Viral NephropathiesLaura H. Mariani | Jeffrey S. Berns

28HUMAN IMMUNODEFICIENCY VIRUS,

HEPATITIS C VIRUS, AND HEPATITIS B VIRUS

Human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) are among the most important viral-induced causes of kidney disease worldwide. Each can present with glomerular as well as other types of kidney disease, whereas therapy for HIV infection may also be associated with significant nephrotoxicity as well as cer-tain electrolyte and acid-base disorders. Some of the most important features of the kidney diseases associated with these viruses are shown in Table 28.1.

HUMAN IMMUNODEFICIENCY VIRUS

EPIDEMIOLOGY

Kidney disease occurs frequently in the course of HIV dis-ease and has become the fourth leading condition contrib-uting to death in acquired immunodeficiency syndrome (AIDS) patients. Up to 30% of patients with HIV in the United States have chronic kidney disease (CKD) or pro-teinuria, and HIV is a leading cause of end-stage renal dis-ease (ESRD) among young African-American men; however, the burden of kidney disease resulting from HIV worldwide, especially in sub-Saharan Africa, remains unclear, with esti-mates of CKD prevalence ranging from 5% to 50% depend-ing on the population studied. Combination antiretroviral therapy (cART) has decreased the incidence of many com-plications of HIV infection, including HIV-related kidney disease, and has improved life expectancy; as a result of the increased life span of HIV patients, the prevalence of ESRD resulting from HIV has increased. The classic kidney disease related to HIV is a form of collapsing focal segmen-tal glomerulosclerosis (FSGS) referred to as HIV-associated nephropathy (HIVAN), which occurs in 2% to 10% of HIV-infected patients. Other renal complications include fluid and electrolyte disturbances, medication toxicity, acute kid-ney injury (AKI), and immune-mediated glomerulopathy.

PATHOPHYSIOLOGY OF HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED NEPHROPATHY

GENETIC SUSCEPTIBILITYHuman immunodeficiency virus-associated nephropathy (HIVAN) has a strong racial predisposition with nearly 90% of U.S. patients living with ESRD attributed to HIVAN being of African ancestry. Even in transgenic mouse models of

253

HIVAN, only certain genetic backgrounds are susceptible to the disease. International studies have confirmed that a variety of African populations are at much greater risk compared to East Asian and European populations, possi-bly reflecting polymorphisms in the APOL1 gene. The gene encodes apolipoprotein L1 (apoL1), a protein that lyses the African parasite Trypanosome brucei brucei. The biologic mechanism by which variants in APOL1 and the apoL1 pro-tein lead to HIVAN and whether there is also a contribution of polymorphisms in the MYH9 gene (which encodes non-muscle myosin heavy chain IIA and was also associated with FSGS) remain unknown.

DIRECT VIRAL EFFECTSEvidence from clinical and animal studies supports a direct role for the HIV-1 infection of renal parenchymal cells in the pathogenesis of HIVAN. In humans, HIVAN is typically seen in patients with advanced disease with high viral loads, and the introduction of cART has decreased the incidence of HIVAN. Animal models of HIVAN include a transgenic mouse that expresses a replication-defective HIV-1 construct. These mice develop proteinuria, reduced kidney function, and histologic kidney disease nearly identical to HIVAN. Wild type littermates transplanted with kidneys from the transgenic mice develop nephropathy, but reciprocal trans-plants from wild type mice into the transgenic mice do not. Similarly, podocyte-specific expression of HIV or HIV genes supports a direct effect of the virus in kidney tissue.

HIV DNA and mRNA have been directly demonstrated in human kidney tissue. A discrepancy between HIV DNA isolated from the kidney and from peripheral mononuclear cells supports local viral replication within kidney tissue and suggests a renal epithelial reservoir for the virus. The mech-anism by which HIV enters renal epithelial cells has been unclear, as these cells lack CD4 and other known corecep-tors for HIV. Several methods have been proposed for direct infection of epithelial cells and podocytes. For instance, one study of T cells with fluorescently tagged HIV virus cocul-tured with renal tubular epithelial cells demonstrated direct viral transfer between the cells. The transfer required cell-cell adhesion but did not require CD4. Internalization of the virus resulted in the synthesis of HIV-specific proteins.

Several studies provide better understanding of the par-ticular HIV genes responsible for HIVAN. In vitro studies using transgenic mice have shown that gag (which encodes several structural proteins) and pol (which encodes several replication machinery proteins) are not necessary; however,

254 SECTION 4 — THE KIDNEY IN SYSTEMIC DISEASE

Table 28.1 Important Clinical Features of Viral Nephropathies

HIV HCV HBV

Major Risk Groups Blacks, individuals of African ancestry Adults with risk factors for chronic HCV infection

Children of HBV endemic areas

Presentation Proteinuria, nephrotic syndromeCKD with rapid progressionLarge, echogenic kidneysCD4 count <200 cells/µL

HematuriaProteinuriaHypocomplementemiaPalpable purpuraSystemic vasculitis

ProteinuriaSpontaneous remission in children

Primary Renal Pathology

Collapsing FSGSMicrocystic dilation of tubulesInterstitial inflammation

Membranoproliferative glomerulonephritis

Membranous nephropathy

Pathogenesis Direct HIV infection of the kidneyHost genetic factors

Direct HCV toxicityCryoglobulinemia

Antigen-antibody complex depositionVasculitis

Therapy cARTACE-inhibitors and ARBs

Antiviral therapyRituximabCyclophosphamidePlasmapheresis in severe cases

Antiviral therapy

ACE, Angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; cART, combination antiretroviral therapy; CKD, chronic kidney disease; FSGS, focal segmental glomerulosclerosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus.

the nef gene, a virulence factor, is necessary and sufficient to produce kidney disease. It appears particularly important in the development of the characteristic glomerular lesion, the proliferation and dedifferentiation of podocytes. Similarly, the vpr gene appears to be important in the characteristic tubular pathology.

