The Glomerulopathies


The Glomerulopathies

Joshua M. Thurman and Ryan J. Goldberg

Disorders affecting the structure and function of the glomeruli (glomerulopathies) are among the most common causes of acute and chronic renal insufficiency. Broadly defined, the glomerulopathies include diseases that may originate in the glomerular capillaries, the glomerular basement membrane (GBM), the mesangium, the podocyte, or outside the glomerular tuft. Such a definition includes diverse diseases such as immune-mediated glomerulonephritis (GN), diabetic kidney disease, and thrombotic microangiopathies. Some of these diseases present as primary diseases of the kidney, and others, such as diabetic nephropathy (DN), represent the renal manifestation of a systemic disorder.

Classification of the glomerular diseases can be complex because the definition of these diseases incorporates etiology, pathogenesis, histologic findings, and clinical syndromes. Disease classification is particularly complex for the different types of GN (Table 15-1). The definition of these diseases relies heavily upon the histologic findings. As more information about the etiology and pathogenesis of glomerular diseases has become available, however, it has enabled more precise subclassification of some disease processes. Patients who previously would have been given the diagnosis of focal segmental glomerulosclerosis (FSGS) or membranoproliferative glomerulonephritis (MPGN) based on the histologic appearance seen on renal biopsy, for example, may now be further subclassified on the basis of genetic factors or infectious etiologies.

It should be emphasized that unique pathogenic events can give rise to diverse morphologic features and a single morphologic pattern can evolve from several pathogenic mechanisms. Furthermore, discrete morphologic abnormalities can evoke a spectrum of clinical syndromes. Refining the definition of a disease as new discoveries are made is important insofar as it may offer more accurate prognostic information and may allow clinicians to choose the most appropriate treatment for a given patient. Recent insights into the pathogenesis of C3 glomerulopathy (C3G), for example, have led to the reclassification of patients who previously would have been diagnosed with MPGN (1). These diseases originally bore similar names because of their histologic appearance by light microscopy, but C3G is now classified based upon the underlying immunologic mechanisms of injury. In the future, genomic, transcriptomic, proteomic, and metabolomic studies will undoubtedly lead to more precise molecular classifications of the glomerular diseases (2). This, in turn, will allow mechanism-based diagnoses, more accurate prognostic information, and may lead to therapies that specifically target the underlying causes of disease.


Glomerulopathies can arise from the effects of environmental agents (microbial infection, drugs, or toxins) or from endogenous perturbations (altered metabolism, biochemical defects, autoimmunity, or neoplasia). In both instances, underlying genetic factors interact with the environmental agents to generate the morphologic and clinical expression of disease. The etiologic agent responsible for the glomerular disease is well understood in some circumstances (e.g., drug-induced membranous nephropathy [MN]), although the pathogenic mechanisms responsible for the disease are unknown. For others, the etiologic agent remains obscure even though the effector systems engaged in tissue injury are reasonably well known. The search for the etiologic entities involved in the glomerulopathies continues.

Clinicopathologic Patterns of Injury

The glomerulus is a highly organized structure, and immunologic glomerular injury generally falls into one of several morphologic patterns. Patients with glomerular disease also tend to present with clinical findings that fit into one of several syndromes. Diseases of varying etiologies may cause glomerular injury with similar morphologic and clinical findings. Conversely, patients with the same underlying disease, such as systemic lupus erythematosus (SLE), may present with different clinical and pathologic patterns of injury. In general, the clinical findings are insufficient to accurately diagnose and treat glomerular diseases and a renal biopsy is necessary. Renal biopsies are processed for evaluation of the tissue by light microscopy, electron microscopy (EM), and immunofluorescence microscopy in order to fully classify the morphologic features of the disease. Various special stains can also be used to distinguish particular diseases.

The glomerular diseases are associated with several clinical syndromes. The nephrotic syndrome (see also Chapter 14) is usually defined as >3 to 3.5 g of proteinuria per day. Patients with the nephrotic syndrome have hypoalbuminemia, edema, and hypercholesterolemia. The urine of patients with the nephrotic syndrome does not typically contain dysmorphic red blood cells or red blood cell casts. Patients with the nephrotic syndrome are at increased risk of venous thrombosis and infection. Diseases causing subnephrotic range proteinuria (<3 g of proteinuria per day) may pose a significant threat to the patient, but they are less likely to develop symptoms of the nephrotic syndrome. The nephritic syndrome often refers to disease presenting with hematuria, proteinuria, and dysmorphic red blood cells or red blood cell casts. Proteinuria is usually present, and can range from subnephrotic levels to >10 g/day. Depending upon the extent of glomerular involvement, patients may develop hypertension, edema, and/or renal insufficiency. As will be discussed in detail later, there is great heterogeneity in the presentation of the glomerular diseases. Thus, disease etiologies commonly described as presenting with one of these syndromes may present with variable constellations of signs and symptoms.


Numerous cellular and molecular mechanisms of glomerular injury have been identified, but immune complex (IC)–mediated injury warrants additional attention as the glomerulus is a common site for IC deposition (Table 15-2). The size and charge of ICs is a function of several factors, including the nature of the antigen, the isotype of the antibodies and their affinity for the antigen, and the relative abundance of antigen and antibody. Circulating ICs may be trapped in the glomerulus, a process that could be enhanced by the large flow of plasma through the kidneys, high intraglomerular pressures, permeable capillary walls, and an anionic basement membrane that can bind cationic antigens (3). Circulating ICs will tend to accumulate in the mesangium and subendothelial space as they are too large to pass through the GBM. ICs may also form in situ when antibodies bind to antigens that are expressed within the glomerulus or that become trapped there. For example, antibodies to the M-type phospholipase A2 receptor (a protein present on podocytes) are present in approximately 70% of patients with idiopathic MN (4). In situ IC formation may lead to deposition between the GBM and the podocytes, and identification of the antigen in various IC-mediated renal diseases is instrumental for understanding the disease process.

ICs trigger the generation of several pro-inflammatory factors. They activate complement, thereby generating C5a and the membrane attack complex. They also trigger the release of numerous other pathologic factors by resident or infiltrating cells, including chemokines, prostaglandins, platelet-activating factor, procoagulant factors, and adhesion molecules. Many of these molecules are involved in leukocytes trafficking to the site of inflammation, and infiltrating polymorphonuclear neutrophils (PMNs), macrophages, and T cells then release additional factors that also contribute to tissue injury.

Mesangial IC deposition—mesangial expansion—hematuria and proteinuria. Several diseases, such as immunoglobulin A nephropathy (IgAN) and lupus nephritis, are associated with the deposition of ICs in the mesangium (Fig. 15-1). Mesangial IC deposition is associated with the development of hematuria and proteinuria, but nephrotic range proteinuria and significant changes in the glomerular filtration rate (GFR) are not typically seen. Injury of the mesangial cells stimulates the cells to proliferate and to produce extracellular matrix. Over time, this can lead to glomerular sclerosis and irreversible renal injury.

Subendothelial IC deposition—endovascular proliferation—nephritic syndrome. In diseases such as lupus, postinfectious GN, and MPGN, ICs deposit in the subendothelial space (Fig. 15-2). The complement activation fragments and inflammatory factors generated at this location have access to the circulation and tend to cause an inflammatory lesion. Subendothelial ICs cause endocapillary proliferation, where the glomerular capillaries appear hypercellular and are filled with inflammatory and endothelial cells. Clinically, patients with these diseases commonly present with the nephritic syndrome. The extent of glomerular involvement tends to correlate with disease severity (e.g., diffuse involvement causes a greater decline in GFR than focal), but clinical parameters are an unreliable guide to the severity of the underlying lesion. Antibodies may be pathogenic in diseases in which ICs are not seen in the kidney biopsy. In small vessel vasculitis, for example, patients may present with a nephritic syndrome. Although they can appear “pauci-­immune” on biopsy, antibodies probably play a critical role in the pathogenesis of these diseases (vide infra). The thrombotic microangiopathies may also cause endothelial injury and present with signs of acute GN.

Figure 15–1 Fluorescent antibody staining, showing diffuse, coarse immunoglobulin deposits located predominantly in the glomerular mesangium. This finding is characteristic of a large group of diseases that often demonstrate focal or diffuse mesangial proliferative glomerulonephritis by light microscopy, including IgA nephropathy.

Figure 15–2 Fluorescent antibody staining of the glomerulus, demonstrating discrete granular deposition of immunoglobulin along the basement membrane, which is characteristic of immune complex–mediated glomerulopathies. The immune complexes contained within the granular deposits may have deposited from the circulation or formed locally (in situ) as a consequence of interaction of a circulating antibody with a native glomerular capillary wall antigen or an extrinsic antigen planted in the glomerulus because of an affinity for constituents of the capillary wall.

Subepithelial IC deposition—podocyte injury—nephrotic syndrome. The podocyte is a highly differentiated cell that forms an important part of the glomerular filtration apparatus. The podocyte has branches that terminate in foot processes that are anchored to the GBM. The foot processes of adjacent cells interdigitate and are separated from each other by a slit diaphragm. ICs that form in a subepithelial location (i.e., between the podocyte and the GBM) can injure the podocyte, disrupt the slit diaphragm apparatus, and cause foot process effacement. Clinically, patients with subepithelial ICs present with the nephrotic syndrome and with a membranous pattern on biopsy (5). The inflammatory factors generated by subepithelial ICs are predominantly excreted in the urine and do not cause leukocyte infiltration or hypercellularity (Fig. 15-3). Consequently, hematuria, pyuria, and cellular casts will typically not be present.

