Primary glomerular diseases include a group of disorders characterized by pathologic alterations in normal glomerular structure and function, independent of systemic disease processes. This distinction is important because the clinical presentation and pathologic findings of glomerulopathies secondary to systemic diseases may mirror primary glomerular disorders, yet the correct diagnosis of the underlying systemic disease may significantly alter the treatment of the patient. Furthermore, an understanding of the typical clinical signs of patients with primary glomerular disorders (e.g., proteinuria, hematuria, hypertension, decline in glomerular filtration rate [GFR], edema, and abnormal urine sediments) is essential. From this, the clinician can classify the clinical presentation of the patient, which is the first step to defining the exact disease accurately (Table 1). However, it should be noted that the same primary glomerular disease as diagnosed on pathologic grounds may manifest differently in patients, from the benign to the severe (Box 1). This likely reflects our poor understanding of their underlying pathophysiology and how a particular disease may actually represent a spectrum of disorders that pathologically may be similar but phenotypically manifest as a wide spectrum.

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Minimal Change Disease

Pathologic Definition

Minimal change disease (MCD), historically referred to as nil disease, is characterized by an absence of glomerular pathology by light microscopy or immunofluorescence. There may be extraglomerular findings by light microscopy, including intratubular lipid and protein resorption droplets—hence the alternate name, lipoid nephrosis—and focal proximal tubular epithelial flattening. However, although not specific to MCD, the classic finding of MCD is effacement of visceral epithelial cell foot processes seen using electron microscopy.

Prevalence and Risk Factors

MCD is the most common primary glomerular disease in children, accounting for 70% to 90% of cases of nephrotic syndrome for those younger than 10 years, with the incidence peaking between ages 2 and 4 years.¹ The prevalence declines with age, whereby it is responsible for only 10% to 20% of cases of nephrotic syndrome in adults. There appears to be a higher predominance in Asia compared with the United States and Europe, although no strong gender predominance exists.²

Pathophysiology and Natural History

The underlying mechanism(s) leading to MCD is unknown. Some studies have implicated upregulation of various cytokine activities, including interleukin-2, during disease activity. It has been postulated that this may induce glomerular permeability factor(s) that interfere with normal function of the charge-selective barrier to filtration of serum proteins.³ As with all primary glomerular disorders, when approaching a patient with a new diagnosis of MCD, it is important to exclude secondary causes. Most notable on this list is the use of medications that have a strong association with MCD, including nonsteroidal anti-inflammatory drugs and certain antibiotics, including rifampin. Additionally, although rare, lymphoid malignancies such as Hodgkin’s disease and leukemia may manifest along with nephrotic syndrome from MCD.

Signs and Symptoms

Patients with MCD typically present with findings consistent with the nephrotic syndrome (see Table 1). Although not specific to primary glomerular disorders, the abrupt onset and generalized distribution of edema are typically what lead the patient to medical attention and should indicate that the clinician consider a primary kidney disorder as the causative factor. More common in children, visceral effusions (pleural, peritoneal, and pericardial) may also accompany the peripheral edema. Children are typically normotensive, but elevated blood pressures may be present in adults. Finally, patients may also present with syndromes resulting from the biologic complications of the nephrotic syndrome that are not necessarily specific to MCD. Venous and, much less commonly, arterial, thromboses may occur, caused by several factors that lead to thrombophilia, including loss of normal anticoagulants in the urine (e.g., antithrombin III, plasminogen) and excessive hepatic production of procoagulants (e.g., fibrinogen, factors II, V, VII, VIII, X, and XIII).⁴ Additionally, loss of immunoglobulins in the urine may predispose patients to infections of various types.

