Viral Glomerulonephritis

Warren Kupin

Viral diseases represent a significant and often unrecognized cause of glomerular disease both in the United States and worldwide.¹,² Viruses are associated with a variety of pathways leading to glomerular disease, which are not mutually exclusive or unique to a single virus species (Table 47.1). The main exception to this pattern is the singular association of type II cryoglobulinemia from IgMκ-IgG immune complexes with a hepatitis C infection, which does not occur with any other viral infection. Moreover, many viruses employ more than one pathway for mediating glomerular injury and can be associated with a diverse range of glomerular syndromes. The two primary pathways for viral-induced renal injury are the direct viral infection of renal tissue and the presence of viralinduced immune complex deposition in the kidney.

This chapter will detail the current understanding of the epidemiology, clinical presentation, diagnostic workup, pathogenicity, and therapeutic interventions for the spectrum of glomerular syndromes caused by different viral infections.

HEPATITIS C

Epidemiology

The hepatitis C virus (HCV) is the leading cause of cirrhosis and the need for liver transplantation in the United States.³ HCV is an enveloped, spherical, positive-stranded RNA virus that belongs to the family Flaviviridae and has been assigned its own individual genus, Hepacivirus. This is the same viral family as yellow fever and dengue. Approximately 170 million people worldwide are chronic carriers of HCV, which represents 70% to 80% of all patients exposed to this virus as compared to a carrier rate of 15% for patients exposed to the hepatitis B virus (HBV).⁴ According to the National Health and Nutrition Examination Survey (NHANES), there are 4.1 million people with HCV in the United States, accounting for 1.6% of the population.⁵

The most common methods for the acquisition of HCV are percutaneous exposure, especially from intravenous drug abuse (60%); nosocomial exposure due to failure to adhere to universal precautions; blood transfusions and blood products (prior to enzyme-linked immunosorbent assay [ELISA] screening); and the use of solvent detergents and interpersonal exposure (vertical transmission/sexual partners).⁶ Once established in a carrier state, 30% of patients will eventually develop cirrhosis.

Differences in nucleotide sequences allow for the subclassification of HCV into six major genotypes (1 through 6) and further subgenotypes (la and 1b, 2a and 2b, 3a and 3b, and 4a). These genotypes show significant geographic heterogeneity and differ not by virulence but by response to interferon (IFN) therapy.⁷ The following data show the worldwide distribution of the different genotypes: Genotype 1 is present in 60% to 70% of HCV isolates in the United States; genotype 2 is found in the Caribbean and in Southeast Asia; genotype 3 is found in Asia; genotype 4 is noted in Africa and the Middle East; and genotypes 5 and 6 are found in both South Africa and Southeast Asia.⁸

The Pathophysiology of Infection

HCV is a hepatotropic virus that directly enters into hepatocytes through specific receptors: CD81, the Low density lipoprotein (LDL) receptor, the DC-SIGN, the L-SIGN, the human scavenger receptor SR-B1, and claudin-1.⁹,¹⁰ Viral tropism exists for many other cell types, especially monocytes and B and T cells. After exposure to HCV, both humoral and cell-mediated immunity play a role in an effort to contain viral replication. IgG antibodies directed against both structural (envelope proteins El and E2) and nonstructural (NS3, NS4, NS5) proteins are almost universally present in HCV patients, but their presence does not correlate with viral clearance.¹¹ In fact, clearance of HCV can occur even in the absence of an antibody response.¹² The key element in achieving HCV control lies in the CD8 cytotoxic T-cell response in conjunction with natural killer (NK) cell proliferation. Production of IFN by these cells is downregulated in HCV carriers, thus allowing for viral replication, and this finding has led the way for the use of exogenous IFN as a therapeutic modality.¹³

The antibody response to HCV is measured through an ELISA, which does not distinguish between the individual targets of the IgG response. A recombinant immunoblot assay
(RIBA) can be used for confirmation, and this test can provide individual antibody specificities. There is no clinical relevance for measuring IgM antibodies to HCV because the detection of viremia is a more sensitive marker for acute and chronic infection. Following a positive ELISA/RIBA, the detection and quantification of HCV RNA is needed to determine the viral burden.¹⁴ A reverse transcriptase polymerase chain reaction (RT-PCR) will provide not only a diagnostic value for HCV replication but also a means of following the response to therapy.

TABLE 47.1 Mechanisms of Viral Mediated Glomerular Disease

Direct
	Cytopathic effect on glomerular mesangial or epithelial cells
		HIV
			HIV-associated nephropathy
		CMV
			Glomerulitis/transplant glomerulopathy
		Parvovirus
			Collapsing FSGS
	Cytopathic effect on glomerular endothelial cells
		CMV
			Thrombotic microangiopathy
		HIV
			Thrombotic microangiopathy
		Parvovirus
			Thrombotic microangiopathy
		Hantavirus
			Mesangial proliferative glomerulonephritis/nephrotic syndrome
	Deposition of or in situ formation of immune complexes
		Hepatitis C
			Type I membranoproliferative glomerulonephritis
		HIV
			HIV immune complex disease of the kidney
		Parvovirus
			Acute proliferative glomerulonephritis
			IgA nephropathy
		Hepatitis B
			Membranous glomerulopathy
			Membranoproliferative glomerulonephritis
			Polyarteritis nodosa
			IgA nephropathy
		Hepatitis A
			Acute proliferative glomerulonephritis
			IgA nephropathy
Indirect
	Stimulation of host immune response – Cytokines/chemokines/growth factors
		HIV
		Hantavirus
		Hepatitis B virus
		Coxsackievirus B
CMV, cytomegalovirus; FSGS, focal segmental glomerulosclerosis.

There are two special circumstances where the use of ELISA screening alone for HCV does not provide a high enough degree of specificity and must be complemented by a RT-PCR. These exceptions occur in patients unable to generate an antibody response to HCV and include HIV patients and patients with end-stage renal disease (ESRD). Approximately 5% to 10% of patients in these groups will have a negative ELISA but a positive RT-PCR. In both of these circumstances, reliance on ELISA screening is not enough to exclude active HCV infection.

Glomerular Syndromes

Extrahepatic disease is present in 30% to 40% of patients with chronic HCV infection and includes the following syndromes: mixed cryoglobulinemia with or without membranoproliferative glomerulonephritis type I (MPGN), autoimmune thyroiditis, porphyria cutanea tarda, Sjögren syndrome, pulmonary fibrosis, Mooren corneal ulcers, lichen planus, and diabetes mellitus.¹⁵ In addition to MPGN type 1, HCV has been associated with a variety of other glomerular lesions, including membranous glomerulonephritis (GN), IgA nephropathy, postinfectious GN, focal and segmental GN, antineutrophil cytoplasmic antibodies (ANCA), positive vasculitis, and fibrillary glomerulonephritis (Table 47.2).¹⁶
In addition, a recent biopsy survey demonstrated the unexpected presence of diabetic nephropathy in 18% of HCV patients due to the high incidence of type II DM in HCV patients.¹⁷

TABLE 47.2 Glomerular Syndromes of Hepatitis B and Hepatitis C

Hepatitis B
	Acute proliferative glomerulonephritis
	Membranous nephropathy
	Type I MPGN
	FSGS
	Polyarteritis nodosa
Hepatitis C
	Type I MPGN
	Membranous nephropathy
	FSGS
	IgA
	Diabetic nephropathy
MPGN, membranoproliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis; IgA, immunoglobulin A.