Crescentic renal disease—rapidly progressive glomerulonephritis (RPGN). Glomerular crescents are extracapillary aggregates that form in Bowman space and compress the capillary tuft (Fig. 15-4). They are composed of cells (proliferating parietal epithelial cells, infiltrating monocytes, and fibroblasts) and fibrous material. Crescents may be seen in many types of immune-mediated glomerular disease, including anti-GBM disease, IC-mediated GN, and pauci-immune small vessel vasculitis (Table 15-3). It is believed that crescent formation starts with injury of the capillary wall sufficient to allow cells and plasma proteins into Bowman space. Biopsies in which >50% of the glomeruli have crescents are often referred to as “crescentic,” regardless of the disease etiology, and this finding is associated with a rapid loss of renal function, oliguria, and signs of acute GN.


Tubulointerstitial injury is common in disease processes regarded as primarily targeting the glomeruli. Tubulointerstitial injury often correlates better with renal function than the glomerular lesion, and the degree of tubulointerstitial fibrosis is also predictive of the long-term outcome in patients with glomerular disease (6). The glomerular capillaries and the peritubular capillaries are arranged as sequential capillary beds. Glomerular diseases can therefore reduce blood flow to the peritubular capillaries. There is also experimental evidence that altered permselectivity at the glomerulus allows molecules into the ultrafiltrate that can harm the downstream tubular epithelial cells, including transferrin and complement proteins. These may be common processes that are important to the progression of glomerular diseases of different etiologies.

Figure 15–3 Light microscopic appearance of membranous glomerulonephritis. Note diffuse thickening of the capillary walls without associated inflammatory response.

Figure 15–4 Light microscopic findings characteristic of crescentic glomerulonephritis. Note necrotizing glomerulonephritis with marked extracapillary reaction, including crescent and periglomerular fibrosis.

Important Clinical Scenarios


As will be discussed later, diseases such as Goodpasture disease and granulomatosis with polyangiitis (GPA; formerly known as Wegener granulomatosis) can simultaneously affect the lungs and the kidneys. Severe pneumonia can also present with renal failure, and patients with the sepsis syndrome or congestive heart failure frequently have both pulmonary and renal involvement. Given the importance of early treatment for patients with Goodpasture disease or small vessel vasculitis, however, patients presenting with acute disease of the lungs and kidneys should receive close scrutiny. Proteinuria, an active urine sediment, or serologic evidence of vasculitis may be useful for identifying the underlying etiology, but a renal biopsy may be necessary for definitive diagnosis.


Several types of glomerular disease have been associated with underlying tumors. Overall, the incidence of glomerular disease in cancer patients is rare, but cancer may be found relatively frequently in certain groups of patients with glomerular disease. For example, solid tumors may be found in 23% of patients over 60 years old who are diagnosed with MN (7), and basic cancer screening (e.g., chest X-ray, screening for occult blood in the stool, and colonoscopy) is warranted. A high incidence of solid tumors has also been found in older patients with IgAN (8). Hodgkin disease is associated with minimal change disease (MCD), and non-Hodgkin lymphoma has been associated with several types of glomerular disease including crescentic GN. Monoclonal immunoglobulin deposition diseases of the kidney are frequently caused by underlying lymphoproliferative diseases and are discussed in detail below.


The normal pregnancy is associated with several changes in renal physiology (see Chapter 13). Reports have suggested that pregnancy may cause exacerbations of renal disease in patients with chronic GN of several different etiologies. Given the prevalence of lupus nephritis in women of childbearing age, flares of lupus nephritis are relatively common. There are also reports suggesting that pregnancy may cause hypertension or disease flares in patients with preexisting IgAN, MPGN, and FSGS. In all of these diseases, however, there are conflicting data as to whether pregnancy actually increases the likelihood of a disease flare or whether these reports simply reflect a coincident worsening of disease during pregnancy. The degree of proteinuria often increases during pregnancy, but this is a result of hemodynamic changes and does not indicate a worsening of the renal disease. Regardless of the disease etiology, preexisting hypertension or renal insufficiency are risk factors for complications of the pregnancy. Preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome are glomerular diseases of pregnancy. These conditions can be difficult to distinguish from the exacerbation of a preexisting glomerular disease, such as lupus. This distinction is made harder by the fact that preexisting renal disease is a risk factor for preeclampsia.

General Treatment Strategies

The glomerular diseases share many pathogenic mechanisms—such as engagement of elements of the innate and adaptive immune systemsand our understanding of the molecular pathogenesis of this diverse group of disorders is constantly growing. Nevertheless, the commonly used therapies usually have broad effects on the overall function of the immune system (Table 15-4). Newer biologic therapies are being developed, however, that offer the possibility of a more targeted approach to the treatment of these diseases. General treatments aimed at controlling the blood pressure and reducing proteinuria are also important for maintaining renal health, even in diseases regarded as being autoimmune in origin.

Primary (Idiopathic) Glomerulopathies


MCD, otherwise known as Nil (Nothing-In-Light microscopy) disease or lipoid nephrosis, accounts for 10% to 15% of primary nephrotic syndrome in adults in industrialized countries (9), and it is the most common cause of nephrotic syndrome in children. Experts continue to debate whether MCD is its own disease or whether it exists as part of a continuum with FSGS.

In adults, MCD is diagnosed by kidney biopsy. Few, if any, changes are seen on light microscopy, and immunofluorescence is also usually unremarkable. EM shows extensive podocyte foot process retraction and effacement. These podocyte changes are not specific to MCD and it is important to exclude other pathologies when making the diagnosis. The lesion of early FSGS may be sparse and usually first appears in deeper glomeruli at the corticomedullary junction. The number of glomeruli obtained by biopsy is important for excluding other diseases. A biopsy with 10 glomeruli has a 35% chance of missing a focal lesion, whereas a biopsy containing 20 glomeruli only has a 12% chance of missing a focal lesion (10). Thus sampling error may miss glomeruli affected by FSGS if <20 cortical glomeruli are obtained. Other rarer disorders may also appear normal by light microscopy, including C1q nephropathy, IgM nephropathy, and idiopathic mesangial proliferative GN. Immunofluorescence typically helps distinguish among these diseases.

Table 15–4 Drugs Commonly Used to Treat Glomerular Diseases

Proposed Mechanism of Action

Immunomodulatory Agents


Steroids suppress B-cell and T-cell functions. High doses appear to act in part by inducing the synthesis of IκBa, a protein that traps and inactivates NF-κB thereby decreasing cytokine generation. Steroids may also have cell membrane effects altering the action of membrane-bound proteins and receptors.


An alkylating agent that covalently binds and crosslinks DNA, RNA, and proteins leading to either cell death or altered cellular function. Cyclophosphamide causes neutropenia and lymphopenia.

Mycophenolic acid

Inhibits T- and B-cell proliferation by blocking purine synthesis via inhibition of inosine monophosphate dehydrogenase.


Inhibits the phosphatase calcineurin preventing the translocation of nuclear factor of activated T cells leading to reduced transcriptional activation of early cytokine genes. There is evidence that cyclosporine may also stabilize the actin cytoskeleton of podocytes maintaining podocyte function.


Murine/human chimeric anti-CD20 monoclonal antibody that depletes B cells.


Inhibits T- and B-cell proliferation by blocking purine synthesis.


An alkylating agent that crosslinks DNA. It reduces the number of both B cells and T cells.

Plasma exchange

Removes large molecular weight substances—autoantibodies, immune complexes, cryoglobulins, myeloma light chains—from the plasma. When replacement fluid is plasma, allows large volumes of plasma to be infused without the risk of intravascular volume overload.


Monoclonal antibody to the complement protein C5. It blocks cleavage of C5, thereby preventing the formation of C5 and the membrane attack complex.

Adrenocorticotropic hormone

Mechanism uncertain. May mediate its effects via the α-melanocyte-stimulating hormone and may reduce autoantibody formation.

Nonimmunomodulatory Agents


Decrease in intraglomerular pressure. May also have an antifibrotic effect.

Fish oil

Eicosapentaenoic acid and docosahexaenoic acid serve as substrates for cyclooxygenase and lipoxygenase pathways leading to less potent inflammatory mediators than those produced through the arachidonic acid pathway.


Phosphodiesterase inhibitor that inhibits cell proliferation, inflammation, and extracellular matrix accumulation perhaps through suppressing tumor necrosis factor and other cytokines.

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.


MCD and FSGS are similar clinically and pathologically, and there is debate as to whether they are separate diseases or different ends of a single disease spectrum. Their origins are also, not surprisingly, thought to be similar and likely derive from an immunologic source. A role for T cells in the pathogenesis of MCD was first suspected in the 1970s, and some evidence has accumulated in recent decades to support this hypothesis. A T cell–derived soluble “permeability” factor, perhaps the Th-2 derived cytokine IL-13 (11), may impair the glomerular capillary wall or slit diaphragm’s ability to exclude larger proteins. Other molecules, including angiopoietin-4 (12), have been implicated as possible permeability factors.

Secondary Causes

Most cases of MCD are idiopathic; however, in a small population of patients a secondary cause can be found (Table 15-5). MCD has been associated with a number of drugs, malignancies, infections, environmental allergens, and other glomerular diseases.


