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  Table of Contents    
CASE REPORT  
Year : 2018  |  Volume : 61  |  Issue : 4  |  Page : 610-613
Fibrillary glomerulonephritis in a human immunodeficiency virus-positive, hepatitis C-negative Indian patient: Expanding the profile of renal involvement in human immunodeficiency virus infection


1 Department of Pathology, Central Electron Microscopy Facility, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India

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Date of Web Publication10-Oct-2018
 

   Abstract 


Highly active anti retroviral therapy (HAART) has dramatically improved life expectancy of human immunodeficiency virus (HIV) infected patients, converting HIV infection into a chronic illness with associated changes in its attendant renal complications. The past two decades have witnessed a decrease in the prevalence of HIV associated nephropathy (HIVAN), traditionally considered to be the hall mark of renal involvement in HIV infection. Simultaneously a host of other glomerular and tubulo-interstitial diseases have emerged, expanding the spectrum of HIV associated renal diseases, predominant among which is HIV associated immune complex mediated kidney diseases (HIVICK). Of the diverse glomerular diseases constituting HIVICK, fibrillary glomerulonephritis (FGN) remains a rarity, with only two existing reports to date, confined to patients co-infected with Hepatitis C virus (HCV). The pathogenetic role of HIV in these patients remains under a cloud because of previously well established association of HCV infection and FGN. We report a case of FGN in a HIV seropositive, HCV negative Indian patient, highlighting the diagnostic electron microscopy (EM) findings of FGN and strengthening the causal association of HIV with FGN. In view of increasing heterogeneity of renal complications in HIV infection, the diagnostic utility of a comprehensive renal biopsy evaluation inclusive of EM is emphasized for appropriate selection of treatment modalities.

Keywords: Fibrillary glomerulonephritis, HIV associated immune complex mediated kidney disease, HIV associated nephropathy, HIV associated renal disease, Human Immunodeficiency virus infection

How to cite this article:
Matthai SM, Valson AT, Duhli N, Rupali P, Pulimood AB, Varughese S. Fibrillary glomerulonephritis in a human immunodeficiency virus-positive, hepatitis C-negative Indian patient: Expanding the profile of renal involvement in human immunodeficiency virus infection. Indian J Pathol Microbiol 2018;61:610-3

How to cite this URL:
Matthai SM, Valson AT, Duhli N, Rupali P, Pulimood AB, Varughese S. Fibrillary glomerulonephritis in a human immunodeficiency virus-positive, hepatitis C-negative Indian patient: Expanding the profile of renal involvement in human immunodeficiency virus infection. Indian J Pathol Microbiol [serial online] 2018 [cited 2018 Dec 15];61:610-3. Available from: http://www.ijpmonline.org/text.asp?2018/61/4/610/242993





   Introduction Top


With the advent of highly active antiretroviral therapy (HAART), the disease burden of renal involvement in human immunodeficiency virus (HIV)-infected patients is currently on the rise along with a parallel change in its profile. A wide spectrum of HIV-associated immune complex-mediated kidney disease (HIVICK) has been described of late, especially in Caucasian and Asian populations,[1],[2] in addition to classical HIV-associated nephropathy (HIVAN). HIVICK lesions with organized glomerular deposits are quite rare and mostly described in patients with concurrent seropositivity for hepatitis C virus (HCV).[3],[4] The causative role of HIV in such scenarios remains suspect. We report a case of fibrillary glomerulonephritis (FGN) in an HIV-positive but HCV-negative patient, emphasizing the role of renal biopsy with ultrastructural analysis in the diagnosis and management of HIV-infected patients with renal disease.


   Case Report Top


A 46-year-old Indian male presented with bilateral pedal edema and weakness of 6-month duration. He gave a past history of being diagnosed with HIV infection, 9 years back, but had never taken HAART, opting for native/nonallopathic medical treatment at the time. He was not on follow-up till 2 months before current presentation when he developed pyrexia of unknown origin, weight loss, and anorexia for which he was initiated empirically on antituberculous treatment (ATT) with isoniazid, rifampicin, pyrazinamide, and ethambutol at his local medical center. However, ATT was discontinued after 5 days when he developed vomiting and was found to have transaminitis. He was referred to us for further management, on suspicion of ATT-induced hepatitis and background history of positive retroviral status.

