Peri-infectious Glomerulonephritis Associated With Viral Infections

Qiyu Wang

Meghan Sise

INTRODUCTION

Chronic viral infections, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) can cause glomerular disease in a subset of infected patients. The COVID-19 (coronavirus disease 2019) pandemic has highlighted that some acute viral infections can also trigger kidney disease. Each can involve glomeruli and other compartments of the kidney, manifesting a wide spectrum of kidney pathology. Several mechanisms are involved in the pathogenesis of virus-related kidney disease, including tropism of the virus in the kidney causing direct cytopathic effects, and host immune response to the virus leading to production and deposition of immune complexes or podocyte dysregulation. This chapter reviews the glomerular disease associated with HIV, HCV, HBV, and COVID-19 infection.

HUMAN IMMUNODEFICIENCY VIRUS

In the early 1980s, human immunodeficiency virus-associated nephropathy (HIVAN), a form of collapsing focal segmental glomerulosclerosis (FSGS), was described in patients with very high viral load and low CD4 count.¹ In the current era, with a wide use of antiretroviral therapy (ART) leading to long-term survivorship, the incidence of classic HIVAN is significantly reduced, with a shift toward a variety of glomerular diseases including immune complex diseases.²,³,⁴

Pathogenesis of Classic Human Immunodeficiency Virus-Associated Nephropathy

Evidence from clinical and animal studies supports a direct role of HIV infection of kidney parenchymal cells in the pathogenesis of HIVAN. Viral replication and expression of HIV transgenes in podocytes and renal tubular epithelial cells eventually result in loss of expression of important structural proteins (eg, nephrin), leading to apoptosis, cell proliferation, and tubular microcyst formation. Expression of HIV regulatory and accessory proteins in HIV transgenic mice (Tg²⁶ or TgFVB) even in the absence of intact virus recapitulates the HIVAN phenotype and has led to an important understanding of this disease.⁵,⁶,⁷

HIVAN has an important genetic predisposition in patients with African ancestry because of the association with APOL1 genetic polymorphisms on
chromosome 22.⁸,⁹ The G1 (two missense mutations) and G2 (two base pair deletion) variants confer risk factors for HIVAN and an HIV-associated noncollapsing form of FSGS, which is thought to be an attenuated form of classic HIVAN due to virologic suppression from ART.⁴,¹⁰,¹¹ The genetic effect is largely recessive, and homozygous (G1/G1 or G2/G2) or compound heterozygous (G1/G2) individuals have the highest risk of HIVAN. A lifetime incidence of HIVAN was estimated to be 50% among patients from African ancestry with two APOL1 risk alleles without ART therapy.⁹ The mechanisms by which the risk alleles alter chronic kidney disease (CKD) progression remain unknown and are a matter of ongoing research.

Clinical Presentation and Pathologic Findings

A salient feature of HIVAN is a nephrotic syndrome with rapid glomerular filtration rate (GFR) loss and progression to end-stage kidney disease (ESKD) in a matter of months in patients with advanced HIV (high viral loads, CD4 counts <200 cells/µL), although HIVAN can also be seen in acute HIV infection.¹,¹² Many patients are normotensive and relatively edema-free despite advanced CKD and nephrosis, possibly due to salt wasting from the prominent tubular abnormalities in HIVAN.

The characteristic light microscopy features include global or segmental collapse of glomerular tufts, podocyte hypertrophy, and proliferation surrounding the shrunken glomerulus forming “pseudocrescents.” Tubulointerstitial involvements (dilated tubules filled with proteinaceous casts resembling microcysts, tubular reabsorption droplets, and interstitial inflammation) are usually prominent and may occur out of proportion to the glomerular disease (Figure 17.1). HIVAN kidneys are typically enlarged because of numerous microcystic formations. On electron microscopy, endothelial tubuloreticular inclusions, also known as “interferon footprints,” are characteristic features that are almost always present. Immunofluorescence microscopy findings are generally nonspecific and may show staining for immunoglobulin (Ig) M, complement factor (C3), and C1q due to nonspecific entrapment in the collapsed glomerular tufts.