Two important common findings are present among the diverse group of renal lesions seen with HCV: a lack of correlation with the degree of HCV liver disease and the ubiquitous presence of active HCV viremia.¹⁸

Membranoproliferative Glomerulonephritis Type I

MPGN type I comprises >85% of the glomerular lesions seen in HCV patients.¹⁹ An essential characteristic of HCVrelated MPGN in 80% of patients is the concomitant presence of cryoglobulinemia. In the Brouet classification, cryoglobulinemia is divided into three distinct types with the key differentiation among them being the nature of the protein that forms the cold dependent insoluble complex.²⁰ In each type of cryoglobulinemia, the primary protein is an immunoglobulin, usually an IgM antibody. In type 2 and Type 3 cryoglobulinemia, the IgM molecule targets the Fab or Fc portion of an IgG antibody. The difference between these two types lies in the character of the IgM antibody. In type 2 cryoglobulinemia, previously called mixed essential cryoglobulinemia, the IgM is a monoclonal IgMκ; whereas in type 3 cryoglobulinemia, the IgM is polyclonal. This IgM antibody for both types of cryoglobulinemia in HCV has rheumatoidlike activity. Unrecognized HCV is now considered to have been the cause of >90% of all previously described cases of mixed essential cryoglobulinemia.²¹

The IgG antibody that is the target of the IgM antibody in both type 2 and type 3 cryoglobulinemia has anti-HCV properties and is the antibody measured by the standard ELISA used for the diagnosis of HCV infection. These IgG antibodies target the HCV circulating RNA and the envelope proteins El and E2 and are complement fixing of the IgG1 and IgG3 subclasses. Consequently, the cryoglobulin immune deposit consists of IgMκ-IgG-E2/HCV RNA and is exceptionally large, resulting in deposition exclusively in the subendothelial space of the glomerular capillaries.²²

On renal biopsy, instead of the typical subendothelial deposits seen in idiopathic MPGN type 1, HCV patients demonstrate extremely large pseudothrombi extending from the subendothelial space into the capillary lumen. On light microscopy these large, eosinophilic deposits can be easily confused with microthrombi such as those seen in a thrombotic microangiopathy, but on immunofluorescence and electron microscopy, their origin is clearly identified as being part of an immune deposit.

The typical Immunofluorescent pattern seen in the glomeruli of HCV patients is granular staining for IgM, IgG, C3, and C4. In addition, light chain staining reveals the predominant deposition of κ light chains in conjunction with IgM, indicating a clonal origin of this antibody.

Measurable cryoglobulinemia is present in approximately 50% of patients, regardless of the HCV genotype and geographic location. Typically, the cryocrit, a reflection of the quantity and potential pathogenicity of the cryoglobulins, is >2%. Importantly, despite the frequency of cryoglobulinemia, these immune complexes are clinically symptomatic in only 5% of patients.²³

HCV-related cryoglobulinemia is rarely restricted to renal involvement alone and in >70% of cases, it is also associated with cutaneous, neurologic, and/or gastrointestinal disease.²⁴ The presence of multiorgan dysfunction and renal disease in a patient with long-standing HCV should raise the suspicion of cryoglobulinemia. Renal disease develops significantly more often with type II cryoglobulinemia as compared to type III cryoglobulinemia, possibly related to the solubility, charge, and size of the immune complexes.²⁵

The clinical presentation seen with MPGN is typical of a patient with acute nephritis: new onset severe hypertension, acute kidney injury, active urinary sediment, and either nonnephrotic or nephrotic range proteinuria. Demographically, although more men than women are hepatitis C carriers (64% versus 36%), cryoglobulinemia tends to occur more frequently in women (56%).²⁶ This may have to do with the higher frequency of a TH2 response in women from a chronic antigenic stimuli like HCV, resulting in B-cell overactivity and consequent plasma cell antibody production.

There is an important time sequence leading to the development of MPGN from cryoglobulinemia in HCV patients. Initially, HCV patients demonstrate type III cryoglobulinemia as an early response to the HCV carrier state, and this phase occurs between 5 to 10 years after the acquisition of HCV After 10 to 15 years in select patients, this type III cryoglobulinemia with a polyclonal IgM eventually transitions to a monoclonal IgM, changing it to a more virulent type II cryoglobulinemia.

Noncryoglobulinemic Membranoproliferative Glomerulonephritis

Not every case of type I MPGN secondary to HCV is related to the presence of cryoglobulinemia.²⁷ In 20% of MPGN cases in HCV patients, there is no evidence on renal biopsy of cryoglobulin deposition. These patients have the typical subendothelial immune deposits seen with type I MPGN, but their composition is distinct from the large eosinophilic pseudothrombi seen with cryoglobulinemia. HCV viral antigens, IgM and IgG, along with C3, are present by immunofluorescence.²⁸ In this circumstance, MPGN occurs in isolation from any systemic signs of vasculitis, and hypocomplementemia is not predictable as it is for cryoglobulinemia.

Laboratory Evaluation of Membranoproliferative Glomerulonephritis

Subclinical cases of MPGN have been reported from autopsy series of patients with HCV A 5% incidence of HCV renal disease that was predominantly MPGN was noted, demonstrating the need for early detection. In addition, for patients
undergoing liver transplantation who underwent routine renal biopsies, unsuspected MPGN was noted in 10% to 20% of samples in the presence of normal renal function.²⁹ This unsuspected frequency of MPGN in liver transplant recipients may explain the decline in renal function that occurs over time after transplantation, which previously may have been ascribed to calcineurin toxicity or pretransplant hepatorenal syndrome.

Clinically, the presence of HCV renal disease can be detected by the presence of albuminuria. In the NHANES study, the odds ratio for albuminuria was 1.84 in HCVpositive patients.³⁰ The urinalysis findings of patients with cryoglobulinemia are consistent with a nephritic syndrome, and both dipstick and microscopic analyses of urine samples are recommended at regular intervals in HCV patients.³¹

Prior to a renal biopsy, the presence of type II cryoglobulinemia can lend strong support for the presence of MPGN. Cryoglobulinemia is associated with activation of the classical pathway of complement, leading to systemic consumption of C3 and C4. It is rare to have clinically significant cryoglobulinemia in the absence of markedly depressed levels of both C3 and C4. In addition to directly measuring the cryoglobulin concentration, an indirect assessment of the presence of cryoglobulinemia is the presence of rheumatoid factor activity. The IgM monoclonal or polyclonal antibody directed against the HCV IgG antibody has crossover rheumatoid activity, which may provide an indirect quantitative reflection of the amount of cryoglobulins present. The assay for the measurement of cryoglobulin concentrations has been complicated with a high false-negative rate due to frequent improper collection and handling techniques, supporting the use of the rheumatoid factor in general clinical care.³²

In patients with type II cryoglobulinemia, a serum protein and immune electrophoresis will show a gamma globulin spike of IgMκ. A free light assay will confirm the presence of abundant kappa light chain production with a kappa/lambda ratio >2.0. The selective presence of this unique type of monoclonal antibody is characteristic of the cryoglobulinemia of all genotypes of HCV