Physical examination was remarkable for oral candidiasis, bilateral pitting pedal edema, right supraclavicular lymph node enlargement, bilateral pleural effusion, and nontender hepatomegaly extending 4 cm below the right costal margin. There were no lymph node swellings elsewhere. Blood pressure was 140/80 mmHg. Laboratory studies showed serum creatinine – 1.67 mg/dL and 24-h urinary protein – 3.2 g; urine analysis showed 23 red blood cells and 2–3 white blood cells per high-power field. Complement levels were normal (serum C3: 104 mg/dL [normal 90–180] and serum C4: 10.9 mg/dL [normal 10–40]). Hepatitis B surface antigen, hepatitis C antibody, and polymerase chain reaction were negative, and there were no detectable cryoglobulins or monoclonal bands. CD4 count was 119 cells/μL and liver function tests were normal apart from serum albumin of 2.1 g/dL. HIV serology was positive for HIV-1 antibodies. Pleural fluid aspirate showed a lymphocyte predominant transudative effusion. Biopsy of the right supraclavicular lymph node revealed caseating granulomatous inflammation, with culture growing Mycobacterium tuberculosis. Chest X-ray and ultrasound abdomen did not show any hilar or abdominal lymph node enlargement.

With a working clinical diagnosis of HIVAN, an ultrasound-guided percutaneous renal biopsy was performed to ascertain the cause of nephrotic-range proteinuria.

Light microscopic examination of renal tissue cores received, showed a total of 19 glomeruli with 12 glomeruli on 4 micron thin (H&E stained) sections and 7 glomeruli on 1 micron semi-thin (toluidine blue stained) sections respectively. There was diffuse mesangial expansion and focal mesangial hypercellularity associated with irregular capillary wall thickening. Five glomeruli were globally sclerosed and two showed secondary focal segmental sclerosis. Focal double contouring of capillary walls with segmental endocapillary proliferation was noted. The interstitium showed foci of fibrosis with tubular atrophy (IFTA) involving up to 25% of the cortical tissue present in the core examined. Few dilated tubules containing hyaline casts and aggregates of chronic inflammatory cells were seen adjacent to these foci. Hyaline arteriolosclerosis and arteriosclerosis were observed [Figure 1]a, [Figure 1]b, [Figure 1]c. There were no collapsing features or podocyte hyperplasia to suggest HIVAN. Features of acute tubular injury were not present. Immunofluorescence showed granular peripheral capillary wall deposits of immunoglobulin G (IgG) (2+), IgM (2+), IgA (1+), and C3 (1+). There was no light chain restriction. Congo red stain for amyloid was negative [Figure 1]d. Based on these findings, a preliminary diagnosis of HIV-associated immune-mediated proliferative glomerulonephritis was made.
Figure 1: (a) Low-power view of renal core showing glomeruli with proliferative features and interstitial expansion by foci of fibrosis and chronic inflammatory cell infiltrates (H and E, ×100). (b) Glomerulus showing mesangial expansion, capillary wall thickening, and segmental proliferation (H and E ×200). (c) Glomerulus with focal segmental sclerosis, capsular synechiae, and mildly PAS-positive mesangial deposits (periodic acid–Schiff, ×200). (d) Negative Congo red staining rules out amyloidosis (Congo red ×200)

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Electron microscopy demonstrated expansion of the mesangium by fibrillary deposits extending into the capillary walls and focally involving entire thickness of glomerular basement membranes. The deposits were composed of randomly oriented fibrils measuring 21–29 nm in diameter without central lucencies on cross section. Extensive foot process effacement was noted [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. There was no evidence of a microtubular substructure, ruling out immunotactoid glomerulonephritis (ITGN) and cryoglobulinemic glomerulonephritis. The final diagnosis was FGN with secondary focal segmental sclerosis in a case of HIVICK.
Figure 2: (a) Electron microscopy view at scanning magnification showing early nodular condensation of mesangial matrix associated with proliferative features (transmission electron microscopy, ×1250). (b) Expanded mesangium (M) containing abundant fibrillary deposits (transmission electron microscopy, ×20,500). (c) Capillary wall showing randomly oriented fibrillary deposits involving full thickness of glomerular basement membranes. Overlying podocyte (P) foot processes are effaced (arrow) (transmission electron microscopy × 26,500). (d) Substructure analysis of mesangial deposits showing random fibrils measuring approximately 25–29 nm in diameter and absent central lucencies on cross section, diagnostic of fibrillary glomerulonephritis (transmission electron microscopy ×43,000). P: Podocyte, E: Endothelial cell, M: Mesangium

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ATT was restarted and liver function remained normal. One month later, he was started on HAART with abacavir, lamivudine, and efavirenz. Proteinuria was managed with losartan. At last follow-up, proteinuria was 2 g/day and serum creatinine was 0.9 mg/dL.