Multiple cellular pathways are likely responsible for the HIVAN phenotype. The vpr gene upregulates the ubiquitin-like protein FAT10, which has a role in apoptosis and cell cycle arrest in the tubular epithelium and may be the cause of the tubular dilation and atrophy seen on biopsy. HIV induces a number of inflammatory mediators in tubular epithelial cells. Activation of the MAPK1,2 and Stat-3 path-ways in podocytes has been correlated with the proliferative podocyte phenotype. Transgenic mice and human glomeru-lar tissue have shown downregulation of cyclin-dependent kinase inhibitors. The mammalian target of rapamycin path-way also appears upregulated in a mouse model. Several of these pathways may become possible therapeutic targets.

CLINICAL PRESENTATION

HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED NEPHROPATHYThe classic presentation of HIVAN is nephrotic syndrome with moderate or heavy proteinuria, a urinary sediment with relatively few cells or cellular casts, and large, often densely echogenic kidneys on renal ultrasound. Most patients are normotensive and relatively edema-free despite advanced CKD. Untreated, these patients typically experience rapidly progressive kidney failure, often reaching ESRD in a few months. There have been cases of HIVAN occurring at the time of seroconversion, but the majority of cases occur late in the course of HIV disease with high viral loads and low CD4 counts (less than 200 cells/µL).

OTHER GLOMERULAR DISEASESAlthough up to 60% of kidney biopsies of HIV-infected patients reveal the typical HIVAN phenotype, several other glomerular diseases have been observed; these include minimal change disease, postinfectious glomerulonephritis, amyloidosis, and IgA nephropathy. Coinfection with hepa-titis B and C are common, with membranous nephropathy and membranoproliferative glomerulonephritis (MPGN) somewhat more often observed in such patients.

ACUTE KIDNEY INJURYThe typical causes of AKI that occur in patients without HIV infection are also seen in the HIV population. Prerenal azote-mia and acute tubular necrosis can result from volume deple-tion, sepsis, and hypotension. Nephrotoxic medications used to treat opportunistic infections are also common causes. Interstitial nephritis may result from infections such as cyto-megalovirus (CMV), candida, tuberculosis and histoplasmosis, or medications such as antibiotics and nonsteroidal antiinflam-matories. CMV-related disease can be associated with neph-rocalcinosis. Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura (HUS/TTP) are described and can be the presenting manifestation of HIV disease. The clini-cal manifestations, pathologic findings, and treatment regi-mens are similar to the idiopathic form of TTP, although the mechanism by which HIV infection leads to these thrombotic microangiopathies is not well understood. Several medica-tions, specifically acyclovir, sulfadiazine, atazanavir, and indina-vir, can result in crystal-induced obstructive AKI, with indinavir causing asymptomatic crystalluria in up to 20% of patients.

ELECTROLYTE AND ACID-BASE DISORDERSElectrolyte disorders are common in hospitalized HIV-infected patients, particularly hyponatremia, which may affect up to 30% to 50% of hospitalized patients with AIDS. Similarly,

hyperkalemia has been reported in up to 20% of hospitalized AIDS patients. These and other disturbances are the conse-quence of direct effects of HIV infection, opportunistic infec-tions, antimicrobial therapy for opportunistic infections, and cART therapy. Some of the more common electrolyte and acid-base disturbances and their mechanisms are listed in Table 28.2.

MEDICATION TOXICITYPatients with HIV infection are exposed to a variety of medi-cations with potential kidney toxicity (Table 28.3). In par-ticular, nucleoside reverse transcriptase inhibitors (NRTIs) may cause lactic acidosis. Tenofovir, a NRTI, is a well-known cause of AKI, although other drugs in this class may also cause AKI. Tubulopathies such as Fanconi syndrome and nephrogenic diabetes insipidus also occur with tenofovir. It is important to note that NRTIs require dose adjustment in patients with reduced kidney function.

DIAGNOSIS OF HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED NEPHROPATHY

PATHOLOGYKidney biopsy remains the gold standard for the diagnosis of HIVAN. Light microscopy reveals collapsing FSGS, which

Table 28.2 Common Electrolyte Disorders in Patients With Human Immunodeficiency Virus Infection

Electrolyte Disturbance

Mechanisms in HIV-Positive Patients

Hyponatremia Volume depletionSIADH caused by pulmonary and

central nervous system diseasesAdrenal insufficiency

Hypernatremia Volume depletion with impaired oral intake

Acquired nephrogenic diabetes insipidus from medications

Hyperkalemia Medication effect, especially trimethoprim and pentamadine

Hyporeninemic hypoaldosteronismAdrenal insufficiency

Hypokalemia Diarrheal losses resulting from GI tract opportunistic infections

Fanconi syndrome from adefovir, tenofovir, others

Hypocalcemia HypoalbuminemiaMedication effect, especially

pentamidine and foscarnetHypercalcemia Granulomatous disease

Disseminated CMVHypomagnesemia Renal magnesium wasting from

amphotericin and pentamidineMetabolic acidosis Diarrhea

Lactic acidosis resulting from NRTIs, especially didanosine and stavudine

Fanconi syndrome Medication effect, especially cidofovir, adefovir, and tenofovir

CMV, Cytomegalovirus; GI, gastrointestinal tract; HIV, human immunodeficiency virus; NRTIs, nucleoside reverse transcrip-tase inhibitors; SIADH, syndrome of inappropriate antidiuretic hormone.