Pathogenesis of Membranoproliferative Glomerulonephritis

The mechanisms responsible for the development of type I MPGN from HCV-induced type II cryoglobulinemia must take into consideration not only the link between the viral infection and cryoglobulin production, but also the pathway of injury caused by these immune complexes. Significant cryoglobulinemia is unique to HCV and is not typically seen with other forms of viral hepatitis. Consequently, the genesis of cryoglobulinemia is not related to the hepatotropic nature of this virus and must be a result of the unique lymphotropic properties of HCV.³³

HCV has now been clearly shown to be B-cell lymphotropic with specific binding to the CD81 receptor, with additional receptors being identified as Toll-like receptors (TLR-3), scavenger receptors (SRB-1), and the LDL receptor.³⁴ The binding of HCV to B cells may result in both endocytic-mediated entry of the virus into the cell and also independently may directly stimulate the B cell. CD81 is a member of a signaling complex that involves CD19 and CD21 and lowers the threshold for cell activation and proliferation.³⁵ Clusters of B-cell aggregates have been identified on liver biopsies in patients with HCV cryoglobulinemia, confirming the separate proliferation of B cells distinct from the standard T-cell response seen in the liver from an HCV infection.³⁶

CD5+ B cells appear to be a preferential cell type for HCV stimulation through CD81 and represent the primary cell phenotype seen in the peripheral blood and in liver tissues of patients with cryoglobulinemia.³⁷ CD5+ B cells are rare in adults and more common in fetal life, where they are responsible for innate immunity.³⁸ These cells have the propensity to produce IgM antibodies with a restricted set of immunoglobulin V genes, predominantly the VH/VL gene pair 51pl/kv325 with rheumatoidlike properties.³⁹ Once activated, CD5+ cells may produce interleukin (IL)-10 to catalyze further cell proliferation through an autocrine pathway. Patients with hepatitis B do not demonstrate this form of CD5+ clonal expansion because HBV is not lymphotropic.

In theory, the initial B-cell proliferation will lead to a generalized, broad-based antibody response that is associated with type III cryoglobulinemia. As discussed, this sequence of events occurs after 5 to 10 years of a chronic carrier state in up to 50% of patients. However, maturation of type III cryoglobulinemia into type II cryoglobulinemia requires the emergence of a B-cell clone. How a HCV infection results in clonal B-cell proliferation is still not definitely established, but the following two mechanisms have been suggested: chromosomal mutations and/or cytokine-mediated B-cell hyperplasia.

Initial studies suggested that B-cell clones in HCV type II cryoglobulinemia contained a chromosomal translocation identified as T(14;18).⁴⁰ This well-described mutation occurs in 80% of B-cell lymphomas and results in the translocation of the antiapoptotic gene BCL-2 from chromosome 18 to chromosome 14, leading to indefinite B-cell survival.⁴¹ This acquired (somatic) genetic alteration would explain the B-cell clonality found in these patients, as well as the risk of B-cell lymphoma that is 35 times the rate in the general population. Recent work has cast doubt on this theory and has failed to confirm the widespread presence of this chromosomal aberration in HCV-related cryoglobulinemia.⁴²,⁴³ Alternative hypermutations in antibody production from HCV CD81 binding independent of the T(14;18) translocation may still explain the generation of type II cryoglobulinemia.⁴⁴

Alternatively, circulating IgG-HCV immune complexes may bind to a specific B-cell repertoire (RF+), stimulating the production of B-lymphocyte activating factor (BAFF), leading to further B-cell proliferation. However, the link to the production of a monoclonal IgM antibody from this B-cell proliferation still must be elucidated.

Once formed, the deposition of type II cryoglobulins in the kidneys occurs both in the subendothelial space and in the mesangium. HCV antigens have been colocalized to these regions, confirming their role in the formation of the immune complex.⁴⁵ The mesangial localization of the complexes results from binding to fibronectin with TLR-3 activation. The role of TLRs on mesangial cells is now recognized as an important mediator of renal injury from viral infections, particularly HCV immune complexes. The subsequent activation of IL-6, IL-1β, M-CSF, IL-8/CXCL8, RANTES/CCL5, MCP-1/CCL2, and ICAM-I all contribute to the cascade of intrarenal inflammation, leading to progressive loss of glomerular filtration rate (GFR).⁴⁶

The Treatment of Membranoproliferative Glomerulonephritis

The identification of cryoglobulinemia as the primary cause of MPGN provides a key target for therapeutic intervention. Consequently, the removal of circulating cryoglobulins and the prevention of new immune complex production remain the goals of therapy. Ultimately, the prevention of further cryoglobulin production will rest on the control of HCV viremia, but achieving this endpoint is a slow and prolonged process. Current protocols on the use of pegylated or standard IFN mandate a 48-week period of therapy to achieve viral remission. Depending on the viral genotype, control of viral replication will be achieved in only 50% to 60% of patients.⁴⁷ This delay in controlling HCV and the unpredictable response and frequent intolerance to this therapy will not be able to attenuate the severity and permanency of glomerular injury.⁴⁸ Therefore, control of viremia must be complemented by efforts to reduce the inflammatory response to cryoglobulin deposition, to remove preformed immune complexes, and to directly target the B-cell clonal population.

The most extensive experience in the treatment of HCV related MPGN comes from the previous studies in mixed essential cryoglobulinemia (MEC). Because it is now estimated that >90% of cases that were labeled as MEC were in fact related to HCV, data from those studies may be applicable in the current approach to therapy. The primary treatment consisted of high-dose corticosteroids, cyclophosphamide, and/or plasmapheresis with no antiviral therapy. Control of cryoglobulinemia and the normalization of serum complement occurred in only 25% and 30% of patients, respectively. Although none of the patients developed worsening liver disease, there were significant infectious complications, including pneumonia and sepsis.⁴⁹,⁵⁰ Therefore, concerns over exacerbating the risk of HCV cirrhosis as a result of steroid and cytotoxic therapy do not appear to be major concerns as compared to their role in preventing life-threatening systemic vasculitic complications.

IFN alone for the treatment of MPGN can lead to a remission of MPGN in 40% to 50% of cases.⁵¹ This is associated with a decrease in cryoglobulin levels and a normalization of serum complement.⁵² Importantly, in patients that were able to achieve a viral response to IFN, a marked downregulation of CD81 was found on peripheral B cells, which increased during periods of relapse.⁵³ Control of MPGN is only achieved with a sustained viral remission, and relapses occurred with a breakthrough of HCV replication after IFN therapy was completed.

Rituximab, as a B-cell targeted therapy, has been successfully used in the treatment of non-viral-mediated cryoglobulinemia.⁵⁴ This experience has been applied to the treatment of HCV-related cryoglobulinemia and MPGN. In comparison to IFN therapy, patients treated with rituximab had a 25% higher rate of renal remission with an associated decrease in circulating cryoglobulinemia and normalization of serum complement levels. The HCV viral load increased with therapy but did not result in a clinical worsening of hepatic function. A review of the literature shows that the dose of rituximab used in most reported studies was 375 mg per square meter infused weekly for 4 consecutive weeks. Adjunctive steroids were always used in combination with rituximab. An overall response rate of clinical vasculitis was 80% to 93% with a relapse rate of 30% to 40% over 1 year of follow-up.⁵⁵

As a consequence of the increased viral load seen with rituximab therapy, the next generation of trials have used a combination of IFN and rituximab. This combination resulted in a renal remission of >80% compared to <50% in patients receiving IFN only. Most importantly, there was a significant decrease in viral load in the combination arm similar to that in the IFN-only group.⁵⁶,⁵⁷ Long-term safety of this combination over a 24-month period has been reported and also supports the option of retreatment with rituximab if a relapse occurs.⁵⁸

The following treatment algorithm can be considered based on the published data and a consensus conference on the management of HCV cryoglobulinemia⁵⁹:

For mild cases of cryoglobulinemia either isolated to the kidney without significant acute kidney injury (AKI) or with low-grade systemic involvement, IFN alone is a satisfactory option.
As the renal lesion intensifies or with more significant systemic organ involvement, rituximab can be added to IFN with term steroid therapy.
In life-threatening cases of necrotizing systemic vasculitis from cryoglobulinemia, plasmapheresis can be added in conjunction with rituximab, steroid therapy, and IFN.