Treatment

ART is the key to preventing and treating HIVAN. Observational studies have shown a significant decline in HIVAN incidence and lower risk of ESKD with early
use of ART. Current guidelines recommend initiating ART in all patients with HIV as soon as possible, regardless of the CD4 count.¹³,¹⁴,¹⁵,¹⁶ Traditional kidney protective strategies including blood pressure control and proteinuria reduction with angiotensin-converting enzyme inhibitors or angiotensin receptor blockade are important to slow progression of HIVAN. There is insufficient evidence supporting the use of corticosteroids in HIVAN, and most treatment efficacy data were derived from small, retrospective, uncontrolled studies before or during the initial phase of widespread ART use.¹⁷

FIGURE 17.1: Schematic representation of glomerular and tubular pathology in HIVAN. HIVAN has characteristic findings in all three compartments (glomerular, tubular, and interstitial space) on kidney pathology. HIVAN, human immunodeficiency virus-associated nephropathy. (Figure created by Dr. Xavier Vela Parada.)

Despite ART, patients with HIVAN and other forms of kidney pathology associated with HIV may still progress to ESKD. Survival of HIV-positive individuals receiving kidney replacement therapy is comparable to HIV-negative individuals in the ART era.¹⁵ With effective ART, kidney transplant is safe and effective for patients with HIV infection and ESKD. There is a clear survival advantage for patients with HIV who undergo kidney transplantation compared to those remaining on dialysis.¹⁸ To be listed as a potential kidney transplant recipient, aside from a transplant center’s general criteria, patients with HIV must also have an undetectable viral load, a CD4 count greater than 200, be on a stable ART regimen, and without active opportunistic infections.¹⁹ Patients with HIV who receive a kidney transplant have similar patient and graft survival compared to their HIV-negative counterparts, whereas those with HIV/HCV coinfection have worse outcomes.²⁰,²¹ Important drug-drug interactions must be considered in the posttransplant care because many immunosuppressants and antivirals are cytochrome P450 (CYP450) substrates, inducers, or inhibitors. Coadministration of potent CYP450 inhibitors such as protease inhibitors may decrease the metabolism of tacrolimus, resulting in increased drug levels and necessitating dose reduction of tacrolimus. Conversely, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are CYP450 inducers that may increase clearance of tacrolimus and necessitate higher doses to maintain adequate levels.²²,²³ Therefore, the integrase inhibitor-based highly active ART regimen (eg, raltegravir) is generally preferred over a protease inhibitor-based or an NNRTI-based regimen in the management of posttransplant immunosuppression for patients with HIV to achieve steady therapeutic levels of immunosuppressive agents.²⁴ There is a significantly increased risk of acute rejection (AR) in HIV-positive transplant recipients,¹⁹ and observational studies have supported a role of induction immunosuppression with anti-thymocyte globulin in decreasing the risk of AR.²⁵,²⁶ The tacrolimus-based regimen is generally preferred as maintenance immunosuppression.²⁷,²⁸

Immune Complex Diseases in Patients With Human Immunodeficiency Virus Infection

Modern biopsy series in patients with HIV have shown that immune complex diseases are now among the most common findings (Visual Abstract 17.1).⁴ Cryoglobulinemic glomerulonephritis (particularly in HIV/HCV coinfection), membranous glomerulopathy, IgA nephropathy, and “lupus-like” glomerulonephritis are among the most common reported kidney pathologies. “Lupus-like” glomerulonephritis was first described in a series of 14 patients in 2005 who had a proliferative glomerulonephritis with “full-house” staining by immunofluorescence microscopy, but without serologic or clinical evidence of systemic lupus erythematosus.²⁹ Chronic HIV infection is associated with polyclonal expansion of Igs, and immune complex disease may result from deposition from the systemic circulation or from in situ binding of Igs to lodged HIV antigens (Table 17.1).

TABLE 17.1 Evaluation and Treatment of Immune Complex Disease in Human Immunodeficiency Virus Infection

Immune Complex-Mediated Kidney Disease in PWH	Evaluation/Associated Conditions	Treatment
IgA nephropathy	Cirrhosis	Immunosuppression vs supportive management^a
Lupus-like nephritis	Check lupus serology. Evaluate for clinical symptoms of SLE.	Immunosuppression (prednisone and MMF)
Membranous nephropathy	Check HBV serology and anti-PLA2R. Exclude malignancy and other secondary causes.	Consider immunosuppression.
Membranoproliferative glomerulonephritis	Check HCV serology and viral load.	DAAs if HCV coinfection Consider immunosuppression if rapidly progressive kidney failure.
Infection-related glomerulonephritis	Blood culture, TTE	Antibiotics Surgical source control
Immunotactoid glomerulonephritis	Evaluate for paraproteinemia and lymphocyte/plasma clonal expansion.	Clone-directed targeted therapy or chemotherapy
DAA, direct-acting antiviral; HBV, hepatitis B virus; HCV, hepatitis C virus; IgA, immunoglobulin A; MMF, mycophenolate mofetil; PLA2R, phospholipase A2 receptor; PWH, patients with HIV; SLE, systemic lupus erythematosus; TTE, transthoracic echocardiogram.^aThe role of immunosuppressive treatment is controversial in immunoglobulin A nephropathy, and particular caution is needed in patients with cirrhosis who are at high risk for infectious complications.