255 CHAPTER 28 — VIRAL NEPHROPATHIES

typically involves the entire glomerulus (Fig. 28.1). Podo-cyte proliferation and hypertrophy surround the shrunken glomerulus. Tubular injury is classically marked by micro-cystic tubular dilation, tubular atrophy, and proteinaceous casts (Fig. 28.2). Tubular cells can contain eosinophilic pro-tein resorption droplets. Many patients have a modest inter-stitial inflammation with lymphocytes, plasma cells, and monocytes. Immunofluorescence is generally nonspecific. Electron microscopy shows diffuse foot process effacement and tubuloreticular structures in the endothelium without immune complex deposits (Fig. 28.3).

The clinical constellation of proteinuria, azotemia, and low CD4 count is not sufficient for diagnosis without a kid-ney biopsy; similarly large kidney size and dense kidney echogenicity on ultrasound are also insufficient. Recent small studies suggest that urinary neutrophil gelatinase-associated lipocalin (uNGAL) may be a useful noninvasive

Table 28.3 Drug-Induced Nephrotoxicity in Patients With Human Immunodeficiency Virus-1 Infection

Drug Toxicity

cART

Abacavir Lactic acidosisAtazanavir Nephrolithiasis, acute interstitial

nephritis, crystalluriaDidanosine Lactic acidosis, AKI, Fanconi

syndrome, nephrogenic diabetes insipidus

Emtricitabine Lactic acidosisIndinavir Crystalluria, nephrolithiasis, interstitial

nephritisLamivudine Lactic acidosisRilpivirine AKIRitonavir AKI, hyperuricemiaStavudine Lactic acidosisTenofovir AKI, Fanconi syndrome, lactic acidosis,

nephrogenic diabetes insipidusZidovudine Lactic acidosis

Other Antimicrobials

Acyclovir AKI, crystalluria, obstructive nephropathy

Adefovir Fanconi syndrome, AKIAminoglycosides AKI, renal tubular acidosis, Bartter-like

syndromeAmphotericin AKI, hypokalemia, hypomagnesemia,

renal tubular acidosisTrimethoprim-

sulfamethoxazoleHyperkalemia, acute interstitial

nephritisCidofovir Proximal tubular damage, bicarbonate

wasting, proteinuria, AKIFoscarnet AKI, hypo- and hypercalcemia, hypo-

and hyperphosphatemia, hypo-magenesemia, nephrogenic diabetes insipidus

Pentamidine AKI, hyperkalemia, hypocalcemiaRifampin Interstitial nephritisValacyclovir Thrombotic microangiopathy

AKI, Acute kidney injury; cART, combination antiretroviral therapy.

256 SECTION 4 — THE KIDNEY IN SYSTEMIC DISEASE

biomarker for HIVAN, indicating tubular damage. A small series of 25 HIV-positive patients with a variety of glomeru-lar disease showed that elevated uNGAL demonstrated 94% sensitivity and 71% specificity for the diagnosis of HIVAN. Currently, however, if confirmation of HIVAN and exclusion of other kidney lesions is needed for clinical decision mak-ing, a kidney biopsy is necessary.

TREATMENT

ANTIRETROVIRAL THERAPYAlthough no randomized controlled clinical trials have evaluated the efficacy of cART therapy in the prevention or treatment of HIVAN, multiple observational studies sug-gest that it is effective. On an epidemiologic basis, a plateau in the incidence of HIVAN coincided with the introduction

Figure 28.1 Focal segmental glomerulosclerosis of the collaps-ing variant seen in human immunodeficiency virus-associated nephropathy (HIVAN). (Jones methenamine silver stain, ×400 mag-nification.) (Courtesy Glen Markowitz, Columbia University.)

Figure 28.2 Tubulointerstitial disease in human immunodeficiency virus-associated nephropathy (HIVAN), characterized by tubular at-rophy, microcystic tubular dilation with proteinaceous casts, and mild interstitial inflammation. (Trichrome stain, ×200 magnification.) (Cour-tesy Glen Markowitz, Columbia University.)

of cART in the mid-1990s, and several small retrospective studies document patients with biopsy-proven HIVAN, in whom the disease either slowed or even reversed after treat-ment with cART. Modern cART may also protect against the development of HIVAN; in a retrospective study of 4000 patients with HIV infection, the risk of nephropathy was 60% lower in patients treated with cART, and there were no cases reported among patients who began cART before the development of overt AIDS.