Interferon Nephrotoxicity

Because IFN is now established to be the foundation for the treatment of HCV-related MPGN, attention must be placed on the potential nephrotoxicity of this therapy. As a consequence of the upregulation of cell-mediated and humoral-mediated immunity, IFN has been associated with de novo interstitial and glomerular syndromes as well as the exacerbation of underlying GN.⁶⁰ Most frequently, a combination of acute
kidney injury with nephrotic syndrome has been reported with renal histology, demonstrating minimal change disease with or without an accompanying interstitial nephritis.⁶¹,⁶² Acute kidney injury has been ascribed to coexisting acute tubular necrosis in most cases. Focal segmental glomerulosclerosis (FSGS) and MPGN have been described in IFN-treated patients, but they are rare manifestations that may or may not be related to the drug exposure.⁶³ In patients receiving IFN for hematologic malignancies, approximately 25% develop transient low-grade proteinuria and 10% experience acute kidney injury.⁶⁴ Recovery occurred after the discontinuation of therapy with remission of the nephrotic syndrome.

Differentiation between HCV-related MPGN and IFN nephrotoxicity can often be made by checking the HCV PCR and serum complement levels. In IFN-associated glomerulopathy characterized by minimal change disease and/or interstitial nephritis, both C3 and C4 will be normal and the viral load should reflect the control of viremia from the therapy. In HCV MPGN, the HCV PCR must reflect active viremia and the serum complement levels will be depressed due to the presence of cryoglobulinemia.

Hepatitis C Virus-Related Renal Disease after Transplantation

There are three scenarios where HCV may result in renal disease after organ transplantation: after kidney transplantation in a patient with known HCV, after combined liver/kidney transplantation in an HCV patient, and in the native kidneys after a liver transplant only in an HCV patient. The common link between each of these scenarios in the development of HCV-related renal disease is the presence of immunosuppression.

ESRD patients with HCV are considered viable kidney transplant candidates as long as there is no evidence of cirrhosis or active extrahepatic immune complex disease. The majority of these patients have ongoing low-level HCV viremia at the time of transplantation and may be at risk for posttransplant HCV-related renal disease. In the posttransplant period, type I MPGN due to cryoglobulinemia in the renal allograft remains the most frequently reported renal syndrome from HCV⁶⁵ This may or may not represent recurrent renal disease because many HCV-positive patients on dialysis do not have prior native kidney biopsies to document their original cause of renal failure and may be first diagnosed with HCV at the time of the transplant workup or upon initiating dialysis therapy.

Cryoglobulinemia is detectable in up to 80% of HCV-positive renal transplant recipients, which represents a significantly higher incidence compared to the average of 40% to 50% in regular, nontransplant HCV patients.⁶⁶ The impact of posttransplant immunosuppression in promoting a greater degree of HCV viremia and altering the TH2/TH1 balance favoring the TH2 response may be responsible for this finding. Type III cryoglobulinemia was noted more frequently than type II cryoglobulinemia (78% versus 22%), supporting the low incidence of clinically significant cryo-globulinemic renal disease after transplantation.⁶⁷ MPGN may develop in 10% of patients with cryoglobulinemia posttransplant, which represents a higher incidence than in the general population (3%).⁶⁸

Membranous nephropathy (MN) has also been reported posttransplant as a consequence of a preexisting HCV infection.⁶⁹ The presence of HCV was reported in 50% of cases of de novo postrenal transplant MN, and may be found more frequently in those patients treated with IFN prior to transplantation.⁷⁰ It is presumed that modulating the severity of the viremia before the exposure to immunosuppression may blunt the cryoglobulin production posttransplant, and only IgG-HCV immune complexes will be present, leading to a subepithelial localization and membranous disease.

In liver transplant recipients either with or without a simultaneous kidney transplant, the prevalence of posttransplant cryoglobulinemia is approximately 30%, with clinical renal disease being noted in 10% of cases.⁷¹,⁷² This risk of cryoglobulinemic GN after liver transplantation is significantly higher than the 3% risk in patients with cryoglobulinemia in the general population.

The choice of treatment for posttransplant HCV-related MPGN is complicated by the risk of inducing acute antibodymediated (humoral) rejection of the allograft by the use of IFN.⁷³ These antiviral agents also possess the capacity to increase human leukocyte antigen (HLA) class I and class II expression, leading to increased antigenicity of the allograft. They also increase the number of cytolytic immune effector cells and decrease T-suppressor cell function. The risk of rejection during and after a course of IFN in kidney transplantation has been reported to be between 50% and 100%.⁷⁴ In liver/kidney recipients, the use of IFN also may increase the risk of rejection of either or both organs.⁷⁵ Therefore, if left untreated, recurrent MPGN in a renal allograft is associated with eventual graft loss, and the treatment of MPGN with IFN may also lead to graft loss.

Ribavirin as a solitary therapy for HCV is not effective at reducing the progression to cirrhosis, but may have clinical use in posttransplant MPGN.⁷⁶ Anecdotal cases have shown a reduction in proteinuria and a stabilization of renal function with ribavirin alone and a relapse of renal disease with the cessation of treatment. This therapy was associated with a significant risk of anemia and is limited in its use based on the GFR. The presumed mechanism of action would be through a reduction of viral load with reduced immune complex generation.

Rituximab has been used in HCV patients posttransplant and has been associated with an improvement in renal function and a decrease in cryoglobulinemia.⁷⁷ However, in the absence of antiviral therapy, this agent leads to a significant increase in viral load and a potential worsening of the underlying liver function.⁷⁸

The prevention of posttransplant HCV renal disease can be effectively achieved by reducing viremia prior to transplantation. The use of IFN therapy to induce a sustained viral remission prior to kidney transplantation significantly reduced the risk of posttransplant MPGN.⁷⁹ Currently, the
guidelines for treatment of HCV prior to transplantation focus on reducing the risk of posttransplant cirrhosis but do not take into account the prevention of HCV-related renal disease in either liver or renal transplant recipients.

Hepatitis C Virus-Related Vasculitis

Chronic bacterial and viral infections have been associated with the development of antineutrophil cytoplasmic antibodies (ANCA) and antinuclear antibodies (ANA).⁸⁰,⁸¹ In HCV patients, a wide spectrum of autoantibodies have been reported in addition to ANCA and ANA, including antismooth muscle (ASM), antimitochondrial, antithyroid microsomal (ATM), antithyroglobulin (ATG), and anti-liver kidney microsomal (LKM1) autoantibodies. The titers of these autoantibodies are usually low and they are often transient in nature.⁸² Of all cases of viral-related vasculitis, HCV was responsible for either C-ANCA or P-ANCA disease in 30% of patients. Both systemic and renal complications from small vessel vasculitis may be present, with renal disease characterized by hematuria and acute crescentic GN. This syndrome is distinguished from cryoglobulinemia-induced vasculitis by the absence of immune complexes and normal serum complement levels.