Adults typically present with mild renal impairment and the sudden onset of nephrotic syndrome, including proteinuria >3.5 g/24 hours hypoalbuminemia, hyperlipidemia, and edema. Hypertension is common. Microscopic hematuria is not uncommon. In a retrospective review, 20% of patients had acute kidney injury (AKI) at the time of presentation (13).


The prognosis of adult onset MCD is generally good and is related to how patients respond to the initial treatment with steroids (see section on “Treatment”). In current clinical practice most patients are treated at the time of diagnosis; however, there are some older data that suggest a spontaneous remission rate of anywhere from 20% to 65% (14,15). Adults tend to respond to therapy more slowly than children, often requiring over 3 months of therapy before remission is detected (13,15). Over 70% of treated adults have a complete remission (13), but the relapse rate is common with almost 60% to 75% of patients having at least one relapse and 30% to 40% of patients having frequent relapses. Patients who present with AKI can typically expect to return to their baseline renal function with treatment. Progression to end-stage renal disease (ESRD) is uncommon in MCD but is reported in steroid-resistant cases (15); however, subsequent biopsies may demonstrate FSGS that may be from progression of MCD or the original diagnosis that was missed by sampling error.

When children with MCD enter adulthood, less is known about their relapse rate and prognosis. One study found that among steroid-sensitive children, young age at onset (<6 years) and more severe disease in childhood, indicated by a greater number of relapses and more frequent use of immunosuppressive drugs, were predictive of the occurrence of MCD relapse in adulthood when evaluated by univariate analysis. On multivariate analysis, only the number of relapses during childhood was predictive of adulthood relapses (16). Severe nephrotic syndrome has nonrenal-related complications as well, including thrombosis and infections (see Chapter 14). Complications arising from these disorders can also impact morbidity and mortality.


There are no large, randomized controlled trials on treating adults with MCD. The majority of studies that have helped guide treatment are from the pediatric literature. Prednisone is the treatment of choice for adult MCD (17), with the majority of adults experiencing a complete remission by 3 months. Experts have different strategies for dosing prednisone, length of treatment, and tapering. Generally, prednisone is dosed at 1 mg/kg/d or 2 mg/kg every other day and continued for 2 months. If at 2 months complete remission has been obtained, prednisone is slowly tapered. If at 2 months a remission has not occurred, then the high-dose daily prednisone is continued. If a remission has not been achieved by 4 months, the patient is considered to be steroid resistant and other agents are required. Second-line agents typically used include cyclophosphamide, tacrolimus, cyclosporine, mycophenolate mofetil (MMF), and rituximab. Each agent has been shown to be useful in treating steroid-dependent and steroid-resistant patients; however, there are no adequately powered, randomized studies to help guide practitioners toward one treatment over another.

Relapses of MCD occur frequently. If patients responded well to prednisone during original treatment and there are no contraindications against more prednisone, then a shorter course of high-dose daily prednisone is usually tried. For frequent relapsers, low-dose prednisone over an extended period of time is a reasonable choice. Again, the second-line agents mentioned earlier have also been employed in treating frequently relapsing disease.


IgM nephropathy is a rare disease that is characterized by the mesangial deposition of IgM and complement (18). Light microscopy may be normal or may show diffuse proliferation of mesangial cells and accumulation of mesangial matrix with varying degrees of sclerosis (18). EM usually shows dense deposits in the mesangium. Experts argue as to whether IgM nephropathy is its own entity, or whether it is a variant of MCD or FSGS and that the IgM deposits are a secondary event. Patients usually present with nephrotic syndrome, although patients with hematuria and asymptomatic proteinuria have been described (18). Patients with IgM nephropathy are less likely to respond to immunosuppressive agents when compared to patients with MCD (19).


C1q nephropathy is another uncommon disorder that can be confused with MCD on light microscopy. By light microscopy, C1q nephropathy can present with no visible lesions, mesangial proliferation, FSGS, or a proliferative GN (20,21). Immunofluorescence demonstrates mesangial staining of C1q in all biopsies and mesangial IgG, IgM, and C3 in the majority of biopsies. IgA and C4 are not uncommon. EM can show mesangial, subendothelial, and subepithelial deposits with or without foot process effacement. Patients present with the nephrotic syndrome and hematuria. Renal function is usually normal but there have been reports of renal insufficiency at diagnosis. There is debate as to whether C1q nephropathy is its own disease or if it is a variant of MCD or FSGS. Most treatment strategies are based on the histologic lesion. Those with an FSGS pattern of injury are more likely to progress to ESRD.


FSGS is one of the most common causes of the nephrotic syndrome in the United States and is the most common primary GN listed as the cause for ESRD (22,23). It shares many features with MCD and experts continue to debate whether the two processes are different diseases or whether FSGS is just a more severe form of MCD. As with other glomerulonephritides, FSGS is a nonspecific pattern of injury diagnosed by renal biopsy. FSGS may be idiopathic or secondary. In order to make a diagnosis of idiopathic FSGS there must not be a history of any other GN, known systemic disease with possible glomerular involvement, or family history of FSGS (24). Secondary FSGS may be caused by structural functional adaptations mediated by elevated glomerular pressure, genetic diseases, or as the final common histology of other glomerulonephritides. Differentiating between primary and secondary FSGS is often clinically challenging.

FSGS has several morphologic variants that are seen with light microscopy. Generally, FSGS is characterized by the presence of some but not all glomeruli (focal) having segmental mesangial collapse and glomerular sclerosis with partial occlusion of the capillary loops by hyaline material. Hyalinosis, acellular material within the sclerotic area caused by the insudation of plasma proteins, used to be considered a specific histopathologic feature of FSGS but is now not a diagnostic necessity. Mild mesangial hypercellularity may be seen. Tubular atrophy and interstitial fibrosis are frequently present. EM shows foot process effacement, but in secondary forms of FSGS the extent of effacement is usually less than in primary disease (25,26).

Five histologic variants of FSGS have been described: classic FSGS, collapsing variant, tip variant, perihilar variant, and the cellular variant (27). The different lesions have different presentations and responses to therapy (see “Presentation” and “Prognosis” sections below). The collapsing variant shows collapse and sclerosis of the entire glomerular tuft with podocyte hypertrophy resembling pseudo-crescents (28). The tip variant shows a lesion adjacent to the “tip” of the glomerulus, which is the area next to the origin of the proximal tubule (27). The perihilar variant consists of hyalinosis and sclerosis adjacent to the hilum of the glomerulus. This lesion is frequently observed in secondary FSGS thought to be caused by increased capillary pressure at the hilum. The cellular variant shows segmental endocapillary hypercellularity that occludes the capillary lumen. The cellular lesion is very similar in appearance to the collapsing lesion and many pathologists make no distinction between the two variants. In a study examining the recurrence of FSGS in renal allografts, 81% of recurrences occurred in the same pattern as the original disease, giving credence to the different variants proposed (29).

Uninvolved glomeruli in FSGS show no lesions and one segmentally sclerosed glomerulus is sufficient to make the diagnosis of FSGS. Experts have concluded that it takes a biopsy containing 20 glomeruli to decrease the risk of missing glomeruli affected by FSGS by sampling error to approximately 10% (30). FSGS usually starts in the corticomedullary glomeruli, so a biopsy should have adequate evaluation of this region.


The podocyte appears to be at the focal point of FSGS and injury to this resident renal cell likely initiates the process that leads to the FSGS pattern of injury. In idiopathic FSGS, as in MCD, a circulating permeability factor has been implicated as the cause of podocyte injury (31). This permeability factor has been blamed for the rapid onset of recurrent FSGS in newly transplanted kidneys. The soluble urokinase plasminogen activating receptor (suPAR) was identified as a circulating factor that might be related to FSGS (32), although this has not been confirmed in more recent studies (33).

Variants in the apolipoprotein L1 (APOL1) gene on chromosome 22 have also been associated with FSGS in African Americans (34). Polymorphisms in APOL1 are also only thus far seen expressed in those of African ancestry. A number of other genetic forms of FSGS have been identified and are discussed in other sections of this chapter.

Podocyte injury is also likely the inciting event in secondary FSGS and is caused by the compensatory hypertrophy of functional glomeruli that occurs after other glomeruli are lost or injured (35). This hypertrophy causes podocyte connections to the basement membrane and to other podocytes to become diminished; this leads to podocyte detachment and loss. Inflammatory cell infiltration, extracellular matrix accumulation, resident renal cell proliferation, and cytokines then contribute to the sclerotic scar (36).

Secondary Causes

FSGS can occur secondary to a number of different disorders. These can be broken down as structural or functional adaptations, genetic diseases, viral infections, drugs, or as a final pattern of injury after another GN (Table 15-6).


FSGS can occur in all age groups. It affects a disproportionate number of African Americans. Patients with primary FSGS usually present with the acute onset of the nephrotic syndrome—peripheral edema, hypoalbuminemia, and nephrotic range proteinuria. Hypertension is common. Renal function may be diminished at the time of diagnosis. Microhematuria is not uncommon. Secondary FSGS typically presents with nonnephrotic proteinuria, renal insufficiency, and hypertension.

Of the different variants, the tip and cellular/collapsing lesions frequently have a greater amount of proteinuria (37,38). The cellular/collapsing variants also usually have more severe renal dysfunction at presentation (37).