IMMUNOSUPPRESSIONSmall, uncontrolled studies demonstrate mixed results regarding the efficacy of corticosteroids, although one small uncontrolled study in children showed an improvement in proteinuria with cyclosporine. In patients with aggressive kidney disease and prominent interstitial inflammation on biopsy, immunosuppressive therapy can be considered, but its use must also be weighed against the potential risk of worsening infections and other toxicities. With the availabil-ity of cART, the use of corticosteroids and other immuno-suppressive therapies is rarely, if ever, indicated.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERSSeveral retrospective studies demonstrate that conserva-tive therapy with angiotensin-converting enzyme inhibitors (ACE-inhibitors) and angiotensin receptor blockers may slow progression of kidney disease in HIVAN and improve overall survival; however, these are potentially confounded by concomitant cART therapy, and recommendations for renin-angiotensin-aldosterone system blockade are gener-ally extrapolated from other proteinuric kidney diseases. The specific role of these agents in the era of modern cART is poorly defined, although they are appropriate to use to treat hypertension and for the reduction of proteinuria.

DIALYSIS AND TRANSPLANTATION

Patients with HIV can be successfully treated with peritoneal dialysis or hemodialysis. Although overall survival of these patients was historically much less than other patients with ESRD, it has improved substantially with cART, and survival

Figure 28.3 Tubuloreticular inclusions in the endothelium classi-cally seen on electron microscopy in human immunodeficiency virus- associated nephropathy (HIVAN). (Electron micrograph, ×50,000 magnification.) (Courtesy Glen Markowitz, Columbia University.)

is now much closer to that of the broader dialysis popula-tion. Obviously, careful attention to universal precautions to prevent infection of other patients and dialysis-unit staff is essential.

Safe and effective kidney transplantation in HIV-infected patients was demonstrated in a prospective, nonrandom-ized trial of 150 patients with CD4 counts greater than 200 cells/µL, undetectable viral loads, and stable antiviral regi-mens across 19 U.S. transplant centers between 2003 and 2009. Patient survival at 1 and 3 years was 94.6% and 88.2%, respectively, and graft survival at 1 and 3 years was 90.4% and 73.7%, respectively. These survival rates are slightly higher than those seen in ≥65-year-old transplant recipients, another high-risk group. Overall, HIV disease course was sta-ble posttransplant. A variable CD4 drop was seen during the first year, but then recovered and was stable at the end of the study. Interestingly, there was a high rate of acute rejection (31% at 1 year), which may have been a result of difficulty with dosing immunosuppressive agents because of interac-tions with cART. These results indicate that transplantation is a reasonable option in carefully selected patients with well-controlled HIV.

HEPATITIS C

EPIDEMIOLOGY

The World Health Organization estimates that HCV infec-tion affects 130 to 170 million people worldwide. In the United States, although HCV infection has fallen from a peak of 230,000 new cases per year in the mid-1980s to less than 20,000 new cases per year more recently, 1.6% of the population is HCV-antibody positive, reflecting a high rate of chronic infection.

Large retrospective studies demonstrate an association between HCV infection and the development of CKD and ESRD. The exact incidence of nephropathy caused by HCV is unknown, and a large proportion of HCV-related disease may be undiagnosed. One study of 30 HCV-infected patients undergoing kidney biopsy at the time of liver transplanta-tion showed that 25 had an immune complex glomerulo-nephritis, with most being unsuspected and asymptomatic. The kidney disease classically associated with HCV infection was cryoglobulinemia with systemic vasculitis and MPGN, but other glomerular diseases have also been observed. Recent advances in therapy for hepatitis C liver disease and associated glomerular disease make accurate identification of HCV-related kidney disease essential.

PATHOPHYSIOLOGY

DIRECT TOXICITYDirect cytopathic effects of the HCV are thought to play a role in HCV-related kidney disease, but the exact mechanisms by which HCV affects the kidneys are unknown. Kidney tissue expresses many proteins needed for direct viral attachment, endocytosis, and cell entry, but these have not been conclu-sively demonstrated to occur in renal epithelia or other renal cells; however, several studies have shown HCV-related pro-teins and RNA in kidney tissue of patients with glomerular disease. In one study, the presence of HCV-related proteins

257 CHAPTER 28 — VIRAL NEPHROPATHIES

in the mesangium was associated with greater proteinuria. One proposed mechanism involves the upregulation of mesangial toll-like receptor 3 (TLR-3), which has been dem-onstrated in kidney biopsy tissue of patients with HCV-related MPGN and is associated with chemotactic and inflammatory host responses.

CRYOGLOBULIN-MEDIATED INJURYChronic HCV infection causes B cells to overproduce mixed cryoglobulins (type II and III); the cryoglobulins may form with or without viral protein immune complexes. In type II cryoglobulinemia, polyclonal IgG associates with a mono-clonal immunoglobulin (typically IgM) to form rheumatoid factor. Type III cryoglobulinemia, composed of polyclonal immunoglobulins, is also seen in HCV infection. Cryoglobu-lins are deposited in the mesangium and glomerular cap-illaries. Specifically, the IgM κ component of rheumatoid factor binds fibronectin in the mesangial matrix, leading to complement activation, inflammatory cytokine release, vas-culitis, fibrinoid necrosis, and crescent formation.

