Viral Nephropathies: Human Immunodeficiency Virus, Hepatitis C Virus, and Hepatitis B Virus

Abstract

Human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) are among the most important viral-induced causes of kidney disease. Each can present with a spectrum of clinical manifestations reflecting both glomerular as well as other types of kidney diseases. Some medications used to treat HIV infection are associated with nephrotoxicity and electrolyte and acid-base disorders.

Keywords

hepatitis, human immunodeficiency virus, antiviral, HIVAN, FSGS, cryoglobulinemia

Human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) are the most important causes of viral-related kidney disease in the world. Several mechanisms are involved in the pathogenesis of virus-related kidney disease, including tropism of the virus in the kidney, direct cytopathic effects, and immune response to the virus and production of immune complexes. These lead to a spectrum of glomerular and tubulointerstitial diseases. Some of the most important features of the kidney diseases associated with these viruses are shown in Table 23.1 .

Table 23.1

Important Clinical Features of Viral Nephropathies

	HIV	HCV	HBV
Major risk groups	Infected individuals of African ancestry, HIVAN Infected individuals of European and Asian ancestry, HIV-ICD	Adults with risk factors for chronic HCV infection	Children from HBV endemic areas
Presentation	Proteinuria, nephrotic syndrome CKD with rapid progression Large, echogenic kidneys Advanced HIV (if HIVAN)	Hematuria Proteinuria Hypocomplementemia Palpable purpura Systemic vasculitis Cryoglobulinemia	Proteinuria Nephrotic syndrome
Primary kidney pathology	Collapsing FSGS Microcystic dilation of tubules Interstitial inflammation/fibrosis	MPGN	MN
Pathogenesis	Direct HIV infection Host genetic factors Immune complex deposition	Direct HCV toxicity Cryoglobulinemia	Antigen-antibody complex deposition Vasculitis
Therapy	cART ACE-I and ARBs	Antiviral therapy Rituximab Cyclophosphamide Plasmapheresis in severe cases	Antiviral therapy

ACE-I, Angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; cART, combined antiretroviral therapy; CKD, chronic kidney disease; FSGS, focal segmental glomerulosclerosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HIVAN, HIV-associated nephropathy; HIV-ICD, HIV immune complex disease; MN, membranous nephropathy; MPGN, membranoproliferative glomerulonephritis.

Human Immunodeficiency Virus

Kidney disease is a frequent complication of HIV infection. The incidence of HIV-related kidney disease has decreased, and the distribution of HIV-associated kidney disease has changed with the widespread use of combined antiretroviral therapy (cART). The classic kidney disease related to HIV is a form of collapsing focal segmental glomerulosclerosis (FSGS), referred to as HIV-associated nephropathy (HIVAN). This occurs in 3.5% to 10% of HIV-infected patients. After the introduction of cART, there has been a decline in the incidence of HIVAN, with a corresponding reduction in end-stage renal disease (ESRD) attributed to HIVAN.

Pathophysiology

In the setting of HIV infection, kidney disease is mediated by factors related to the virus, host genetic predisposition, host response to infection, and environmental factors.

Genetic Susceptibility

Susceptibility to HIV-related kidney disease is most striking in patients of African descent. This predilection is associated with high frequencies of APOL1 genetic polymorphisms on chromosome 22 in this population, specifically G1 (two missense mutations) and G2 (two base pair deletion). The G1 and G2 variants confer risk for HIVAN and an HIV-associated noncollapsing form of FSGS, as well as other glomerular diseases and arteriolar nephrosclerosis. The effect is largely recessive, in that homozygous (G1/G1 or G2/G2) or compound heterozygous (G1/G2) individuals have the highest risk of HIVAN. The mechanisms by which the risk variant proteins alter kidney cell function and lead to chronic kidney disease (CKD) and ESRD remain unclear and are a matter of considerable interest and ongoing research.