The presumed pathophysiology for the development of vasculitis in HCV is the chronic antigenic stimulation of B cells in HCV carriers. The expansion of CD5+ B-cell clones through stimulation of CD81 by HCV may increase the risk of autoimmunity, leading to ANCA generation. Limited experience is present, however, in the treatment of HCV-related vasculitis.

Focal Segmental Glomerulosclerosis and Immunoglobulin A Nephropathy

Case series have demonstrated an unexpected incidence of FSGS on the renal histology of HCV-infected patients.⁸³,⁸⁴ In one case, the FSGS lesion appeared to resolve with IFN therapy and HCV was localized by in situ hybridization to renal tissue.⁸⁵

IgA nephropathy has also been reported on pathology series in patients with HCV, especially in Asian and European case series.⁸⁶,⁸⁷ These populations already have a high incidence of background IgA nephropathy, and it is not clear if this is a chance association between these two frequent diseases. Similar to the anecdotal FSGS case reported previously, IFN therapy has also resulted in the successful resolution of a case of IgA nephropathy in an HCV carrier.⁸⁸

Diabetic Nephropathy

HCV patients have a significant risk for developing type II diabetes, with an odds ratio (OR)= 1.7.⁸⁹ This insulinresistant state may be a consequence of postreceptor inhibition of insulin action by the HCV envelope proteins, especially E2.⁹⁰ Biopsy series of patients with HCV now demonstrate a frequency of diabetic nephropathy in 5% to 10% of cases with no coexisting evidence of MPGN or cryoglobulinemia.⁹¹ Therefore, because diabetes is a direct result of HCV infection, diabetic nephropathy should be considered among the glomerular syndromes associated with HCV

Kidney Disease: Improving Global Outcomes Guidelines for HCV Renal Disease

In 2003, a nonprofit foundation was formed to promote clinical guidelines based on the scientific review of the literature in the management of kidney disease. The Kidney Disease: Improving Global Outcomes (KDIGO) foundation has addressed the issue of HCV in chronic kidney disease (CKD), end stage renal disease (ESRD), and transplant recipients and published a set of guidelines on the diagnosis, evaluation, and management of this viral infection.⁹² The following summary of the KDIGO recommendations is applicable to the area of HCV-related glomerular disease:

Testing is recommended annually for GFR, proteinuria, and hematuria in HCV patients to provide for the early detection of renal disease.
A kidney biopsy should be performed in cases suspected of HCV renal disease due to the diversity of renal syndromes that may occur.
Antiviral therapy with IFN and ribavirin (based on GFR) should be initiated in all cases of HCV renal disease and continued for 12 months.
Plasmapheresis, steroids, immunosuppressive agents, and antiviral therapy should be used for patients with active cryoglobulinemia.
- Immunosuppressive drug choices include rituximab or cyclophosphamide.
Ribavirin should be used with extreme caution in patients with Stages 3 through 5 CKD due to the risk of severe anemia.
Angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) therapy is recommended for patients with significant nephrotic syndrome as adjunctive therapy.

Key Points: Hepatitis C Virus and Glomerular Disease

HCV has unique B-cell tropism especially for CD5 + B cells, which is not a feature of other hepatidites.
The HCV virus not only enters the B cell, but can also directly stimulate B-cell proliferation and antibody production.
Approximately 50% of HCV patients develop cryoglobulinemia, but it is clinically symptomatic in only 3%, with a female predilection for disease.
Type III cryoglobulinemia is a precursor for the eventual transition to type II cryoglobulinemia, and is composed of an IgMκ monoclonal antibody with rheumatoid factor activity that is characteristic of HCV
Type I MPGN is the most common glomerular lesion seen with HCV and results from type II cryoglobulinemia.
Controlling active HCV viremia is the therapeutic target for the treatment of HCV MPGN and systemic cryoglobulinemia, and this can best be achieved with IFN therapy
Rituximab is considered the first adjunctive add-on therapy for more severe cases of renal and systemic disease, followed by plasmapheresis.
HCV renal disease may occur in the posttransplant period of either liver or kidney transplantation; however, IFN therapy is relatively contraindicated due to its association with a high risk of vascular rejection.
HCV may also be associated with ANCA-positive vasculitis due to the B-cell hyperplasia with diffuse autoantibody production.

HIV

Epidemiology

HIV infection has become a global pandemic, resulting in 35 million deaths since the initial description of AIDS in 1981. Currently, over 33 million people worldwide are carriers of the HIV virus with 65% of the cases residing in sub-Saharan Africa and 11% living in Asia, primarily in India.⁹³ Over 2.5 million new HIV cases are diagnosed each year. In the United States, 1.2 million people carry the HIV virus, with an annual incidence of >55,000 new cases reported each year.⁹⁴ Compared to the 330 million carriers of hepatitis B and the 170 million carriers of hepatitis C, HIV infection carries a significantly higher case fatality rate.

HIV genetically arose from the simian immunodeficiency virus and crossed over into a human pathogen from monkeys and chimpanzees in Cameroon and East Africa.⁹⁵ HIV is a lentivirus and consists of three main distinct groups: M, N, and O. The majority of infections seen worldwide belong to group M.⁹⁶ The M group is further categorized into 10 subtypes or clades (A through J), with subtype B being the most common species found in the United States and Europe.⁹⁷

Demographically, the most common method of transmission of HIV worldwide is through heterosexual exposure, which explains the finding that 50% of HIV patients are women.⁹⁸ The vertical transmission of HIV occurs in one third of infected mothers and remains a major route of HIV acquisition in Africa. Parenteral transmission from intravenous drug abuse and homosexuality continue to be important ongoing sources of HIV infection.

In the United States, African American and Hispanic patients are overrepresented within the HIV population compared to their distribution in the general population.⁹⁹ Both of these ethnic groups each comprise 15% of the U.S. population, but account for 50% (African American patients) and 35% (Hispanic patients) of the HIV population.¹⁰⁰ This excess risk may be related to both socioeconomic as well as genetic susceptibility factors. Caucasian patients may carry a high rate of polymorphism for the primary HIV receptor: chemokine receptor 5 (CCXR5). Inheritance of these alleles either as a heterozygous or a homozygous expression for the altered receptor may prevent HIV cellular entry and provide a state of resistance to acquiring HIV disease after exposure. African American patients have a significantly lower rate of CCXR5 polymorphism and subsequently express the entire HIV receptor in its fully functional form.¹⁰¹ In addition, genetic variation on chemokine receptor 2 and IL-2 expression may also play a pivotal role in the risk for acquiring HIV infection and in the development of systemic complications that may arise after a carrier state is established.

The Laboratory Diagnosis of HIV

HIV can be detected through both qualitative and quantitative assays. The serologic diagnosis of HIV is based on the detection of IgG antibodies targeting any of three specific HIV antigens: p24, gp120, and/or gp41. An ELISA is used as an initial screening test, and a positive result is confirmed through a Western blot, which yields a sensitivity and specificity of >99%.¹⁰²

Quantification of the viral load is accomplished through measuring viral RNA by reverse transcription and subsequent PCR amplification. This test provides a reliable method to diagnose HIV infection and quantitatively follow therapeutic interventions.