CLINICAL PRESENTATION

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITISMembranoproliferative glomerulonephritis in the setting of cryoglobulinemia is the most common glomerular disease observed with HCV infection. It can develop years or even decades after the initial infection. Cryoglobulinemia often presents with a systemic vasculitis, commonly with palpable purpura that typically involves the lower limbs, arthralgias, neuropathy, and nonspecific symptoms of fever, fatigue, and malaise; however, many patients with cryoglobulinemia are asymptomatic or have mild nonspecific symptoms. Kid-ney disease presents as hematuria, proteinuria, and acute or chronic reductions in glomerular filtration rate (GFR). Hypertension can be severe, affecting up to 80% of patients, and up to 5% of patients present with severe, oliguric AKI. Laboratory evaluation typically shows marked hypocomple-mentemia, characterized by a greater reduction in C4 than C3, as well as positive anti-HCV and HCV RNA. Serum ami-notransferases are elevated in 70% of patients.

The natural history of this disease can be variable. An Italian series of 146 patients showed that overall survival at 10 years was 80%. Risk factors for ESRD included older age, male gender, and higher serum creatinine and greater pro-teinuria at the time of diagnosis. Cardiovascular disease was the primary cause of death, but infection, hepatic failure, and malignancy were also seen. At 5 years, 11% of patients reached kidney failure.

MEMBRANOUS NEPHROPATHYSmall case series suggest an association between chronic HCV infection and membranous nephropathy. In one study of HCV-positive transplant patients, 3.6% developed mem-branous nephropathy within 5 years. A recent biopsy series from Japan indicated that 14% of HCV-positive patients who underwent kidney biopsy had membranous nephropathy; however, HCV overall accounts for a very small fraction of all cases of membranous nephropathy. In most series, patients with membranous nephropathy in the setting of HCV infec-tion have normal or only slightly low complement levels and do not have cryoglobulinemia.

258 SECTION 4 — THE KIDNEY IN SYSTEMIC DISEASE

POLYARTERITIS NODOSAPolyarteritis nodosa (PAN), although classically associated with hepatitis B infection, has also been observed in patients with chronic HCV infection. In one series of 161 patients with HCV-related vasculitis, 19% were diagnosed with PAN. Compared to cryoglobulinemic vasculitis, these patients had a more severe presentation but a higher rate of clinical remission. Five-year survival was 86% for all types of vasculi-tis. Interestingly, cryoglobulin levels did not differ between those patients who presented with PAN versus those with cryoglobulinemic vasculitis.

OTHER GLOMERULAR DISEASESSeveral other glomerular diseases have been reported in the setting of HCV infection, including FSGS, IgA nephropathy, postinfectious glomerulonephritis, immunotactoid glomer-ulopathy, and fibrillary glomerulonephritis. Immunotac-toid glomerulopathy and fibrillary glomerulonephritis may share a pathogenesis involving glomerular immunoglobu-lin deposition. On electron microscopy, random fibrillary deposits are seen in the mesangium and glomerular capil-laries, which are larger than those seen with amyloidosis (16 to 24 nm in fibrillary GN, 30 to 50 nm in immunotactoid glomerulopathy, and 10 nm in amyloid). These fibrils do not demonstrate any immunoglobulin light-chain specificity and are Congo-red negative.

DIAGNOSIS

Kidney disease frequently lags many years behind initial infection with HCV and does not appear to correlate well with disease activity in the liver. Cryoglobulin levels are vari-able and are positive in many patients without kidney dis-ease. As such, kidney biopsy remains the gold standard for diagnosis of HCV-associated glomerular disease.

The classic histologic pattern of MPGN is characterized by an expanded and hypercellular mesangium, endocapillary proliferation, and thickened glomerular capillary loops on light microscopy. There is infiltration of the glomerulus by inflammatory cells, including mononuclear cells. Silver stain-ing shows double contour glomerular basement membranes resulting from immune complex deposition and mesangial cell matrix interposition between the GBM and the endo-thelial cell, with a new basement membrane forming around these deposits (Fig. 28.4). Immunofluoresence typically shows IgG and C3 granular deposits. Electron microscopy shows subendothelial deposits that can be fibrillary.

TREATMENT

ANTIVIRAL THERAPYInterferon alpha (IFN-α) has been used with success both as monotherapy as well as in combination therapy. A recent metaanalysis of 11 studies with IFN-α based therapies showed a statistically significant decrease in mean protein-uria of 2.71 g/24 h but a decrease in creatinine by only 0.23 mg/dl with IFN-α treatment. As reported in previous series, those patients with a sustained virologic response to therapy did better than nonresponders. For example, in one trial of 53 patients (40 with kidney involvement) with cryoglobulinemic vasculitis who were randomized to conservative therapy versus IFN-α, 15 of 27 patients in the

IFN-α arm who had a virologic response showed significant improvement in their clinical symptoms and labs, including serum creatinine level. When the medication was stopped, all 15 patients experienced a recurrence of both cryoglobu-linemia and viremia.

Side effects of IFN-α can be severe and include depres-sive symptoms, malaise, nausea, myalgias, and low-grade fevers. Flulike symptoms are most severe at initiation of therapy and tend to improve over time. Importantly, there have been reports of new onset or worsening of glomerular disease in patients treated with IFN-α for HCV and other conditions.

Pegylated IFN-α (PEG-IFN) is a slow release form of the treatment, which can be dosed weekly and is more com-monly used than standard IFN-α. Clearance of PEG-IFN may be reduced in patients with advanced kidney disease; accord-ingly, guidelines recommend against its use in patients with eGFR less than 15 mL/min/m2 and in dialysis patients. The most frequent treatment course is 12 months, but longer duration of therapy has been shown in some small series to have higher rates of virologic response, especially in HCV genotype 1, which is generally less responsive to therapy.