The direct or indirect role of HIV in each of these immune complex-mediated kidney injuries is not well understood. The 2018 Kidney Disease: Improving Global Outcomes (KDIGO) consensus guideline recommended that the old terminology HIV-associated immune complex kidney disease (“HIVICK”) be replaced with the specific description of the immune complex disease followed by “in the setting of HIV.”¹⁵ Patients with HIV who develop immune complex disease need a thorough workup for other potential causes of these kidney diseases rather than anchoring on the causal link of kidney pathology with HIV. In patients with well-controlled HIV infection, consideration of immunosuppressive therapies using standard-of-care approaches to treat the underlying immune complex-mediated glomerular disease is warranted. Immune complex-mediated glomerular diseases typically have a better kidney prognosis compared to HIVAN (Visual Abstract 17.2).³⁰,³¹

Finally, HIV-related thrombotic microangiopathy (TMA) is an uncommon presentation that typically occurs in patients with very advanced acquired immunodeficiency syndrome. It presents similarly to idiopathic forms of TMA with hypertension, acute kidney injury (AKI), microscopic hematuria, and nonnephrotic proteinuria, along with features of a microangiopathic hemolytic anemia.³²

Differential Diagnosis

Nephrotoxicity from ART has emerged as an important cause of CKD in patients with HIV. Tenofovir disoproxil fumarate (TDF), a nucleoside reverse transcriptase inhibitor, can cause proximal tubular dysfunction because of the uptake of its active metabolite, tenofovir, into the proximal tubular cell where it can inhibit mitochondrial DNA synthesis.³³ Patients usually present with elevated creatinine and tubular (nonalbumin) proteinuria.³⁴ In comparison, tenofovir alafenamide fumarate (TAF), a novel prodrug of tenofovir that achieves a higher intracellular concentration of its active moiety, may be associated with less kidney adverse effects given the lower plasma tenofovir drug levels.³⁵,³⁶

Atazanavir may cause nephrolithiasis or intratubular crystalline nephropathy.³⁷ Darunavir, another protease inhibitor, is also rarely associated with crystalluria, nephrolithiasis, and crystalline nephropathy.³⁸ Atazanavir and darunavir stones are radiolucent and can be hard to diagnose even on computed tomography.

Both dolutegravir, an integrase inhibitor, and cobicistat, a CYP inhibitor used to boost levels of certain protease inhibitors, may cause a small increase in the serum creatinine level (˜0.3 mg/dL) because of the inhibition of creatinine secretion via different proximal tubule transporters.²² Cystatin-C-based estimated glomerular filtration rate (eGFR) equations more accurately reflect kidney function in patients taking these two agents.

Increase in the life span of patients with HIV in the ART era has led to an increase in comorbidity burden including CKD. As the HIV-infected population ages, the high prevalence of diabetes, hypertension, and smoking promote common causes of CKD, such as diabetic kidney disease and arterionephrosclerosis.

KEY POINTS

Classic HIVAN is a form of collapsing FSGS typically seen in patients with advanced HIV who are of African ancestry and is directly linked to viral infection of the kidney parenchymal cells. The classic presentation is nephrotic syndrome with rapid GFR loss and progression to ESKD in months.
The incidence of HIVAN has significantly decreased with the wide use of ART since the 1990s. Immune complex-mediated diseases are now emerging as the most common findings in modern biopsy series.
Other causes of kidney disease in patients with HIV include ART nephrotoxicity and comorbid CKD.