Glomerular Syndromes and HIV

A variety of glomerular syndromes have been described as a direct consequence of HIV infection (Table 47.3).¹⁰³ In addition,
HIV patients are frequently coinfected with HCV (25% to 30%) and/or with HBV (2% to 9%), and these viral diseases may result in their own characteristic glomerular syndromes. Glomerular disease represents only a subset of all HIV-related renal diseases that otherwise involve a spectrum of acid base and electrolyte disorders, AKI, CKD, and highly active antiretroviral therapy (HAART)-related nephrotoxicity.

TABLE 47.3 Glomerular Syndromes in HIV Patients

HIV-associated nephropathy (HIVAN)
	Collapsing variant of focal segmental glomerulosclerosis (FSGS)
HIV immune complex disease of the kidney (HIVICK)
	Diffuse proliferative glomerulonephritis
	IgA nephropathy
	Proliferative glomerulonephritis (lupus-like variant)
	Membranous glomerulonephritis
	Mesangial proliferative glomerulonephritis
Thrombotic microangiopathy
Hepatitis-related glomerulonephritis (coinfection)
	Hepatitis C
		Type I membranoproliferative glomerulonephritis with cryoglobulinemia
	Hepatitis B
		Membranous glomerulonephritis
		Membranoproliferative glomerulonephritis
“Classic” FSGS
Fibrillary glomerulonephritis
Postinfectious glomerulonephritis
Diabetic nephropathy
Amyloidosis

HIV-Associated Nephropathy

Epidemiology

The pathologic lesion of collapsing FSGS has been considered the hallmark of HIV renal disease and carries the designation HIV-associated nephropathy (HIVAN). This glomerular finding was originally described in AIDS patients in 1984 in New York and Miami.¹⁰⁴ Subsequently, HIVAN was documented to account for >90% of all glomerular disease found in HIV patients prior to the HAART era, which started in 1995. More recently, only 35% to 50% of renal biopsies in HIV patients demonstrate this classic lesion.¹⁰⁵

HIVAN represents the third leading cause of ESRD in African American males ages 20 to 64 years old in the United States.¹⁰⁶ In the U.S. dialysis population, 1.6% of patients are HIV positive with HIVAN being responsible for approximately 50% of these cases of ESRD.¹⁰⁷ Looking at this data from the alternate perspective, non-HIVAN-related renal disease accounts for up to 50% of the cases of ESRD in HIV patients, and these etiologies may be related to HIV-associated immune complex disease of the kidneys (HIVICK), diabetes, hypertension, FSGS, HCV, and/or HAART therapy.

HIVAN is considered to be a consequence of uncontrolled viral replication, with the majority of patients having a CD4 count <200/mm³ and having a markedly elevated viral load.¹⁰⁸ The presence of a low CD4 count with a low viral load confers a significantly greater risk for developing HIVAN (OR = 3.5) than the presence of a high viral load but with a CD4 count >200 mm³ (OR = 2.0). These data suggest that it is the biologic effect of the virus at the cellular level that is more important for the development of renal disease than simply the amount of circulating virus. The combined presence of both a low CD4 count and a high viral load resulted in the highest risk of HIVAN, with an OR of 6.1.

Conversely, the presence of a viral load <400 copies per milliliter is a strong negative predictor for the presence of HIVAN.¹⁰⁹ However, recent reports show that approximately 20% to 30% of HIV patients may have HIVAN in the absence of circulating viremia. In these patients, the detection of proviral DNA in peripheral blood mononuclear cells or renal tissue will demonstrate the HIV viral infection.¹¹⁰

Current estimates place a 2% to 10% lifetime risk of developing HIVAN in untreated HIV patients.¹¹¹ The most comprehensive data on the risk of HIVAN comes from sub-Saharan Africa, where a conservative estimate of 2.6 million cases of HIVAN may be present (10% of the total HIV population).¹¹² In the HAART naive populations of Nigeria, Rwanda, and South Africa, the presence of proteinuria in the adult population with HIV ranged between 10% to 30%, with biopsy-proven HIVAN being present in 70% to 80% of these patients.¹¹³

HIVAN has a unique racial predisposition, with >95% of cases being diagnosed in Black patients. This overrepresentation of the Black race may be a consequence of multiple genetic risk factors influencing viral entry into cells and the host cytokine response. In addition to the polymorphism for the CCXR5 receptor, as previously discussed, the most recent genetic risk factor described for HIVAN deals with variants of the myosin heavy chain 9 (MHY9) protein. This IIa isoform is a nonmuscle-associated heavy chain that is present in the podocyte and is associated with actin and is coded for on chromosome 22.

Linkage disequilibrium studies have demonstrated 14 single nucleotide polymorphisms for this gene, which lead to a higher risk of ESRD and idiopathic FSGS but, in addition, resulted in a significant risk of HIVAN in Black patients.¹¹⁴ The presence of these polymorphisms is rare in the Caucasian European population and may explain the marked susceptibility of Black patients to developing CKD and ESRD.¹¹⁵

More recent data suggest that the MHY9 polymorphisms may be a surrogate marker by linkage to inheritance of another gene disorder of the apolipoprotein 1 gene (APOL1).¹¹⁶ This gene is also present on chromosome 22 and is highly associated with FSGS and ESRD in patients of African origin.¹¹⁷ Variations in APOL1 (G1 and G2) confer resistance to trypanosome infections, which may explain the persistence of this recessively inherited gene in the African population.¹¹⁸ The localization and role that APOL1 plays in podocyte function has not been defined and the expression of mRNA for APOL1 in the podocyte has only recently been demonstrated in the cell culture.¹¹⁹

Additional HIVAN susceptibility genes may be present, which interact with viral gene products to increase the risk of developing podocyte injury and renal disease.¹²⁰ In the mouse transgenic model for HIVAN (Tg26), three distinct gene loci have been identified, with one (HIVAN1) having a human counterpart on chromosome 3 and additional potential candidates for susceptibility genes being located on chromosomes 11,14, and 16.¹²¹ The important contribution of a genetically susceptible host combined with virusmediated gene products as a cause of HIVAN is becoming increasingly emphasized.

The method of acquisition of HIV has not been shown to be a risk factor for the development of HIVAN. Previous reports have linked intravenous heroin use with a risk of HIVAN based on the frequent finding of FSGS as part of the spectrum of heroin nephropathy.¹²² However, the FSGS reported as part of heroin nephropathy differs from the collapsing variant of FSGS seen with HIVAN, and may have been related to adulterants of the heroin itself and therefore unrelated to undiagnosed HIV infections.¹²³
HIVAN is not synonymous with heroin nephropathy and is a distinct disorder related directly to HIV, regardless of the method of exposure.

Clinical Diagnosis

There are six clinical clues that can be used to predict the diagnosis of HIVAN: (1) patient demographics, (2) the presence or absence of effective HAART therapy, (3) the degree of proteinuria, (4) the presence or absence of hypertension, (5) the radiologic appearance of the kidneys, and (6) the presence or absence of hematuria. Black race remains one of the most important discriminating features between HIVAN and HIVICK and non-HIV-related renal disease. HIVAN is distinctly unusual in non-Black patients (<10%), and this immediate demographic finding should lead to an alternative differential diagnosis other than HIVAN.¹²⁴

Because HIVAN is a manifestation of uncontrolled HIV infection, the presence of a HAART-treated patient should raise suspicion that an alternative cause of renal injury is present. The measurement of the CD4 count and viral load, as discussed, will usually differentiate the risk of HIVAN from other causes of nephropathy.

