane on immunofluorescence. C1q and IgM were negative. Biopsy findings were suggestive of Membranoproliferative glomerulonephritis.

Figure 3.

Histopathology of renal biopsy specimen showing diffuse thickening and splitting of basement membranes with endocapillary and mesangial hypercellularity with mild neutrophilic infiltrate.

Figure 4.

Histopathology (enlarged view) showing mesangial hypercellularity.

Differential diagnosis

Varicella infection predisposes to infection by streptococcus and post-streptococcal glomerulonephritis was our closest differential which may present similarly, ASO titre negativity ruled out its possibility. The absence of history of pharyngitis and syn-pharyngitic hematuria as well as typical biopsy findings ruled out IgA nephropathy. Our patient had a self-limiting clinical course rather than a deleterious presentation negating focal segmental glomerulosclerosis and crescentic glomerulonephritis which was further substantiated by the findings on renal biopsy.

Treatment

Patient received oral diuretic, statin and ACE inhibitor during hospital stay.

Outcome and follow-up

Patient was discharged with diuretic, statin and ACE inhibitor in afebrile and haemodynamically stable condition with marked resolution of symptoms. He was asked to follow-up in outpatient department after 2 weeks which showed significant reduction in proteinuria (4.5 g/24 hours), absent hematuria and normalisation of renal function (eGFR 88 mL/min/1.73 m²).

Discussion

Varicella zoster virus, human herpes virus type 3, is the causative agent of chicken pox, a highly contagious, usually childhood disease (peak incidence 5–9 years). The most common complications seen more in adults are related to central nervous system like aseptic meningitis, Guillain-Barre syndrome and transverse myelitis.⁶ Back in 1884, Henoch first pointed out the association of varicella with nephritis, when he described four cases of nephritis in children suffering from chicken pox. Varicella related nephritis is very rare with only 3 (0.12%) developing clinical nephritis in a large series of 2534 patients in a 1935 study.⁷ The complications of varicella may appear before, during, or after onset of the rash.⁸ Renal lesions like proliferative glomerulonephritis, tubular necrosis, interstitial inflammation, fibrinoid necrosis and the presence of crescents^{9 10} have been described in varicella nephritis.

The precise mechanism of varicella-induced glomerulonephritis is yet to be studied. It may occur by both direct and immune-mediated mechanisms.^{1 11} Clinical and histological evidence suggests that renal damage in varicella is caused by viruria resulting from active infection of kidney cells. This mechanism explains glomerulonephritis occurring prior to or with the appearance of the varicella rash.¹² Glomerulonephritis in our patient was due to immune-mediated damage; this fact is suggested by the characteristic latent period and depression of serum complement activity.

There is a consensus regarding the use of steroids leading to reactivation of severe varicella in a few studies.¹³ Our patient did well with diuretics, statin and ACE inhibitor and the use of steroid was deliberately avoided. Although steroids had been used in a fatal case of varicella associated rapidly progressive glomerulonephritis¹⁴ in view of clinical severity. Corticosteroids, if needed, should be used in low dosage(5–20 mg/kg) and for shortest duration possible as per a 1993 study.¹⁵

Our report adds to the already existing evidence that varicella can be a potential cause of hypocomplementenemic post-infectious glomerulonephritis, most cases being clinically benign as was our case. Proteinuria of this range (16.6 g/24 hours) had not been reported previously to the best of our knowledge. Although immunological mechanisms have been proposed, the exact pathophysiology of how varicella causes renal damage is yet to be deciphered and should be the focus in future clinical research.

In conclusion, one must not ignore puffy face and swollen feet after chicken pox.

Learning points.

• Varicella can be a potential cause of post-infectious glomerulonephritis.

• Clinical course is usually benign and self-limiting with very few fatal cases being reported.

• Clinician should give an alert eye to the renal function after an episode of chicken pox.

• Further studies are warranted to strengthen the causative link between varicella and glomerulonephritis.

• Overambitious use of corticosteroids should be avoided