Untreated FSGS usually follows a progressive course leading to ESRD. Immunosuppressive treatment for idiopathic FSGS has a significant chance of improving outcomes if a partial or complete remission is obtained (39). Higher levels of proteinuria and increased serum creatinine at the time of diagnosis are predictive of lower renal survival. Histologic findings may also predict outcomes, and many experts believe that the “tip” variant is more responsive to therapy and thus more likely to have a favorable prognosis. The collapsing/ cellular variant portends a poor prognosis. As in other renal diseases, the amount of interstitial fibrosis predicts poor renal survival. Idiopathic FSGS can return in renal allografts.


Only patients with idiopathic FSGS should be treated with immunosuppressive medications, and those patients with idiopathic FSGS and nephrotic range proteinuria are almost universally offered aggressive therapy, although discretion should be taken with those patients who have significant renal dysfunction. There are no large, randomized, placebo-controlled trials investigating the best initial treatment for idiopathic FSGS; however, most experts agree that an initial trial of prednisone (1 mg/kg) for at least 16 weeks followed by a taper based on patient response is the best initial strategy (40). Although the criteria can vary, a complete response is often defined as a reduction in proteinuria to <300 mg/day, and a partial response is often defined as at least a 50% reduction in proteinuria. Published reports indicate that close to half of those treated will have at least a partial response to therapy (39). In patients who cannot tolerate high-dose steroids, calcineurin inhibitors with low-dose prednisone have been shown to be effective, but the relapse rate is high.

Relapsing FSGS manifested by nephrotic range proteinuria after either a complete or partial remission is often treated with another round of steroids if the side effects were minimal during the first period of treatment. If steroid side effects were significant, cyclosporine or tacrolimus and low-dose prednisone are recommended. FSGS is considered steroid dependent if a patient relapses while on therapy. Steroid-resistant FSGS is defined by little or no reduction in proteinuria after 12 to 16 weeks of adequate prednisone therapy or if the criteria for partial remission are not met.

Experts recommend that both steroid-dependent and steroid-resistant FSGS be treated with calcineurin inhibitors combined with low-dose prednisone (40,41). Other agents have been used and reported on for refractory disease, including adrenocorticotropic hormone (ACTH), rituximab, and the co-­stimulation blocker abatacept; however, the data are sparse and mainly consist of observational reports. For patients who have failed other therapies or who should not be exposed to calcineurin inhibitors, MMF may be effective (42). Plasmapheresis is also available for patients with primary FSGS after failure of other therapies.

Nonimmunosuppressive therapy with renin–angiotensin–aldosterone system (RAAS) inhibitors (e.g., angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) should be used in all patients with idiopathic or secondary FSGS. Blood pressure should be well controlled. Lipids should be managed with statin medications.


MN is one of the most common causes of the nephrotic syndrome. MN is diagnosed by kidney biopsy. The characteristic histologic lesion on light microscopy is diffuse thickening of the GBM, with lesions usually affecting all glomeruli. The glomeruli may appear normal by light microscopy early in the course of the disease. Chronic sclerosing glomerular and tubulointerstitial changes develop as the disease progresses. Immunofluorescence shows a diffuse granular pattern of IgG and C3 staining along the GBM. EM demonstrates subepithelial electron-dense deposits, effacement of the podocyte foot processes, and expansion of the GBM. Advanced disease may have the presence of “spikes” of membrane interdigitating between immune deposits.

Making a distinction between idiopathic MN and secondary MN can be challenging. There are certain clues on biopsy that can be helpful. In idiopathic MN, electron-dense deposits on EM are almost exclusively subepithelial and intramembranous (43). Secondary forms of MN are often associated with mesangial and/or subendothelial deposits, which suggest a circulating IC (43). Tubular basement membrane staining for IgG on immunofluorescence is rare in idiopathic MN, but is common in secondary forms such as SLE (43).


MN is an IC-mediated disease as evidenced by the presence of subepithelial ICs visualized by immunofluorescence and EM. Several podocyte antigens have been identified in subsets of patients with idiopathic MN. In the majority of patients, antibodies specific for the phospholipase A2 receptor are detectable in the serum and in the glomerular deposits (4). Antibodies to thrombospondin type-1 domain-containing 7A (THSD7A) are also seen in some patients with MN (44). Interestingly, MN patients with antibodies to THSD7A do not have antibodies to the phospholipase A2 receptor, indicating that autoimmunity to these proteins occurs in distinct groups of patients but presents with a similar clinical phenotype. Cases have also been reported in which neutral endopeptidase (NEP), an enzyme present on podocyte cell surfaces, has acted as a target antigen for anti-NEP antibodies that crossed the placenta and caused MN in infants (45).

Antibodies to the phospholipase A2 receptor are usually of the IgG4 subclass, which is a poor activator of the complement system, yet glomerular C3 deposits are seen in the majority of patients (46). It is not yet certain how the deposited antibody activates the complement cascade. Once activated, however, the complement system causes podocyte injury via the sublytic action of the membrane attack complex (C5b–9) inserted into podocyte membranes.

Secondary Causes

Secondary causes of MN represent 25% to 35% of all patients, with a slightly higher prevalence in children and older adults (Table 15-7) (47). In 85% of secondary causes, the etiology can be attributed to infections, neoplasia, or lupus (47). Infections that have been reported to cause MN include hepatitis B, hepatitis C, human immunodeficiency virus (HIV), syphilis, schistosomiasis, and malaria (43). A minority of older adults with MN have an associated cancer, usually a solid tumor and less frequently a hematologic malignancy (43). The list of medications and toxic agents associated with MN is long and includes penicillamine, gold salts, nonsteroidal anti-inflammatory drugs (NSAIDs), captopril, anti-tumor necrosis factor (TNF) agents, mercury, and formaldehyde (43). The mechanisms responsible for drug-induced MN are uncertain. Hematopoietic cell transplantation (HCT) and graft-versus-host disease can also cause MN. De novo MN can occur in transplanted kidneys. In addition, there are a number of case reports linking several other disease states to MN, including sarcoidosis and other autoimmune diseases like Sjögren syndrome and thyroid disease (43).


MN affects patients of all ages but has a peak incidence in the fourth to fifth decade. All ethnic groups can be affected. The diagnosis is made in more men than women in a 2:1 ratio (48). Almost 70% of patients present with the nephrotic syndrome as evidenced by severe proteinuria, low albumin, and edema (49). Lipid abnormalities are common. The rest of the patients present with subnephrotic range or asymptomatic proteinuria. The onset of clinical symptoms is usually gradual perhaps matching the rate of membranous deposit formation. Microscopic hematuria is common but macroscopic hematuria and red blood cell casts are rare (49). Renal function is usually normal at diagnosis. Only a minority of patients have hypertension at the time of diagnosis. Serum complement levels are usually normal. In patients with secondary MN, other clinical or laboratory findings may be present that are attributable to the primary disease process. In patients with an underlying malignancy, almost half had a known cancer diagnosis at the time of renal biopsy, whereas the rest had a MN diagnosis before any cancer diagnosis (50). Work up of an adult patient with MN should include age-appropriate cancer screens or a direct evaluation of symptoms if present. MN has also been well documented to occur concurrently with other glomerular diseases, including diabetes, IgA, FSGS, and crescentic GN.


Spontaneous complete or partial remission of proteinuria occurs in approximately 50% to 60% of patients within 5 years. The remainder of untreated patients develop progressive renal insufficiency over the next 15 years (51,52). Clinical predictors that signal an increased risk of progressive renal decline include age >50 years, male sex, protein excretion >8 g/24 hours, and an increased serum creatinine at presentation (53,54). Histologic findings that may be associated with risk of progression are glomerular scarring and the severity of the tubulointerstitial disease at the time of biopsy (55). Given the toxicity of available medications used to treat MN and the difficulty in establishing what patient group to treat, the Toronto Glomerulonephritis Registry established a model to help classify patients by risk (54). Patients who present with normal renal function, proteinuria <4 g/24 hours, and stable renal function over a 6-month observation period have excellent long-term prognosis and are considered low risk. Patients with normal renal function at diagnosis that remains stable over 6 months but who have between 4 and 8 g/24 hours of proteinuria are considered medium risk and have a 55% chance of developing progressive renal insufficiency. Patients with persistent proteinuria >8 g/24 hours, independent of renal function, have close to an 80% chance of progressing and are considered high risk. Patients who were never nephrotic or who obtain a complete remission of proteinuria have good long-term renal survival, and a partial remission also predicts improved long-term outcome (56).


All patients with MN should be on an RAAS inhibitor for both blood pressure and proteinuria control. Lipids should be controlled. As described above, the decision to initiate immunosuppressive therapy treatment for MN should be based on the patient’s risk for progressive renal decline. Low-risk patients should have continual monitoring but most experts do not recommend disease-specific therapy. Moderate-risk patients who have not improved their degree of proteinuria to <4 g/24 hours over the observation period should be started on immunosuppressive therapy. Available options include a cyclophosphamide/steroid regimen, calcineurin/steroid-based protocols, and rituximab (51,5759). The cyclophosphamide/steroid regimen typically consists of 6 months of therapy. Steroids are administered in months 1, 3, and 5, and cyclophosphamide is administered in months 2, 4, and 6. If patients do not respond to the initial therapy, most experts then recommend trying one of the alternative regimens. Synthetic ACTH may be effective in some patients who do not respond to conventional treatments (60). Studies using MMF have yielded varying results (61,62).

High-risk patients are initiated on treatment if there is no improvement in protein excretion after only 3 months or if renal function is reduced and thought secondary to MN.