HEPATITIS C VIRUS

HCV leads to chronic infection in approximately 75% of those who are exposed and is one of the leading causes of cirrhosis in the United States. HCV can also lead to extrahepatic complications. It is the most common cause of mixed cryoglobulinemic vasculitis, a systemic vasculitis involving small- to medium-sized blood vessels, that is associated with a myriad of clinical manifestations including purpuric skin rash, nonerosive arthralgia, peripheral nerve involvement (mononeuritis multiplex), and cryoglobulinemic glomerulonephritis. HCV is associated with CKD and ESKD risk. Screening urinalysis and eGFR in all HCV-positive patients are strongly recommended.³⁹

Pathogenesis

HCV infection leads to chronic stimulation of B lymphocytes and widespread autoantibody synthesis. Cryoglobulins are proteins that circulate in the serum, precipitate in cold temperatures (below core body temperature), and dissolve upon
rewarming. Chronic HCV infection is typically associated with type II mixed cryoglobulinemia (polyclonal IgG and monoclonal IgM with rheumatoid factor [RF] activity), and cryoglobulinemic glomerulonephritis may result because of the affinity of IgM-RF for mesangial matrix. As cryoglobulins deposit in the glomerular capillaries and mesangium, complement is activated, leading to inflammatory cytokine release and recruitment of immune cells, and ultimately culminating in endocapillary proliferation, fibrinoid necrosis, glomerular basement membrane (GBM) rupture, and crescent formation.

Direct cytopathic effects of HCV may also play a role in HCV-related kidney disease. HCV is able to bind to and penetrate into kidney parenchymal cells. HCV RNA has been found in mesangial, tubular epithelial, and endothelial cells of the glomerulus and peritubular capillaries.⁴⁰,⁴¹

Clinical Findings and Pathologic Features

Severity of cryoglobulinemic glomerulonephritis can range from asymptomatic nonnephrotic-range proteinuria, nephrotic syndrome, to acute glomerulonephritis with rapid GFR loss. Most patients have hypertension at diagnosis. Typical laboratory findings include hypocomplementemia (C4 is more commonly reduced than is C3), and RF-positive monoclonal Ig, almost invariably IgMκ. Most patients with HCV-related cryoglobulinemic glomerulonephritis have both detectable anti-HCV antibodies and high HCV RNA, but it is increasingly recognized that cryoglobulinemic glomerulonephritis can persist, recur, or occur de novo after HCV infection has cleared with antiviral therapy.⁴²,⁴³ Patients with persistent manifestations of cryoglobulinemia should be evaluated for B-cell lymphoproliferative disorders (eg, non-Hodgkin lymphoma).⁴⁴

Light microscopy typically demonstrates a membranoproliferative glomerulonephritis (MPGN) pattern of injury with expanded and hypercellular mesangium, endocapillary proliferation, monocytic infiltration, thickened capillary loops, large eosinophilic and periodic acid-Schiff (PAS) stain-positive intraluminal deposits. Large intraglomerular immune deposits that can fill the capillary lumen are referred to as pseudothrombi (Figure 17.2A). The GBMs may demonstrate
double contours resulting from immune complex deposition and mesangial cell matrix interposition between the basement membrane and endothelial cell, with new basement membrane forming around these deposits. Immunofluorescence microscopy shows C3, IgM, and IgG reactivity with granular deposits in the capillary wall and mesangium (Figure 17.2B). On electron microscopy, subendothelial deposits with tubular substructure can be seen (Figure 17.2C). Approximately one-third of patients may have vasculitis of small arteries of the kidney.

FIGURE 17.2: A, Membranoproliferative glomerulonephritis in hepatitis C virus-associated mixed cryoglobulinemia. Periodic acid-Schiff stain showing mesangial hypercellularity and thickened GBM, with lobular appearance of the glomeruli. The arrow points to a “pseudothrombus” characteristically seen in cryoglobulinemic glomerulonephritis, representing a high burden of circulating immunoglobulin/cryoglobulin. B, Immune complex deposition in cryoglobulinemic glomerulonephritis. Immunoglobulin M immunofluorescence in cryoglobulinemic glomerulonephritis showing multiple large immune complexes “pseudothrombi” (curved arrow), and granular deposits along the GBM (straight arrow). C, Organized tubular structure of the immune complex deposits in the GBM. Electron microscopy showing organized microtubular structures characteristic of cryoglobulin deposits. GBM, glomerular basement membrane. (Figure courtesy of Dr. Robert Colvin.)

Differential Diagnosis

It is important to note that MPGN may be found in patients with chronic HCV even without circulating cryoglobulin. Various other histologic types of kidney diseases have also been reported in the context of HCV infection, including membranous nephropathy (MN), FSGS, fibrillary glomerulonephritis, immunotactoid glomerulonephritis, IgA nephropathy (usually associated with advanced liver disease), TMA, interstitial nephritis, and polyarteritis nodosa (PAN).