Direct Viral Effects

Evidence from clinical and animal studies supports a direct role of HIV infection of renal parenchymal cells in the pathogenesis of HIVAN. Exactly how HIV infection of podocytes and tubular epithelial cells occurs and the subsequent downstream process leading to cellular injury are not entirely understood. Although renal epithelial cells do not generally express viral receptors, uptake of HIV into renal epithelial cells is thought to be mediated by transfer from infected lymphocytes. The various processes that have been implicated in HIVAN, which include effects on glomerular filtration, cellular proliferation, apoptosis, de-differentiation, and immunomodulation, can be related to the presence of HIV transcripts in affected renal parenchymal cells. Expression of HIV regulatory and accessory proteins in transgenic mice produces the glomerular and tubular features of HIVAN-like pathology, even in the absence of intact virus, supporting direct effects of HIV transcript expression in glomerular (mesangial and epithelial) and tubular cells. Expression of HIV transgenes in podocytes and renal tubular epithelial cells results in de-differentiation and/or loss of expression of important proteins (e.g., nephrin) and correlates with proliferation and tubular microcyst formation. The mechanism that drives aberrant expansion of podocyte stem cells, which are located in the parietal epithelium, remains unknown.

Immune Reaction

Chronic HIV infection is associated with polyclonal expansion of immunoglobulins. Immune complexes in the kidney may result from deposition from the systemic circulation or result from in situ deposition of immunoglobulins binding to HIV antigens. Subsequently, there is activation of inflammatory mediators, which results in secondary kidney damage, giving rise to HIV immune complex disease (HIV-ICD). The kidney infiltrate in HIV-ICD primarily consists of B lymphocytes, in contrast to HIVAN, in which there are mainly T lymphocytes and macrophages.

Clinical Presentation

The classic involvement of the kidney by HIV infection is HIVAN. Other kidney diseases include HIV-ICD, HIV-related noncollapsing FSGS, thrombotic microangiopathy, and disorders associated with nephrotoxic HIV therapies. With the introduction and widespread use of cART, there has been a decline in the incidence of HIVAN and an increasing prevalence of noncollapsing FSGS. Progression to ESRD is more likely with high-grade proteinuria, severely reduced estimated glomerular filtration rate (eGFR), hepatitis B and/or C coinfection, diabetes mellitus, extensive glomerulosclerosis, and chronic interstitial fibrosis.

Human Immunodeficiency Virus–Associated Nephropathy

The classic presentation of HIVAN is nephrotic syndrome, GFR loss, relatively bland urinary sediment, and large, often densely echogenic, kidneys on ultrasound. Most patients are normotensive and relatively edema-free, despite advanced CKD. HIVAN occurs predominantly in those of African ancestry with advanced HIV (high viral loads, CD4 counts less than 200 cells/µL), but HIVAN is occasionally diagnosed at the time of acute HIV seroconversion. Untreated, HIVAN progresses rapidly to ESRD, often in a few months.

Other Glomerular Diseases

Prolonged use of cART and increased life span of HIV-infected individuals have led to increasingly common patterns of HIV-associated CKD, including noncollapsing FSGS, HIV-ICD, arteriolar nephrosclerosis, and diabetic nephropathy. Despite the suppression of HIV replication with cART, a state of chronic inflammation and dysmetabolism persists, which is linked to diabetic nephropathy, arteriolar nephrosclerosis, and possibly FSGS. HIV-ICD is the dominant glomerular disease in HIV-positive European-derived populations and is thought to be associated with HCV coinfection. One form of HIV-ICD is a glomerulonephritis with “lupus-like” features on biopsy but which lacks both serologic and clinical evidence of systemic lupus erythematosus. In general, HIV-ICD presents with less proteinuria and higher GFR and is less likely to progress to ESRD than HIVAN. HIV-related thrombotic microangiopathy presents similarly to idiopathic forms with acute kidney injury (AKI), microscopic hematuria, and nonnephrotic proteinuria, along with features of a microangiopathic hemolytic anemia.

Medication Toxicity

cART nephrotoxicity is an important clinical problem ( Table 23.2 ). Common forms of nephrotoxicity are crystalluria and obstruction due to protease inhibitor therapy and proximal tubular damage due to tenofovir. Tenofovir-induced nephrotoxicity causes proximal tubulopathy, Fanconi syndrome, nephrogenic diabetes insipidus, AKI, and CKD. Dose adjustment of tenofovir according to eGFR is mandatory to minimize nephrotoxic effects. It is important to note that nucleoside reverse transcriptase inhibitors (NRTIs) require dose adjustment in patients with reduced GFR. Medications used to treat opportunistic infections can also cause nephrotoxicity (see Table 23.2 ).