Relapse of MN, as evidenced by an increase in proteinuria after a remission, occurs in approximately 30% of patients treated with cyclophosphamide-based protocols and 40% of those treated with calcineurin inhibitors. In patients whose antibodies to the phospholipase A2 receptor decreased after treatment, an increase in the titer of these antibodies may predict a relapse (63). There is not a consensus on how to treat relapses, but the decision is generally between re-treating the patient with the original protocol versus attempting the other protocol. Decisions are based on how well the patient tolerated the first round and if other side effects can be minimized.

In patients with secondary MN, cessation of the offending drug or effective treatment of the underlying disease is usually associated with improvement in the nephrotic syndrome.


MPGN is defined by its morphologic characteristics on renal biopsy. Typically, there is mesangial expansion and hypercellularity, causing a lobular appearance of the glomerular tuft (64,65). Mesangial interposition into the walls of the capillaries causes the GBM to split, causing reduplication of the GBM and a “double contour” best seen with silver–methenamine–period acid–Schiff stains. Mesangial interposition into the capillary wall and subendothelial IC deposits cause thickening of the capillary wall. C3 deposits in the capillary loops are virtually always seen by immunofluorescence microscopy, and granular deposits of IgG are also usually seen.

Type I MPGN is a rare form of primary GN, and this pattern of glomerular injury may also be caused by IC deposition in patients with chronic infections, cryoglobulinemia, autoimmune disease, malignancy, and sickle cell disease (Table 15-5). This morphologic pattern of injury has also been termed mesangiocapillary GN (66). MPGN typically occurs in children or young adults and accounts for approximately 5% of GN. MPGN type II, or dense deposit disease (DDD), is a histologic variant of MPGN that has pathognomonic electron-dense deposits in the GBM (67). Even though DDD can have a MPGN pattern of injury on light microscopy, it is now classified as a form of C3G and will be discussed in a subsequent section of this chapter. A pattern of glomerular injury that is similar to MPGN type I but with abundant subepithelial IC deposits and rupture of the GBM has been termed “MPGN Type III” (68,69).


Circulating ICs are commonly detected in patients with MPGN (70). IC deposition in the subendothelial space and in the mesangium is probably critical to the development of both the primary and secondary forms of MPGN type I. The ICs activate complement and immunoglobulin receptors (Fc receptors) triggering the recruitment of neutrophils and monocytes. Activated inflammatory cells release reactive oxygen species and proteases. These factors and complement activation fragments can directly damage the capillary wall. Platelets may also accumulate and contribute to glomerular injury by releasing chemotactic factors and growth factors. Patients with MPGN often have low platelet levels and a shortened platelet lifespan, supporting a role of platelets in this disease (71). Cytokines and growth factors may induce proliferation of mesangial cells and the production of mesangial matrix.

Patients with MPGN type I are frequently hypocomplementemic (72). This may reflect consumption of classical pathway components (e.g., C3 and C4) by the ICs. An autosomal dominant pattern of transmission of MPGN has been identified in one family and the disease was linked with the area on chromosome 1q, which contains the genes for the complement regulatory proteins (73).

It seems likely that the mechanisms of glomerular injury in primary and secondary MPGN are similar, but that the antigens are distinct. The identity of the antigen in idiopathic MPGN is not known. The incidence of idiopathic MPGN type I has been decreasing in recent decades (74). It is possible that part of the decline of idiopathic MPGN is due to improved diagnosis of secondary causes, such as MPGN caused by hepatitis C and cryoglobulins. Future studies may identify new infectious causes for what is currently considered idiopathic disease.

Secondary Factors

As described above, a pattern of injury on light microscopy similar to idiopathic MPGN may be seen in patients with infectious, autoimmune, and malignant disorders (Table 15-8). Many cases that once would have been regarded as “idiopathic” MPGN are now recognized as being caused by hepatitis C, and many other systemic diseases are associated with this pattern of glomerular injury. In most of these diseases, the glomerular injury results from persistent IC formation. This may be caused by infections that persist in spite of a humoral immune response, autoimmune diseases in which antibodies to endogenous antigens form ICs, or hematologic malignancies.


Patients with MPGN can present with a nephritic syndrome, nephrotic syndrome, and sometimes with an RPGN. Patients presenting with nephritic features usually have microscopic hematuria, but episodes of macroscopic hematuria can occur. Idiopathic MPGN is generally a renal limited disease, but patients often have fatigue, anorexia, and weight loss. Hypertension and anemia are also seen in many patients. Complement levels are frequently depressed in patients with MPGN type I. C3 levels are low in approximately 70% of the patients, and C4 levels are also frequently low.


The course and natural history of untreated MPGN are variable. A minority of patients may have spontaneous remissions, but most have persistent proteinuria. The renal function can slowly decline, and there may also be periods of rapid deterioration. Untreated, renal survival is approximately 50% at 10 years (75). Because of the variable course of MPGN type I and the small size of clinical trials, it is difficult to assess whether treatment of the disease significantly improves the outcome. Uncontrolled studies in children, however, suggest that treatment may improve long-term outcomes, with 10-year renal survival reaching 75% (76). Factors that may predict a worse prognosis include nephrotic range proteinuria, tubulointerstitial fibrosis on biopsy, and renal dysfunction 1 year after diagnosis (77).


Patients should receive nonspecific therapies such as control of the blood pressure, and RAAS inhibitors should be used in patients with proteinuria. Complications of the nephrotic syndrome should also be treated. Uncontrolled studies in children suggest that treatment with corticosteroids may improve the outcome of MPGN type I, although not all authors agree that the risks of treatment are justified given the limited efficacy data. Patients can be treated with 40 mg/m2 of prednisone on alternate days. In patients with severe disease, the high dose can be maintained for 2 years, and then tapered to 20 mg/m2 and maintained for prolonged periods. There is less evidence for the efficacy of prednisone in adults, but in patients with severe disease, a 6-month course of prednisone (1 mg/kg/d) can be tried. Antiplatelet agents, such as aspirin and dipyridamole, may be of benefit (78). There are no controlled trials to support the use of cytotoxic agents in patients with MPGN. There are several reported cases of steroid-resistant MPGN that were successfully treated with mycophenolate, but no randomized trials of this agent have been performed.


DDD refers to glomerular disease associated with electron-dense deposits in the GBM or electron-dense transformation of the GBM (79). As mentioned above, DDD was initially regarded as a variant of MPGN and was referred to as MPGN type II, but kidneys that demonstrate dense deposits by EM (the pathognomonic feature of DDD) do not always have an MPGN pattern by light microscopy (79). Immunofluorescence microscopy of DDD kidneys typically shows abundant C3, but not IgG or C4. The classification of these glomerular diseases was further modified when it was discovered that some biopsies have dominant C3 deposits by immunofluorescence but do not have the characteristic dense deposits by EM (1). Renal biopsies with dominant C3 deposits (at least two orders of magnitude greater than other immune deposits) are now termed as having C3G (80). If dense deposits are seen in the GBM by EM, the disease falls in the subcategory of DDD, and the term C3 glomerulonephritis is used for kidneys in which the characteristic dense deposits are not seen.

There is compelling genetic and animal data demonstrating that unregulated activation of the alternative pathway of complement is central to the development of C3G (81). C3 nephritic factor (C3NeF) is an autoantibody that stabilizes the alternative complement pathway C3 convertase, thus amplifying complement activation through this pathway. Greater than 85% of patients with DDD have detectable C3NeF, and >80% of DDD patients with active disease have decreased levels of circulating C3. In some patients, mutations in factor H (a circulating protein that regulates the alternative pathway) are associated with disease, and a number of other mutations and autoantibodies that cause dysregulated activation of the alternative pathway have been identified (8183). The diagnosis of C3G is based upon the immunofluorescence findings, not a particular pattern of injury by light microscopy. Immunoglobulin can be seen within the glomeruli, but currently the diagnosis of C3G requires that staining for C3 is the dominant finding (84).

DDD currently has a very poor prognosis with >50% of patients progressing to ESRD within 10 years of their diagnosis (85), although the prognosis may be slightly better for C3 glomerulonephritis (82). Blood pressure should be controlled and patients should be treated with RAAS inhibitors, but there are no specific treatments of proven benefit. Plasma exchange may be beneficial in patients with mutations in circulating complement regulatory proteins or who are positive for C3NeF (86). Eculizumab may be beneficial in some patients, but overall the results are mixed (87). Retrospective data also suggest that MMF may be beneficial in some patients (88).


IgAN is an IC disease that is the most common form of GN in the world. In the United States and Western Europe, IgA accounts for 10% to 30% of GN, whereas in China, Japan, and Korea, IgA causes close to 50% of GNs (89,90).

IgAN is diagnosed by renal biopsy. There have been attempts to use serum and urine markers to predict a diagnosis of IgA, including the serum IgA/C3 ratio (91), urine proteomics (92), and serum galactose-deficient IgA levels (93); however, no large-scale studies have been performed to determine if these are sufficiently sensitive and/or specific to reliably aid in making the diagnosis of IgAN. IgAN can have any of the histologic phenotypes of IC-mediated GN, including no lesion by light microscopy, mesangioproliferative GN, proliferative GN, and crescentic GN. A classification system known as the Oxford classification of IgAN, developed by the International IgA Nephropathy Network in collaboration with the Renal Pathology Society, is similar to the World Health Organization’s (WHO) system for lupus (94). Pathology reports should provide numerical scores based upon the presence or absence of mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity, and tubular atrophy/interstitial fibrosis, as these findings seem to correlate with patient outcomes.