Combination therapy with IFN-α and ribavirin leads to improved rates of virologic response and has been shown in several studies to be more effective in treating HCV-related glomerulonephritis than IFN-α monotherapy; however, the kidneys clear ribavirin, and accumulation of the drug in patients with reduced GFR can lead to severe hemolytic ane-mia. Although there are small case series in which ribavirin has been used safely at reduced dosages, it is generally best avoided in patients with an eGFR less than 50 mL/min/1.73 m2.

The NS3/4A protease inhibitors, telaprevir and bocepre-vir, are approved for use in combination with ribavirin and PEG-IFN for treatment of HCV. These agents have been shown as having much higher virologic response rates, espe-cially in genotype 1, but they have not yet been studied for use in HCV-associated glomerular disease.

IMMUNOSUPPRESSIVE THERAPY

In the setting of progressive, severe AKI and nephrotic syndrome, patients are typically treated with aggressive

Figure 28.4 Membranoproliferative glomerulonephritis seen in hepatitis C virus infection with typical glomerular basement membrane double contours (arrowheads). (Jones methenamine silver stain.) (Courtesy Glen Markowitz, Columbia University.)

immunosuppressive therapy before antiviral therapy. Plas-mapheresis may be used to remove circulating cryoglobulins and steroids are often used to control the acute inflamma-tory response. Cyclophosphamide has also been used in this setting. However, increased viral replication caused by immunosuppression remains a concern. Rituximab, a monoclonal antibody directed against the B cell antigen CD20 that causes B cell depletion and decreased antibody production, may be useful. In a clinical trial of 59 patients with severe cryoglobulinemic vasculitis randomized to ritux-imab versus conventional therapy (steroids, cyclophospha-mide, azathioprine, and plasmapheresis), treatment with conventional therapy was associated with more treatment failures than rituximab. Serious adverse effects and deaths were similar in both groups.

TRANSPLANTATION

LIVER DISEASEPatient and graft survival are lower in HCV-positive patients following kidney transplantation compared to HCV-negative patients. The increased risk of death has been attributed to higher rates of infectious complications and liver failure. Importantly, patients with mild and well-compensated liver disease appear to do quite well. A recent study reported on 44 HCV-positive patients who underwent kidney trans-plantation with pre- and posttransplant liver biopsies, and 77% of patients showed stable or improved liver histology. This report also demonstrated improved patient survival at 6 months compared to those patients who remained on the transplant waiting list.

KIDNEY DISEASERecurrence or de novo glomerulonephritis, including MPGN and membranous nephropathy, can occur after kidney transplantation in HCV-infected patients. Addition-ally, renal thrombotic microangiopathy has been described. Antiviral treatment is challenging in this setting, as IFN is frequently associated with acute kidney transplant rejection. IFN increases expression of HLA antigens on cell surfaces and increases cytokine production. The risk of acute rejec-tion may be greater than 50% and is often refractory to ther-apy. Monotherapy with ribavirin has been effective in some series, even when levels of viremia did not decrease, but, as in native kidney disease, ribavirin generally must be avoided when eGFR is less than 50 mL/min/1.73 m2.

HEPATITIS B

EPIDEMIOLOGY

Hepatitis B virus is a major source of morbidity and mor-tality worldwide. Affecting more than 2 billion people and resulting in 350 million chronic hepatitis B infections, it is much more infectious than either HIV or HCV. The preva-lence of chronic infection varies widely based on geography: in the United States and Western Europe, HBV prevalence is less than 1%, whereas in Southeast Asia, Sub-Saharan Africa, and China prevalence can be as high as 15% to 20%. This disparity reflects highly effective vaccine programs in more developed countries and high rates of perinatal

259 CHAPTER 28 — VIRAL NEPHROPATHIES

transmission in endemic areas, with up to 90% of HBV verti-cal transmissions developing into chronic infections. In the United States, risk factors for infection include intravenous drug use and multiple sexual partners. In contrast to perina-tal infections, those infections acquired in adulthood com-monly result in recovery, with only 5% to 10% resulting in chronic infection.

Chronic HBV infection is associated with several kidney diseases, including membranous nephropathy, MPGN, and PAN. These disorders, especially membranous nephropathy, most commonly occur in the setting of chronic infection and thus most frequently affect children in endemic areas. The heterogeneity of presentation, pathology, and natural his-tory has made diagnosis and therapeutic trials challenging.

PATHOPHYSIOLOGY

DIRECT TOXICITYIndirect evidence of HBV as the causal agent for these kid-ney diseases comes from epidemiologic studies, including demonstration of a decrease in incidence of these diseases following the introduction of vaccine programs. Addition-ally, other studies have demonstrated viral antigens as well as viral DNA and RNA in glomerular and renal tubular epi-thelial cells of affected patients, supporting the hypothesis of viral transcription occurring within the kidney and direct toxicity of the virus itself.