Table 23.2

Drug-Induced Nephrotoxicity in Patients With Human Immunodeficiency Virus-1 Infection

Class	Renal Abnormality
*Nucleos(t)ide Reverse Transcriptase Inhibitors*
Abacavir	Lactic acidosis, AIN ^a, Fanconi syndrome ^a
Didanosine	Lactic acidosis, AKI, proximal tubule dysfunction, Fanconi syndrome, nephrogenic diabetes insipidus
Lamivudine	Lactic acidosis, renal tubular acidosis, hypophosphatemia ^a
Stavudine	Lactic acidosis, renal tubular acidosis, hypophosphatemia ^a
Zidovudine	Lactic acidosis
Tenofovir	Proximal tubule dysfunction with Fanconi syndrome, nephrogenic diabetes insipidus, AKI, lactic acidosis, CKD, chronic tubular injury
Adefovir	Proximal tubule dysfunction with Fanconi syndrome, AKI, nephrogenic diabetes insipidus, lactic acidosis
*Non-Nucleoside Reverse Transcriptase Inhibitors*
Efavirenz	Nephrolithiasis
*Protease Inhibitors*
Atazanavir	Nephrolithiasis, crystal nephropathy, AIN ^a
Indinavir	Crystalluria, nephrolithiasis, interstitial nephritis (AKI, CKD), papillary necrosis, hypertension, renal atrophy
Nelfinavir	Nephrolithiasis ^a
Ritonavir	AKI, hyperuricemia
Saquinavir	AKI in association with ritonavir
*Fusion or Entry Inhibitors*
Enfuvirtide	Membranoproliferative glomerulonephritis ^a
*Other Antimicrobials*
Acyclovir	AKI, crystalluria, obstructive nephropathy
Aminoglycosides	AKI, renal tubular acidosis
Amphotericin	AKI, hypokalemia, hypomagnesemia, renal tubular acidosis
Cidofovir	Proximal tubular damage, bicarbonate wasting, proteinuria, AKI
Foscarnet	AKI, hypocalcemia and hypercalcemia, hypophosphatemia and hyperphosphatemia, hypomagnesemia, nephrogenic diabetes insipidus
Pentamidine	AKI, hyperkalemia, hypocalcemia
Rifampin	Interstitial nephritis
Sulfadiazine	Proximal tubule dysfunction
Valacyclovir	Thrombotic microangiopathy

AIN, Acute interstitial nephritis; AKI, acute kidney injury; CKD, chronic kidney disease.

a Case reports.

Diagnosis

The utility of a kidney biopsy in HIV-infected individuals has been debated, as the decision to biopsy depends on how typical or atypical the clinical presentation, which alternative diagnoses seem likely, and whether an alternative diagnosis would lead to new therapy, as well as the risks and patients’ preference.

Pathology

HIV-associated kidney diseases include a broad spectrum of glomerular and tubulointerstitial pathologies secondary to HIVAN, AKI, cART-related toxicities, HIV-associated comorbidities (such as HCV infection, hypertension, and diabetes), and opportunistic infections.

Glomerular Diseases

The characteristic pathologic changes of HIVAN are observed along the full length of the nephron, including glomerular and tubulointerstitial features. Light microscopy reveals a collapse of glomerular capillaries that typically involves the entire glomerulus ( Fig. 23.1 ), visceral glomerular epitheliosis, podocyte hypertrophy and proliferation surrounding the shrunken glomerulus, and mesangial prominence and hypercellularity. Tubular injury is marked by microcystic tubular dilation, tubular atrophy, and proteinaceous casts ( Fig. 23.2 ). Many patients have a modest interstitial inflammation with lymphocytes, plasma cells, and monocytes. Immunofluorescence is generally nonspecific, and electron microscopy shows diffuse food process effacement and possible endothelial tubuloreticular inclusions (TRIs) without immune complex deposits ( Fig. 23.3 ). This classic HIVAN pathology is most common in the presence of advanced HIV disease, including AIDS. The clinical constellation of proteinuria, GFR loss, and low CD4 count is not sufficient for the diagnosis without a kidney biopsy.