The traditional light microscopy histology for IgAN is mesangial proliferation and matrix expansion (95). Crescents are not uncommon but full-blown crescentic GN is the exception. Immunofluorescence shows staining for IgA (IgA1 predominantly) in the mesangium often accompanied by low intensity staining for IgG and IgM. C3 staining is typically present as well. EM shows IC deposition in the mesangium.

IgA deposits have been documented in asymptomatic individuals, primarily in transplant studies (96). The significance of this is unknown. Also, IgA deposits have been reported in other forms of GN, including thin basement membrane nephropathy (TBMN), lupus nephritis, MCD, vasculitis, and DN. It is possible that these findings are nonspecific and unrelated to the primary disease; however, the true significance and clinical applicability remain largely unknown.

Henoch–Schönlein purpura (HSP) is a systemic vasculitis characterized by the deposition of IgA-containing ICs. It usually presents with a nonthrombocytopenic palpable rash (leukocytoclastic vasculitis), polyarthralgias, abdominal pain, and renal disease. The renal lesion of HSP is indistinguishable from IgAN and the pathogenesis is likely similar to IgAN as well. HSP occurs more often in children than in adults; however, adults and older children are likely to have more severe renal disease (97). HSP resolves spontaneously in the majority of adults and children. However, severe or persistent renal dysfunction often requires specific therapy (see section on “Treatment” below).


The recurrence of IgAN in transplanted kidneys implicates a circulating pool of IgA as opposed to local IgA production. Increased polymeric IgA1 plasma cells are found in the bone marrow and tonsils in IgAN (98,99). A number of studies have shown that patients with IgAN have increased levels of serum IgA, but that increased total levels of IgA are insufficient to cause IgAN. The IgA in patients with IgAN is anionic, overrepresented by λ-light chains, and has an O-glycosylation abnormality with reduced galactosylation of the IgA1 hinge region O-glycans, leading to increased frequency of truncated O-glycans (100). The changes in O-glycosylation only seem to become apparent after antigen encounter and may be linked to B-cell maturation and class switching to IgA1 synthesis. The IgA molecule produced in patients with IgAN has low affinity for its antigen, may be poorly cleared, and persists longer in circulation. Aberrantly galactosylated IgA1 molecules also have an increased tendency to self-aggregate and form antigen–antibody complexes. The aberrant glycosylation may also serve as an antigen for autoantibody IgG, and the IgG-IgA1 forms ICs. These complexes are prone to mesangial deposition because of an altered number of sialic acid and galactose units secondary to aberrant O-glycosylation allowing binding to extracellular matrix fibronectin and type IV collagen. Genome-wide association studies have identified risk loci within the major histocompatibility complex (MHC), supporting an immune basis for this disease (101). Variants in the genes for the complement factor H–related proteins were also identified as risk factors, highlighting the importance of complement activation in this disease. IgAN is not usually associated with a cellular infiltrate, except in severe or crescentic disease, suggesting that the mesangial cells and complement mediate injury. Mesangial cells undergo a phenotypic transformation to a pro-inflammatory and pro-fibrotic cell upregulating secretion of extracellular matrix components, transforming growth factor (TGF)-β, platelet-activating factor, IL-1β, IL-6, and other cytokines and chemokines. IgA can activate both the mannose-binding lectin and alternative pathways of the complement cascade (102). This ultimately leads to the generation of the membrane attack complex causing further damage.

Secondary Causes

Idiopathic IgAN, including HSP, is far more common than secondary disease. The deposition of IgA has also been associated with a number of other clinical conditions, including cirrhosis, HIV, celiac disease, seronegative arthritis, and malignancies. Most adult patients with IgA deposition in association with other diagnosis are asymptomatic with relatively bland urine findings, except for HIV-associated IgAN, which can present more typically.


IgAN can present at any age but typically does so in young adulthood. There is a male predominance with Caucasians and Asians being affected much more commonly than blacks. Patients with IgAN typically present in one of three ways (103). Almost half of the patients will present with one or more episodes of gross hematuria often times following an upper respiratory tract infection. These patients may have flank pain during acute episodes reflecting kidney edema and stretching of the renal capsule. Low-grade fever may also be present. Another 30% to 40% of patients will have microscopic hematuria and usually mild proteinuria, which is detected on a routine examination. Gross hematuria may eventually occur in some of these patients. Less than 10% of patients present with either nephrotic syndrome or acute RPGN. It is thought that these patients have had undetected disease for some time.

Rarely, patients present with acute renal failure caused by either crescentic IgAN or by heavy glomerular hematuria leading to tubular occlusion and/or damage by red cells. The latter is usually reversible, although incomplete recovery of renal function has been described (104).


IgAN was initially considered to be a relatively benign disease. Now, with more insight into the disease and with more patient-years of follow-up, it has been determined that approximately half of all patients with IgAN will slowly progress to ESRD (105). Patients with >0.5 g/24 hours of proteinuria, elevated serum creatinine at diagnosis, and hypertension are at greatest risk for progression in the long term, but risk for progression exists in all manifestations of the disease (106,107). As described above, different classification schemes have been devised to describe the histology of IgAN; however, the degree of glomerulosclerosis and tubulointerstitial disease seem to be most strongly associated with a poor prognosis (107). The presence of crescents is also associated with a risk of progressive disease. Elevated serum levels of poorly galactosylated IgA1 may correlate with a higher likelihood of developing ESRD (108). There is also evidence that C4d staining within the mesangium indicates a worse prognosis (109). Histologic recurrence with or without clinical disease can occur in transplanted kidneys.


Treatment of IgAN is typically based on disease severity; however, there is a lack of any unified algorithm that is widely accepted. Part of this uncertainty results from the slow progression of IgAN, which is further complicated by the patient-specific variability of disease progression.

Most experts agree that patients with isolated hematuria, minimal proteinuria, and normal renal function need do not need specific treatment other than possibly initiating treatment with RAAS inhibitors. For patients with >0.5 g/24 hours of proteinuria, a RAAS inhibitor titrated to a dose that attempts to normalize proteinuria is recommended. Evidence suggests that even obtaining a partial remission of proteinuria dramatically slows down progression of renal function decline (110). There have been both positive and negative studies regarding the use of high-dose fish oil (ω-3-polyunsaturated fatty acids) supplements and their ability to slow down the decrease in GFR. If tolerated, some experts advocate using them when RAAS inhibitors are added.

For patients with progressive disease manifested by increasing serum creatinine or proteinuria, a trial of steroids can be tried with the goal of reducing proteinuria and improving renal survival, although the results of trials have been mixed (111114). Regiments including pulse methylprednisolone with oral prednisone or only oral prednisone are described.

For patients who fail to respond to steroid therapy alone or have severe disease at presentation, daily oral cyclophosphamide and steroids with or without azathioprine are typically initiated to decrease proteinuria and improve long-term renal function (115). For patients with crescentic GN and a rapidly progressive clinical course, therapy with intravenous pulse glucocorticoids and cyclophosphamide is recommended. Some experts also advocate the use of mycophenolate or azathioprine (116,117). Other more experimental therapies include tonsillectomy and low antigen diets.

Glomerulopathies Associated with Multisystem Disease


Poststreptococcal GN (PSGN) is a syndrome primarily seen in children in which acute GN develops 1 to 4 weeks after a streptococcal infection. Other bacterial infections are associated with the development of GN concurrent with the infection, particularly if the infection is chronic. Well-described causes include bacterial endocarditis (both subacute and acute cases), chronically infected ventricular shunts, abscesses, and bacterial pneumonia (118). The epidemiology of GN associated with endocarditis has changed in recent years. Improved prevention and treatment of subacute bacterial endocarditis caused by organisms such as Streptococcus viridans has reduced the incidence of GN associated with this disease, whereas GN caused by acute endocarditis with Staphylococcus aureus has risen.


PSGN typically presents as an acute nephritic syndrome that starts within several weeks of an infection with β-hemolytic streptococci. There is typically a latent period between the resolution of the infection and the onset of GN (119). Most cases of PSGN are caused by group A streptococci, and renal disease can develop after pharyngitis or after streptococcal infections of the skin. Cases of PSGN can occur sporadically or they can occur in epidemics. In either instance, it occurs more commonly in children than in adults, and males are affected slightly more commonly than females. The triggering infection in patients with PSGN is not always clinically evident. Patients with PSGN usually present with edema, hematuria, and proteinuria (usually subnephrotic). The urinary sediment is almost always “active,” and dysmorphic red blood cells may suggest a glomerular etiology. Patients can develop renal failure, some with oliguria. Rapidly progressive renal failure with prominent crescents on biopsy can also occur, but only in a small percentage of patients. Hypertension is common. Patients may develop seizures secondary to the hypertension, but there is evidence that this may also be caused by cerebral vasculitis (120).

More than 90% of patients with active PSGN have a low C3 level (121). The C4 is generally normal, consistent with activation through the alternative pathway. Serologic tests may demonstrate antibodies reactive with streptolysin (ASO), hyaluronidase (AHase), streptokinase (ASKase), nicotinamide-adenine dinucleotidase (anti-NAD), and DNAse B (122), but these antibodies may not be detectable in patients who have received antibiotics.