As a consequence of the presence of collapsing FSGS, HIVAN should be suspected in any HIV patient with nephrotic-range proteinuria.¹²⁵ However, due to the presence of other glomerular diseases as a result of an HIV infection, the sensitivity and specificity of nephrotic-range proteinuria for HIVAN was 69% and 67%, respectively, with positive and negative predictive values of 52% and 80%. Although nephrotic range proteinuria is the most common presenting clinical finding for HIVAN, the diagnostic criteria for the presence of the nephrotic syndrome may not be fulfilled. HIVAN patients may have significant hypoalbuminemia but no evidence of edema on physical examination compared to the marked edema in classic FSGS patients. The etiology for this may be related to the production of high levels of nonspecific hypergammaglobulinemia, which may offset the loss of oncotic pressure in these patients, thus preventing edema formation.¹²⁶

The predictive value of microalbuminuria in the early detection of HIVAN has not yet been defined. Overall, microalbuminuria has been detected in 11% of HAART-naive HIV patients, with rates of 15% in Black patients and 7% in Caucasians.¹²⁷ In a longitudinal study, 15.7% of patients with microalbuminuria progressed to overt proteinuria, whereas 14% of patients without microalbuminuria developed microalbuminuria on follow-up.¹²⁸ Microalbuminuria was associated with lower CD4 counts and higher viral loads, suggesting that HIVAN and/or other tubulointerstitial injury may be a likely finding on renal biopsy. Renal biopsies in HIV patients with microalbuminuria have demonstrated unsuspected HIVAN lesions in >85% of patients.¹²⁹ Therefore, in addition to being a predictor of the development of CKD, increased cardiovascular morbidity, and mortality, microalbuminuria in HIV patients may be an early sign of HIVAN.

The Infectious Disease Society of America (IDSA) has now placed urinalysis screening as part of the workup in all HIV patients with a threshold of 1 + proteinuria requiring additional quantitation.¹³⁰ However, a screening urine dipstick target of this level has a sensitivity level of only 79% for significant proteinuria that may be clinically relevant as a sign of intrinsic disease.¹³¹ Therefore, in light of the microalbuminuria data, a random urine microalbumin or albumin/creatinine ratio may be a more sensitive tool as compared to a urinalysis for the evaluation of renal disease in HIV patients.

Although classic FSGS patients universally have hypertension (HTN) associated with progressive CKD, only 12% to 20% of HIVAN patients will demonstrate HTN in the setting of collapsing FSGS. HIV-associated upregulation of cytokines leading to peripheral vasodilation and a possible renal tubular sodium natriuresis may counteract the development of HTN in patients with HIVAN.¹³² The presence of significant HTN should lead to the consideration of an alternative differential diagnosis such as HIVICK, coexistent HBV or HCV renal disease, or HAART-related HTN.¹³³

The presence of large size (>13 cm), highly echogenic kidneys on ultrasound have been widely promoted as markers for the presumptive diagnosis of HIVAN. However, on critical review, these findings do not have the predictive value to make them reliable clinical tools. HIVAN has been associated with large size kidneys due to the development of microtubular dilation.¹³⁴ This pathologic finding is not present in patients with HIVICK. However, only 12% to 28% of HIVAN patients have large kidney size by ultrasound with a sensitivity of 24% and a positive predictive value of only 44%.¹³⁵ In light of this data, the importance of kidney size has been overemphasized as an important feature of HIVAN.

The presence of increased renal echogenicity by ultrasound may be a better reflection of significant renal parenchymal disease. The level of echogenicity of the kidney is compared to the liver and can be graded qualitatively by categories of severity. When the degree of echogenicity is qualitatively defined (0 to 4+), then the predictive value at the extremes of the grades can have a sensitivity of 96% and a specificity of 51%.¹³⁶ Most radiology centers do not use a scale for determining the degree of echogenicity and, therefore, this finding is not a reliable clinical finding for HIVAN. Pelvicalyceal thickening has been reported as a highly specific finding in HIVAN, but this radiologic feature has not been further replicated in a large cohort.¹³⁷

HIVAN should also be considered in patients with HIV that present with AKI. Overall, patients with HIV are more prone to AKI either from acute tubular necrosis (ATN) or nephrotoxic agents and experience a significantly higher mortality compared to AKI in the general community.¹³⁸ HIVAN was noted in the background of AKI in 20% of patients, indicating that this lesion should be considered a potential risk factor for AKI.¹³⁹ Any HIV patient with AKI should be evaluated for the presence of preexisting HIVAN.

The IDSA Guidelines also recommend estimating GFR in addition to a screening urinalysis for all HIV patients. HIVAN
is often associated with a significant reduction in GFR, with the majority of patients having stage 3 CKD at the time of diagnosis.¹⁴⁰ The validity of using estimated GFR (eGFR) equations in HIV patients has not been established, although the Modification of Diet in Renal Disease (MDRD) formula appears to have superior accuracy compared to the Cockcroft and Gault equation in this population.¹⁴¹ The new Chronic Kidney Disease Epidemiology Collaboration formula (CKDEPI) formula has been compared to the MDRD equation and showed significantly closer correlation with isotopic measurements of GFR, especially at a GFR >60 mL per minute.¹⁴²

Pathophysiology of HIV-Associated Nephropathy

HIVAN represents a unique constellation of four key pathologic findings in the renal biopsy: (1) collapsing FSGS, (2) microcystic dilation of the tubules, (3) interstitial nephritis, and (4) the presence of intracytoplasmic tubuloreticular bodies. By definition, the only specific requirement to fulfill the diagnosis of HIVAN is the presence of collapsing FSGS in the setting of an HIV infection with the remaining lesions being found in variable frequencies.

The glomerular lesion of collapsing FSGS seen in HIVAN is distinct from the immune complex proliferative GN of HIV ICK and the classic perihilar and tip lesions seen with idiopathic FSGS. The hallmark of HIVAN is the proliferation and hypertrophy of the glomerular podocytes, leading not only to the physical involution of the glomerular tuft from the mass of overhanging cellular bulk, but also from the impaired synthesis of the normal glomerular basement membrane. The proper collagen composition of the basement membrane is dependent on podocyte function, and an increase in immature type IV collagen production was noted in HIVAN patients.¹⁴³ The decrease in GFR is subsequently related to the loss of ultrafiltration surface area as well as a loss of the ultrafiltration coefficient.