IMMUNE MEDIATEDChronic HBV-associated membranous nephropathy is most commonly seen in children living in endemic areas. It is thought that the subepithelial deposits seen in this form of secondary membranous nephropathy are composed of HBe antigen (HBeAg) and anti-e antibody (anti-HBe) com-plex. This is supported by the clinical observation that this disease often remits when the patient undergoes clearance of the HBeAg and seroconversion to anti-HBe. Further, it has been reported that children who develop membranous nephropathy in the setting of HBV infection have decreased cellular immune response to the virus, resulting in reduced clearance of the antigen compared to chronic carriers who do not develop membranous nephropathy.

MPGN in the setting of HBV is likely caused by the deposi-tion of circulating antigen-antibody immune complexes in the mesangium and subepithelial space. Deposits contain-ing both HBeAg and hepatitis B surface antigen (HBsAg) have both been reported, along with IgG and C3. A mesan-gial proliferative lesion has also been reported with promi-nent IgA mesangial deposition. In some case series, these IgA deposits appear to exhibit a pattern similar to HBsAg and hepatitis B core antigen (HBcAg) deposits; however, it is unclear if this is an incidental finding, as a HBsAg carrier state is less common in IgA nephropathy than in membra-nous nephropathy or MPGN.

VASCULITISThere is a known association between PAN and HBV infec-tion. In HBV-associated PAN, antigen-antibody complexes deposit in vessel walls, producing a clinical syndrome that is identical to idiopathic PAN, with vasculitis involving large and medium-sized vessels, leading to glomerular ischemia with hypertension and AKI.

260 SECTION 4 — THE KIDNEY IN SYSTEMIC DISEASE

DIAGNOSIS

CLINICAL PRESENTATIONThe most common pathologic lesion in HBV-related kidney disease is membranous nephropathy. Patients typically pre-sent with a classic nephrotic syndrome, including proteinuria, hyperlipidemia, hypoalbuminemia, and lower extremity edema. In children or adults from endemic areas, the pre-ceding HBV infection is likely to be asymptomatic, whereas adults in low prevalence regions are more likely to have a his-tory of acute hepatitis. There is a male predominance, which is especially strong in children (up to 80%). The natural his-tory of this disease is not well studied. Several small studies in children suggest that spontaneous remission is common, occurring in up to 60% of patients. The long-term prognosis of those who do not undergo remission is not well known. In adults, remission is less common, and CKD and ESRD may develop in a significant proportion of patients.

The clinical presentation of patients with HBV-associated PAN is similar to idiopathic PAN and classically includes hypertension, reduced GFR, and systemic symptoms such as fatigue, malaise, and fever. Other organ system involve-ment, including the skin, nervous system, and gastrointesti-nal tract, may be present.

LABORATORY DATALaboratory evaluation should include HBV DNA to confirm active replication as well as determination of antigen status, including HBeAg, HBsAg, and HBcAg. Other secondary causes of membranous nephropathy should be excluded, and common coinfections, including hepatitis C and HIV, should also be tested. Unlike idiopathic membranous nephropathy, complement levels may be low. Liver function tests may be normal or only minimally elevated.

PATHOLOGYKidney biopsy is the gold standard for diagnosing glomeru-lar disease in the setting of HBV infection. As noted ear-lier, the most common pathology observed is membranous nephropathy, which is characterized by thickening of the glomerular capillary walls due to immune complex deposi-tion. With silver or trichrome staining, characteristic spikes of the glomerular basement membrane can be seen extend-ing around these deposits (Fig. 28.5). Immunofluorescence demonstrates granular IgG and C3 deposition (Fig. 28.6). Electron microscopy shows classic intramembranous and subepithelial deposits (Fig. 28.7). Some series have reported that membranous nephropathy in the setting of HBV may be differentiated from idiopathic membranous nephropa-thy by the presence of mesangial proliferation and occa-sional subendothelial deposits. Other pathologic patterns have been observed in the setting of HBV infection, includ-ing MPGN, IgA nephropathy, and a small vessel vasculitis.

TREATMENT

Immunosuppressive therapy has not been shown to be effective for HBV-related kidney disease; in fact, steroid therapy is associated with increased levels of viral DNA, and worsening of liver disease has been reported when steroids are withdrawn. Given these findings, steroid monotherapy is not recommended in HBV-related kidney diseases. The

Figure 28.5 Membranous glomerulonephritis seen in the setting of hepatitis B infection. Thickened glomerular basement membrane with spikes extending around immune deposits. (Jones methenamine silver stain, magnification ×400.) (Courtesy Glen Markowitz, Columbia University.)

Figure 28.6 Immunofluoresence with granular deposition of IgG in membranous glomerulonephritis resulting from hepatitis B infec-tion. (Magnification ×400.) (Courtesy Glen Markowitz, Columbia University.)

Figure 28.7 Electron microscopy with subepithelial immune de-posits in membranous glomerulonephritis resulting from hepa-titis B infection. (Magnification ×6000.) (Courtesy Glen Markowitz, Columbia University.)

combination of glucocorticoids with antiviral therapy may be safer than steroids alone and may be reasonable for patients with vasculitis or rapidly progressive glomerulone-phritis. Plasmapheresis may also be indicated in the setting of rapidly progressive glomerulonephritis.