On biopsy, PSGN usually causes endocapillary and mesangial proliferation. The lesion is often termed “exudative” because of the presence of abundant PMNs in the glomeruli. Over time, fewer numbers of PMNs are seen but the glomeruli may contain mononuclear cells. Glomeruli may also contain fibrin thrombi and areas of necrosis. Immunofluorescence microscopy often reveals IgG or IgM. C3 is invariably present in the mesangium and in the capillary walls. This can cause a “starry-sky” pattern of fine, scattered deposits, or a “garland” pattern of large deposits in the glomerular tuft (123). Large subepithelial electron-dense “humps” are classic for PSGN (Fig. 15-5), and mesangial and subendothelial deposits may also be seen.

Patients with GN associated with active bacterial infections usually develop hematuria and proteinuria. If the glomerular involvement is diffuse, patients may develop the nephrotic syndrome, gross hematuria, or renal insufficiency. Systemic symptoms commonly include fever, purpura, and arthralgias. In most instances, the renal injury is caused by glomerular ICs. The location of the ICs may determine the histologic appearance and the clinical presentation. A proliferative pattern is usually seen by light microscopy, and glomerular ICs are accompanied by C3 deposits by immunofluorescence. IgA is the dominant immune deposit in some patients with GN caused by staphylococcal infections (124). Systemic C3 levels are usually depressed during the acute illness, although C3 levels are typically normal in patients with abdominal abscesses or non-endovascular infections with methicillin-resistant Staphylococcus aureus. Antineutrophil cytoplasmic antibodies (ANCA) can be present in elderly patients and in up to 25% of patients with endocarditis (118). Circulating and deposited cryoglobulins are also frequently present in patients with infection-associated GN. In early series, chronic bacterial or tubercular infections caused a significant percentage of the cases of AA amyloidosis, but a more recent series indicates that infection is now rarely the cause (125).

Figure 15–5 Subepithelial deposition of electron-dense material (humps), which may be found in several types of IC glomerulopathies and is characteristic of poststreptococcal diffuse endocapillary proliferative glomerulonephritis.


Two streptococcal molecules may be pathogenic in PSGN: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and streptococcal pyrogenic exotoxin B (126). These molecules may bind within the glomerulus and directly activate the alternative pathway of complement. They may also provide the antigen for ICs that deposit or form in the capillary wall. Circulating cryoglobulins and rheumatoid factor are also common, suggesting that these antibodies may contribute to the glomerular injury. GN associated with other bacterial infections is thought to be mediated by glomerular ICs. These may form in situ after bacterial antigens are planted within the glomerular capillary or they may be caused by the deposition of circulating ICs.

Prognosis and Treatment

Even in patients with severe renal dysfunction, PSGN is usually self-limited and renal function returns to normal within a few weeks. Proteinuria and hematuria can however persist for months or even years. The “garland” pattern on biopsy is associated with a greater likelihood of persistent proteinuria. PSGN only rarely causes ESRD, but some patients go on to develop hypertension or chronic renal disease. Adults are probably more likely than children to develop chronic renal disease. ACE inhibitors may be beneficial, but there are no studies to support improved outcomes with corticosteroids or immunosuppressive medications. There are case reports of patients with severe, crescentic disease who appeared to benefit from treatment with corticosteroids, but controlled trials are lacking.

The clinical presentation of GN associated with active infections is similar to that of PSGN, although the degree of renal failure is more severe in elderly patients. Mildly impaired renal function usually improves with treatment of the underlying infection. Patients with crescentic disease or severe renal impairment, however, may have a progressive decline in renal function in spite of antibiotic therapy. Immunosuppressive drugs and plasmapheresis are of uncertain benefit, and should not be used unless the underlying infection has clearly been eradicated.


HIV-infected patients make up at least 2% of the population with ESRD (127). The prevalence of renal disease related to HIV infection before the highly active antiretroviral therapy (HAART) era is largely unknown; however, a small European autopsy study of primarily Caucasian patients with AIDS found renal pathology in 43% (128). A number of studies in the HAART era have estimated that close to 20% of HIV-infected patients have chronic kidney disease (CKD) (129,130). Patients of African descent with HIV are at particularly high risk of progression to ESRD, and the risk is increased in patients carrying the APOL1 risk allele (131).

There are three main classes of HIV glomerulopathies, including HIV-associated nephropathy (HIVAN), HIV immune–mediated GN, and thrombotic microangiopathy secondary to HIV (132). HIVAN and HIV immune–mediated GNs will be discussed here. A discussion of thrombotic microangiopathy can be found elsewhere in this chapter. Other complications of HIV/AIDS including drug-associated renal injury, neoplasms, metabolic abnormalities, and AKI secondary to opportunistic infections can also contribute to renal morbidity and can be found elsewhere in this book.


The characteristic histologic findings for HIVAN by light microscopy include collapsing FSGS, podocyte hypertrophy, tubular epithelial atrophy with microcystic dilatation of the tubules, and lymphocytic infiltration. Immunofluorescence is usually nonspecific. EM may show endothelial tubuloreticular inclusions related to high plasma interferon (IFN) levels.


The exact pathogenesis of HIVAN is unknown, but it is likely caused by viral infection of resident kidney cells, including glomerular endothelial, epithelial, mesangial, and tubular cells. The presence of HIV may also stimulate the release of cytokines, including fibroblast growth factor and TGF-β, which then contribute to the matrix accumulation, fibrosis, and tubular injury seen in HIVAN (133,134). HIV gene products can directly induce cell-cycle progression, resulting in epithelial cell dedifferentiation and collapse (135).

The increased prevalence of HIVAN in African Americans implies genetic factor involvement as well. Studies have identified single nucleotide polymorphisms, present only in African Americans, in the APOL1 gene on chromosome 22 that are strongly linked to increased risk of HIVAN (131).The pathogenic role of APOL1 in HIVAN pathogenesis is not known (136).


HIVAN can be present in any race but it is typically a disease of patients of African descent. HIVAN classically presents late in the course of HIV/AIDS with low CD4 counts and elevated viral loads. It can, however, also present anytime during the course of HIV with adequate CD4 counts and undetectable viral loads. Patients with HIVAN typically present with heavy proteinuria, hypoalbuminemia, renal dysfunction, and occasionally edema. Microscopic hematuria may also be present. The kidneys often are enlarged and echogenic on ultrasound examination corresponding to the lymphocytic infiltration and tubular dilation seen on biopsy. Blood pressure, surprisingly, is usually normal perhaps related to salt wasting that has been reported in HIVAN. In the HAART era, HIVAN has been reported to present with less severe findings.


When HIVAN was first described the prognosis was dismal, with patients progressing to ESRD in months. In the HAART era, the rate of progression of HIVAN to ESRD has been reduced by an estimated 40% (137). Some evidence also suggests that HAART may prevent the development of HIVAN (138).


HAART is recommended as first-line therapy to treat HIVAN, even though there are only retrospective and nonrandomized trials demonstrating its effectiveness (139). RAAS inhibitors have been shown in small studies to delay the progression to ESRD and decrease proteinuria and should be used and titrated as tolerated (140). Steroids and cyclosporine have also been used in those patients not responding to HAART or RAAS inhibitor therapy (141). Survival rates of patients with HIV on dialysis are similar to non-HIV patients. Transplantation is also an option.

HIV Immune–Mediated Glomerulonephritis

Autopsy and biopsy studies have demonstrated a wide prevalence of immune-mediated GN in HIV-infected patients, with anywhere from 10% to 80% being reported (142). IC GN associated with HIV may present with proliferative, lupus-like (immunofluorescence positive for C1q, IgG, IgM, IgA, C3, λ, and κ), mixed proliferative, or sclerotic histology. Membranoproliferative, IgA, membranous, fibrillary, immunotactoid, and postinfectious GN have also been reported (143). The presence of hepatitis C or B coinfection must also be considered, as they are known to cause a number of the histologic patterns of injury mentioned earlier.


Infection with HIV may lead to polyclonal hypergammaglobulinemia and to the development of circulating ICs, many of which are composed of HIV peptides and their associated antibody (144). Passive trapping of these complexes versus in situ formation of antigen–antibody complexes on glomerular cells can initiate the immune response and trigger IC GN.


HIV immune-mediated GNs occur more frequently in Caucasians and Asians. Patients usually present with hypertension, an active urine sediment, proteinuria, and renal insufficiency. Low levels of serum complement proteins may be seen. Antinuclear antibody (ANA) and antibodies to double-stranded DNA (anti-dsDNA) are typically negative even in those patients with lupus-like histology. CD4 counts and HIV viral loads do not seem to be predictive of disease type or severity.


The prognosis of HIV immune–mediated GNs is largely unknown but is considered to be generally poor in most literature reports. Some studies have demonstrated that renal survival may be predicted in part by the degree of fibrosis at biopsy and by the amount of proteinuria.


Little is known about the specific treatments for HIV immune–mediated GNs. Most patients should likely be on an RAAS inhibitor for proteinuria reduction. The data are mixed about whether HAART improves proteinuria or delays progression of disease (145,146). There are case reports involving the use of immunosuppressant drugs with some degree of success (147,148).


Chronic infection with hepatitis C virus (HCV) has now been firmly associated with the development of mixed cryoglobulinemia, and >90% of patients with cryoglobulin-associated renal disease are infected with HCV in some series (136). HCV infection has also been linked with the development of glomerular disease in the absence of cryoglobulins.