The cells that comprise the hyperplastic cap on top of the glomerular capillary tuft are not solely comprised of visceral epithelial cells but appear to also be of parietal cell origin based on the presence of specific parietal cell markers (CK8 and PAX2).¹⁴⁴ This finding of the coexistence of parietal and visceral epithelial cells in the collapsing lesion of FSGS is not unique to HIVAN and is also present in pamidronate-induced and idiopathic-collapsing FSGS.¹⁴⁵

The current working hypothesis for the genesis of these hyperplastic cells is direct viral infection with the transcription of the viral genome leading to an uncoupling of cell differentiation.¹⁴⁶ HIVAN is categorized as a podocytopathy nicknamed the “dysregulated podocyte syndrome.”¹⁴⁷ An HIV infection of renal cells is not restricted to only glomerular epithelial cells, but can also be found in tubular epithelial cells, collecting duct cells, and mesangial cells.¹⁴⁸ Indeed, renal tissue has been shown to be a potential reservoir for HIV even when there is no detectable viremia.¹⁴⁹

The primary alteration of the podocyte by HIV is characterized by a physical change to a macrophage phenotype. The typical markers of a mature podocyte, including vimentin, synaptopodin, podocalyxin, and WT-1, are lost and the cell acquires new macrophage epitopes such as KP-1 and Ki67.¹⁵⁰ In conjunction with the upregulation of these proliferation markers, there is a loss of p27 and p57, which usually downregulate the cell cycle. Podocytes normally do not replicate but, as a consequence of HIV infection, they now develop a dedifferentiated proliferative and hyperplastic capacity¹⁵¹

A transgenic mouse model (Tg26) has demonstrated the importance of the cellular expression of the HIV genome as a cause of nephropathy.¹⁵² These animals carry a noninfectious HIV construct in renal tissue, which leads to FSGS even when these kidneys are transplanted into normal littermates. In contrast, normal kidneys transplanted into the transgenic animals did not develop glomerular disease. These findings demonstrate the fact that circulating HIV virions are not important for the development of HIVAN, but rather, it is the presence of an intracellular HIV infection that dictates the expression of renal disease.¹⁵³

The entry of HIV into renal cells must occur through a separate and distinct pathway compared to its ability to infect T lymphocytes. The CD4 receptor and the chemokine receptors (CCXR4 and CCXR5) have not been demonstrated in renal tissue. Possible methods for viral entry in the kidney include transcytosis, lipid rafts, microparticles, and C-type lectin receptors.¹⁵⁴,¹⁵⁵

Once viral entry is established, the 15 translation products from the nine genes of the HIV genome interplay to cause HIVAN.¹⁵⁶ Of these genes, at least three have been strongly implicated in directly causing the podocytopathy: Tat (transactivating protein), Nef (negative factor for viral replication), and Vpr (viral protein r). Both the Nef and Vpr genes independently and synergistically result in the development of podocyte dysregulation.¹⁵⁷ These gene products appear to exert their action by activating the Src kinase pathway with increased Stat3 and MAPK1.¹⁵⁸ In addition, Nef may cause proteinuria by interfering with the actin cytoskeleton of the podocyte by inducing a loss of stress fibers and increasing lamellipodia through the activation of Racl and the inhibition of RhoA.¹⁵⁹ The Tat protein complements these changes by causing increased glomerular permeability due to a marked reduction in nephrin expression.¹⁶⁰ Increased cytokine expression also plays a pivotal role in the development of HIVAN with increased vascular endothelial growth factor (VEGF) and nuclear factor kappa B (NF-κB) production by the podocyte.¹⁶¹ These molecules promote further podocyte proliferation, leading to the collapsing lesion and increased cellular apoptosis both in the tubules and in the glomerulus.¹⁶² Finally, newer pathophysiologic pathways have been identified, which include the mammalian target of rapamycin (mTOR) pathway and the notch signaling pathway, both of which are highly upregulated in HIVAN.¹⁶³,¹⁶⁴ The complex interplay of all these pathways is still under investigation but remains a vital goal in order to better develop targeted therapy to interrupt the sequence of events that cause HIVAN.

The second major diagnostic feature of HIVAN after collapsing FSGS is the presence of microcystic dilation of the tubules, which can be found in 60% of cases.¹⁶⁵ By definition, these tubules are ectatic and assume a size three times larger than the diameter of a normal adjacent tubule. They result from the same altered rate of proliferation and apoptosis that occurs in the podocytes, and HIV gene expression can be isolated from the affected tubular cells. Multiple nephron segments are involved by the microcystic dilation, including the proximal and distal tubules and the collecting ducts.¹⁶⁶ Interestingly, as the tubular dilation increases and the epithelium becomes flattened, HIV gene expression ceases and the growth of the cysts becomes self-limiting.¹⁶⁷ This explains why the cysts never reach the size of those seen in autosomal dominant polycystic kidney disease and remain only microscopic and below the cortical surface. The mechanisms responsible for the loss of HIV gene transcription with cyst expansion have not been defined. The kidney size actually increases based on ultrasonography in 12% to 30% of patients due to the abundant tubular microcysts.

The third feature of HIVAN is the presence of an interstitial infiltrate consisting primarily of CD8+ T cells and plasma cells. The average CD4/CD8 ratio in the renal biopsy specimen is 0.35 and may reflect the systemic T-cell subset ratio. Often, the degree of interstitial inflammation may be out of proportion to the degree of glomerulosclerosis.¹⁶⁸ There is a marked upregulation of local α and ρ IFN production, which further increases the antigenicity of the renal tubular cells by enhancing the expression of class II HLA antigens.¹⁶⁹ Additional inflammatory mediators are prominently activated within the interstitial infiltrate, especially NF-κB.¹⁷⁰ The presence of an interstitial infiltrate in the absence of collapsing FSGS in an HIV patient may occur in 20% of cases.¹⁷¹ In these cases, the interstitial infiltrate usually represents an allergic drug reaction possibly to antibiotics, nonsteroidal antiinflammatory drugs (NSAIDs), or HAART therapy.

The presence of tubuloreticular inclusion (TRI) bodies is the fourth most important feature of HIVAN and are present in >90% of cases. These lesions are found in glomerular and tubular endothelial cells as well as in infiltrating leukocytes.¹⁷² TRI bodies are not pathognomonic of HIVAN because they may be seen in systemic lupus erythematosis (SLE). Morphologic analysis shows that these particles are approximately 20 to 25 nm tubule structures, are intracytoplasmic, and are located in the dilated cisternae of the endoplasmic reticulum and the perinuclear Golgi apparatus. TRI bodies are not viral particles but represent the effects of upregulation of IFN on the aggregation of acid glycoproteins. Therefore, an alternative name for the TRI bodies seen in HIVAN and SLE is interferon footprints.

Treatment of HIV-Associated Nephropathy

All treatment recommendations for HIVAN are based on individual center observational reports. In a Cochrane Database Review of HIVAN therapy, no randomized controlled trials were found in the literature and, therefore, the authors could not offer any proven guidelines for therapy.¹⁷³ The treatment strategies discussed in the following section are limited by the individual study designs, but they do offer a reasonable clinical scheme to follow based on the current scientific literature.

The strategy for the successful treatment of HIVAN is based on the basic premise that the glomerular disease results from active viral infection of renal tissue with the transcription of the HIV genome. Elimination of the viral load followed by efforts to reduce cytokine production, to decrease the interstitial infiltrate, and to reduce proteinuria comprise the goals of a coordinated therapeutic plan. Consequently, HAART therapy remains the a priori therapeutic intervention upon which all adjunctive treatments are then added.

HAART therapy can prevent the development of HIVAN in 60% of treated patients and, when initiated after the diagnosis of HIVAN, may reduce the rate of progression to ESRD by 38%.¹⁷⁴,¹⁷⁵ In HIVAN patients who present with a decreased GFR, HAART therapy can result in an improvement in renal function.¹⁷⁶,¹⁷⁷ Conversely, patients with HIVAN who stop HAART therapy experienced an accelerated decline of renal function.¹⁷⁸

The benefit of HAART therapy on the real function in HIVAN can be correlated directly to the degree of viremia control.¹⁷⁹

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