Antiviral therapy, with IFN-α and lamivudine therapy, has been studied extensively for treatment of HBV, including in patients with kidney disease, and it is effective at increas-ing rates of remission of proteinuria and HBV seroconver-sion. In the landmark study of lamivudine therapy in HBV infection, 10 patients with membranous nephropathy were compared to 12 historic controls from the prelamivudine era. Patients treated with lamivudine showed dramatic reductions in proteinuria, improved liver function tests, and increased clearance of HBV DNA. After 3 years of follow-up, none of those treated with lamivudine were on dialysis as compared with 7 of the historic controls. These findings have been confirmed in subsequent trials. Of note, lamivu-dine use is associated with a high rate of viral resistance with prolonged use.

Other antiviral agents have not been well studied in this setting. Adefovir and tenofovir are known to be nephro-toxic and are generally avoided, especially in patients with reduced GFR. There are case reports suggesting that ente-cavir may play a role in treatment of HBV-associated mem-branous nephropathy.

TRANSPLANTATION

Hepatitis B infection is not a contraindication to kidney transplantation. Although some studies, including a 2005 metaanalysis, report decreased patient survival compared to patients who are not infected, many of these studies were undertaken before modern antiviral therapies. More recent studies including patients treated with lamivudine demon-strate higher patient and graft survival.

Reactivation of viremia after transplant is more common in patients with HBeAg positivity or detectable HBV DNA pretransplant, but this can occur in all patients because of immunosuppression exposure. Although not well studied in kidney transplant patients, a preventative approach is generally recommended to prevent reactivation, and this approach is based on other populations including liver transplant patients and HBV-positive patients undergo-ing chemotherapy. Entecavir is generally recommended because of its decreased incidence of resistance, especially as several years of therapy may be indicated. As with hepati-tis C, interferon therapy should not be used because of the high risk of acute, refractory kidney transplant rejection.

261 CHAPTER 28 — VIRAL NEPHROPATHIES

BIBLIOGRAPHYChen P, Chen BK, Mosoian A, et al: Virological synapses allow HIV-1

uptake and gene expression in renal tubular epithelial cells, J Am Soc Nephrol 22:496-507, 2011.

D’Amico G: Renal involvement in hepatitis C infection: cryoglobulin-emic glomerulonephritis, Kidney Int 54:650-671, 1998.

De Vita S, Quartuccio L, Isola M, et al: A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis, Arthritis Rheum 64:843-853, 2012.

Feng B, Eknoyan G, Guo ZS, et al: Effect of interferon-alpha-based antiviral therapy on hepatitis C virus-associated glomerulonephritis: a meta-analysis, Nephrol Dial Transplant 27:640-646, 2012.

Gupta SK, Eustace JA, Winston JA, et al: Guidelines for the manage-ment of chronic kidney disease in HIV-infected patients: recommen-dations of the HIV Medicine Association of the Infectious Diseases Society of America, Clin Infect Dis 40:1559-1585, 2005.

Johnson RJ, Gretch DR, Yamabe H, et al: Membranoproliferative glo-merulonephritis associated with hepatitis C virus infection, N Engl J Med 328:465-470, 1993.

Kamar N, Sandres-Saune K, Selves J, et al: Long-term ribavirin therapy in hepatitis C virus-positive renal transplant patients: effects on renal function and liver histology, Am J Kidney Dis 42:184-192, 2003.

Kopp JB, Nelson GW, Sampath K, et al: APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy, J Am Soc Nephrol 22:2129-2137, 2011.

Lucas GM, Eustace JA, Sozio S, et al: Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study, AIDS 18:541-546, 2004.

Markowitz GS, Cheng JT, Colvin RB, et al: Hepatitis C viral infection is associated with fibrillary glomerulonephritis and immunotactoid glomerulopathy, J Am Soc Nephrol 9:2244-2252, 1998.

Misiani R, Bellavita P, Fenili D, et al: Interferon alfa-2a therapy in cryo-globulinemia associated with hepatitis C virus, N Engl J Med 330:751-756, 1994.

Patel HV, Kute VB, Vanikar AV, et al: Clinical outcome of renal trans-plantation in end-stage renal disease patients with positive pretrans-plantation hepatitis B surface antigen, Transplant Proc 44:72-74, 2012.

Ramos-Casals M, Stone JH, Cid MC, et al: The cryoglobulinaemias, Lan-cet 379:348-360, 2012.

Rosenstiel P, Gharavi A, D’Agati V, et al: Transgenic and infectious ani-mal models of HIV-associated nephropathy, J Am Soc Nephrol 20:2296-2304, 2009.

Roth D, Gaynor JJ, Reddy KR, et al: Effect of kidney transplantation on outcomes among patients with hepatitis C, J Am Soc Nephrol 22:1152-1160, 2011.

Saadoun D, Terrier B, Semoun O, et al: Hepatitis C virus-associated polyarteritis nodosa, Arthritis Care Res (Hoboken) 63:427-435, 2011.

Stock PG, Barin B, Murphy B, et al: Outcomes of kidney transplantation in HIV-infected recipients, N Engl J Med 363:2004-2014, 2010.

Trullas JC, Cofan F, Tuset M, et al: Renal transplantation in HIV-infected patients: 2010 update, Kidney Int 79:825-842, 2011.

Wyatt CM, Meliambro K, Klotman PE: Recent progress in HIV-associ-ated nephropathy, Annu Rev Med 63:147-159, 2012.

Zheng XY, Wei RB, Tang L, et al: Meta-analysis of combined therapy for adult hepatitis B virus-associated glomerulonephritis, World J Gastro-enterol 18:821-832, 2012.