Most patients with cryoglobulin-associated renal disease have proteinuria, hematuria, and an elevated serum creatinine. The presentation can be more fulminant, and some patients present with the full nephritic syndrome and with acute elevations in the serum creatinine. By the time patients present with renal disease, they usually have systemic manifestations of vasculitis. Common extrarenal signs and symptoms include palpable purpura, arthralgias, and weakness. Hypertension is also common. In patients with active disease the serum C4 level is almost always low (149). The cryocrit is quite variable but can usually be detected, and rheumatoid factor is usually present.

HCV infection, even in patients who do not have detectable cryoglobulins, has been linked to the development of MPGN (149,150). HCV has also been linked to MN, although this correlation has not been firmly established. One report also found that many HCV-infected patients with renal involvement may go undetected (151). In this study, 30 patients undergoing liver transplantation for HCV-induced cirrhosis underwent renal biopsy at the time of liver transplantation. None of the patients had detectable cryoglobulins, yet all but one had some type of glomerular pathology. Of 25 patients with glomerular IC deposits, 10 had a normal urinalysis, further suggesting that standard screening of patients with HCV infection may underestimate the degree of renal involvement.


Cryoglobulins are present in the majority of patients with HCV-associated glomerular disease (150). Most patients have type II cryoglobulinemia, in which the cryoglobulins contain a monoclonal antibody (usually an IgM) that binds to polyclonal IgG. Studies of biopsy tissue indicate that HCV complexes are present within the glomerular capillary walls (152). Furthermore, the IgM rheumatoid factor present in the cryoglobulins of HCV-infected patients can cause GN in mice when passively transferred (153). These findings suggest that cryoglobulins containing HCV cause IC-mediated injury of the glomerulus, perhaps because of the affinity of the IgM component for a glomerular target.

Prognosis and Treatment

Cryoglobulin-associated renal disease has a variable course. Approximately 10% to 15% of patients will enter spontaneous remission, and another 30% will have an indolent course with only a mild degree of renal insufficiency. Some patients, however, have acute nephritic flares (154). Treatment of the underlying HCV infection with IFN α and ribavirin can improve symptoms of cryoglobulinemia (155), and antiviral treatment can reduce proteinuria in patients who achieve a virologic response (156). The choice of antiviral treatment depends upon the hepatitis C genotype and a patient’s renal function (157). Sofosbuvir is a recently approved drug that can achieve sustained virologic response with all of the different genotypes (158). Although patients with a GFR <30 mL/minute were not initially studied, subsequent reports have effectively used sofosbuvir in patients with advanced renal failure (159). Acute nephritic flares are not controlled by antiviral therapy. In this setting, aggressive therapy with plasmapheresis, corticosteroids, and cyclophosphamide may be effective at controlling the disease flare (160). Rituximab has also been reported to improve the serologic parameters and the degree of proteinuria (161).


Chronic infection with hepatitis B virus (HBV) is most common in Asia and Africa, where the prevalence of HBV infection is the highest and where there is the highest incidence of vertical transmission. Acute infection with HBV can cause a serum sickness–like syndrome or polyarteritis nodosa (PAN). The latter condition affects small or medium-sized arteries. The glomeruli may show ischemic changes in patients with PAN, and membranous and proliferative glomerular lesions can also occur. Chronic carriers of HBV can develop mesangial, subendothelial, and subepithelial IC deposits, and HBV-associated antigens are frequently detectable within the glomeruli (162). The mesangial and subendothelial deposits cause a MPGN pattern of injury. Subepithelial deposits cause a membranous pattern of disease and nephrotic syndrome, although concurrent mesangial and subendothelial deposits are also frequently present in these patients. HBV infection is also associated with the development of IgAN. Treatment of the HBV infection with IFN probably ameliorates the renal disease in some patients (163), and treatment with lamivudine has improved the renal disease in some case reports. Treatment with immunosuppressive medications can be considered in severe cases, such as in patients with RPGN or severe manifestations of PAN.


Glomerular disease may be seen in patients infected with several types of parasites. Acute IC–mediated GN may be seen in patients with malaria, including a chronic proliferative GN in patients infected with Plasmodium malariae (164). Schistosoma mansoni infections may cause IC-mediated GN and amyloidosis. Several other parasitic infections have also been associated with IC-mediated GN, presenting with proliferative or membranous patterns by light microscopy.


SLE is an autoimmune disease that can affect multiple different organs, including the skin, joints, lungs, and kidneys. Up to 60% of adults and 80% of children who are diagnosed with lupus will develop renal abnormalities at some point (165), but there is patient-to-patient variation in the nature of the renal disease. Aggressive immunosuppressive therapy has greatly improved the outcome in patients with lupus nephritis over the past several decades, and the impact of newer therapies on the overall prognosis is not yet known. Nevertheless, up to 30% of patients with renal involvement may go on to ESRD with long-term follow-up (166,167), and overall patient survival is worse in those with renal involvement (168). One of the great challenges in treating patients with lupus, therefore, is to identify those patients who will most benefit from aggressive immunosuppression while also minimizing the toxicities of therapy.


The pathogenesis of lupus itself remains uncertain, but it likely involves genetic defects that cause a loss of tolerance to self-antigens. Patients with lupus frequently develop high-affinity autoantibodies to nuclear antigens, cytoplasmic antigens, platelets, and erythrocytes. Antibodies to dsDNA, other nuclear components, and α-actinin are associated with renal disease, and there is evidence that these antibodies are pathogenic (169). Antibodies to other glomerular proteins have also been identified, including antibodies to α-enolase, annexin A1, and annexin A2 (170,171). Antibodies to C1q are also commonly seen in the kidneys of patients with lupus nephritis, and these antibodies may exacerbate renal injury (172).

In patients with lupus nephritis, ICs may be found in mesangial, subendothelial, and/or subepithelial locations. ICs cause tissue inflammation by activating complement and through their interaction with Fc receptors on immune cells. The location of the ICs correlates with the light microscopic changes and with the clinical presentation. Mesangial ICs may cause mesangial expansion and hypercellularity, and patients typically have microscopic hematuria and subnephrotic range proteinuria. Subendothelial ICs cause an exudative lesion in the glomerulus. There is leukocyte infiltration and endocapillary proliferation. Subepithelial ICs tend to cause proteinuria and a membranous pattern of glomerular injury. IC deposition and inflammatory cells can also damage the tubules and blood vessels. Some patients develop renal injury caused by antiphospholipid antibody–mediated glomerular thrombosis.

Secondary Factors

Some drugs are associated with the development of a lupus-like syndrome. These patients develop ANA and antihistone antibodies, but anti-dsDNA antibodies and renal involvement are rare. Commonly implicated drugs include procainamide and hydralazine.


Depending on the severity of the renal disease, patients may present with proteinuria (subnephrotic or nephrotic), hematuria (microscopic or gross), red blood cell casts, hypertension, edema, and an elevation in serum creatinine. Patients can present with a pulmonary-renal syndrome, and some patients develop an RPGN. Although the clinical presentation may correlate with the histologic pattern (e.g., a nephritic pattern of disease with subendothelial deposits and endocapillary proliferation), the clinical findings do not accurately predict the histology or the prognosis.

Serologic Findings

Virtually all patients with lupus nephritis have a positive ANA. As mentioned above, anti-dsDNA antibodies may be pathogenic in lupus nephritis and are very specific. C3 and C4 levels are frequently depressed in patients with active disease. In some patients, serologic changes may predict disease flares (173). Persistently high anti-dsDNA antibodies or low C3 levels are also associated with a greater risk of disease flare and disease progression (174,175), but these tests do not reliably predict disease flares. Thus, although perturbations in the levels of these factors may prompt closer monitoring or even a repeat renal biopsy, there is no evidence to support altering treatment in an effort to normalize their levels.

Histologic Patterns

Because the clinical course of lupus nephritis is so variable and the medications used to treat the disease have many potential side effects, great effort has been made to identify patients who benefit from aggressive immunosuppression. The WHO classification scheme was first proposed in 1982 (176), and has been modified several times since then (177). This scheme includes six classes of glomerular involvement, with several different subclasses (Table 15-9). Several series have established the importance of the WHO classification for predicting patients’ long-term outcomes (178). Equally important, this classification scheme has been used as a criterion for the selection of patients in most large clinical trials. To determine whether clinical trials apply to a particular patient, therefore, the patient’s histologic class must be established. Other factors on the biopsy that may help identify which patients are at a high risk of progression include activity and chronicity indices (179). Over time, the histologic pattern of disease can change (167). For this reason, repeat biopsies are often necessary for optimal assessment of disease activity (180).


The course of lupus nephritis has improved in recent decades, but lupus is still a significant cause of CKD and ESRD (166,181). Important prognostic factors include the WHO histologic classification and disease activity and chronicity. In some reports, patients with WHO class IV disease were more likely to respond to treatment than those with WHO class III disease (182), perhaps due to different mechanisms of glomerular injury (183). In patients with severe proliferative disease, those who achieve and maintain remission with therapy have better long-term outcomes (182). A lower serum creatinine and lower urine protein excretion predict a response to therapy, and those patients who enter remission tend to show marked improvement within 4 weeks of initiating therapy. Urine protein excretion at 1 year is predictive of the long term prognosis (184). Several series have reported that black patients are less likely than white patients to respond to therapy (182,185). Patients who have flares of their renal disease, particularly nephritic flares, have a worse long-term outcome (186,187).

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Dec 22, 2019 | Posted by in NEPHROLOGY | Comments Off on The Glomerulopathies

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