   Discussion Top


The most common kidney lesion traditionally described in HIV-infected patients has been termed HIVAN presenting with rapidly progressive renal failure and proteinuria and diagnosed on renal biopsy which shows collapsing glomerulopathy and characteristic tubulointerstitial changes. For more than a decade, HIVAN was considered the prototype of renal involvement in HIV, obviating the need for renal biopsies to search for other causes of proteinuria and renal dysfunction in this population, particularly in low-resource settings. However, in the current era of HAART and increased longevity of HIV-infected patients, the profile of renal pathology in HIV infection has undergone a sea change, moving beyond classical HIVAN.[1],[2] While HIVAN still remains the most common HIV-driven kidney lesion in HAART naive patients of African descent, recent trends reveal a higher prevalence of HIVICK among Caucasians and Asians.[1],[2] Genetic susceptibility due to APOL1 polymorphisms, availability of HAART, and access to health-care systems may be responsible for this expanding renal pathological profile in HIV patients.[2]

The variety of lesions observed in HIVICK includes IgA nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, postinfectious glomerulonephritis, lupus-like glomerulonephritis, cryoglobulinemic glomerulonephritis, ITGN, and FGN.[1],[2] ITGN and FGN are uncommon glomerular diseases with immune deposits demonstrating organized substructure distinct from amyloid and cryoglobulins.[5] The association between ITGN/FGN and HCV infection is well recorded.[6] Only two cases of FGN associated with HIV infection have been reported to date, both of whom were coinfected with HCV,[3] rendering the pathogenic relationship to HIV unclear. Due to the heterogeneity of HIVICK lesions, contemporary renal research focuses on establishing causality and thereby optimizes immunosuppressive therapy of HIVICK in the already immunocompromised HIV-positive patient.[1] The present case of FGN occurring in a patient with HIV monoinfection whose renal symptoms responded to treatment for HIV infection is a valuable pointer to the causal role of HIV in this setting and also reinforces the value of HAART in managing HIVICK without additional cytotoxic therapies for immunosuppression.

Passive trapping of circulating immune complexes resulting from polyclonal hypergammaglobulinemia in HIV infection is the favored theory of pathogenesis of HIVICK and supported by the elegant demonstration of HIV antigens p24, gp41, and gp120 bound to IgG or IgA antibodies in circulating and tissue immune complexes in HIV-infected patients.[2] It is possible to speculate further on the physiochemical nature of the fibrillary deposits by analogous comparison to HCV-related FGN in which a “slow cryoglobulin” (not detectable by standard tests for cryoglobulins) with affinity for matrix proteins such as fibronectin has been postulated to form organized fibrils.[6]

This case illustrates the need to lower our threshold for performing renal biopsies in HIV-positive patients, in support of the “test and treat” policy advocated currently for HIV prevention and management.[1] A composite renal biopsy evaluation inclusive of ultrastructural analysis will go a long way toward expanding our knowledge on the epidemiology, pathogenesis, and optimal management of renal involvement in HIV.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Swanepoel CR, Atta MG, D'Agati VD, Estrella MM, Fogo AB, Naicker S, et al. Kidney disease in the setting of HIV infection: Conclusions from a kidney disease: Improving Global outcomes (KDIGO) controversies conference. Kidney Int 2018;93:545-59.  Back to cited text no. 1
    
2.
Cohen SD, Kimmel PL. Immune complex renal disease and human immunodeficiency virus infection. Semin Nephrol 2008;28:535-44.  Back to cited text no. 2
    
3.
Haas M, Rajaraman S, Ahuja T, Kittaka M, Cavallo T. Fibrillary/immunotactoid glomerulonephritis in HIV-positive patients: A report of three cases. Nephrol Dial Transplant 2000;15:1679-83.  Back to cited text no. 3
    
4.
Martin JL, Thomas D, Colindres RE. Immunotactoid glomerulopathy in an HIV-positive African-American man. Am J Kidney Dis 2003;42:E6-10.  Back to cited text no. 4
    
5.
Bridoux F, Hugue V, Coldefy O, Goujon JM, Bauwens M, Sechet A, et al. Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int 2002;62:1764-75.  Back to cited text no. 5
    
6.
Markowitz GS, Cheng JT, Colvin RB, Trebbin WM, D'Agati VD. Hepatitis C viral infection is associated with fibrillary glomerulonephritis and immunotactoid glomerulopathy. J Am Soc Nephrol 1998;9:2244-52.  Back to cited text no. 6
    

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Correspondence Address:
Anna T Valson
Department of Nephrology, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_52_18

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