Diagnosis

Albuminuria detectable by urine dipstick is the most common laboratory finding in patients with MCD. When quantified by a 24-hour urine collection or spot urine protein-to-creatinine concentration ratio, the degree of proteinuria may be severe. Microscopic hematuria is not the norm, but may occur in up to 25% of patients, and macroscopic hematuria is decidedly rare. Active urine sediment changes (e.g., dysmorphic RBCs and RBC casts) should not be present in patients with MCD. However, lipiduria in the forms of free fat, oval fat bodies, and lipid casts may be present on urine microscopy. Hypoalbuminemia correlates with the severity of the degree of proteinuria, and in children can be severely depressed to lower than 1 g/dL. As a result, the hypoalbuminemia and total serum calcium levels are low, but the corrected calcium and ionized calcium levels are usually normal.

Renal function, as evidenced by serum creatinine level, is typically normal, especially in children. However, some patients with MCD also present in acute renal failure, with an elevated serum creatinine level.⁵ Risk factors for this include age older than 45 years, the coexistence of hypertension, and heavier degrees of proteinuria. Pathologically, these patients exhibit concomitant acute tubular necrosis on their biopsy specimens. Clinically, successful treatment of the nephrotic syndrome invariably is associated with resolution of the acute renal failure.⁵

An increase in total and low-density lipoprotein (LDL) cholesterol levels is often seen, as is hypertriglyceridemia. If the hyperlipidemia is severe enough, pseudohyponatremia may be present.

Although the circulating red blood cell mass remains normal in the absence of renal failure, given that plasma volume is often decreased in patients with MCD and the nephrotic syndrome, elevations of the hematocrit and hemoconcentration can be observed. Erythrocyte sedimentation rate is often elevated because of hyperfibrinogenemia, but complement levels are normal.

Diagnostic Procedures

Given the predominance of MCD as the leading cause of nephrotic syndrome in children younger than 10 years, many clinicians will treat empirically in this age group, resorting to a kidney biopsy only in cases of treatment failure. In older age groups, however, given that the causes of nephrotic syndrome by primary glomerular disorders are varied, a kidney biopsy for older children and adults is indicated.

Summary

• MCD is the most common cause of primary glomerular disease in children.
• The typical presentation is the nephrotic syndrome.
• Renal failure is uncommon, except in older adults.

Treatment

After the diagnosis of MCD is made, therapy should concentrate on management of the biologic consequences of the nephrotic syndrome (e.g., edema, proteinuria, hypertension if present, and hyperlipidemia), as well as on induction of remission with immunosuppressive agents. Regarding the former, escalating doses of loop diuretics given at least twice daily, with or without concomitant thiazide-type diuretics, may be necessary to maintain euvolemia. Additionally, the use of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) reduce proteinuria to some degree; these are the agents of choice if concomitant hypertension is present. Controlling blood pressure to lower than 130/80 mm Hg is advocated for any patient with kidney disorders.^6, 7 Use of antihyperlipidemic agents, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are recommended, although often not sufficient to reach the treatment goals in patients with kidney disease⁸ if the degree of proteinuria remains severe.

Beyond this symptomatic treatment, induction of remission using immunosuppressive agents is indicated for all patients with MCD if not contraindicated. In select patient populations, up to 90% of children and 80% of adults enter complete remission (i.e., absence of dipstick proteinuria) after 2 and 4 months, respectively, of therapy with prednisone. Typical dosing regimens include daily prednisone (1 mg/kg/day for adults, 60 mg/m²/day for children, maximum 80 mg/day), generally using alternate-day dosing soon after remission or sometimes from onset of therapy, with tapering doses for a total course of 2 to 6 months.^9, 10 Relapses of MCD after steroid withdrawal or during steroid wean (steroid dependence) are common, especially in children. If frequent relapses occur, or in cases of steroid dependence, alternate therapies using cytotoxic agents (usually cyclophosphamide) are indicated as steroid-sparing agents. Steroid-resistant patients may respond to therapy with cyclosporine, but often relapse with withdrawal of that agent.

Summary

• Nonimmunosuppressive management includes diuretics, ACE inhibitors, ARBs, and statins.
• Patients are exquisitely steroid sensitive, with a high remission rate.
• Relapses and steroid dependence are common and may require cytotoxics; steroid resistance is rare and may be treated with cyclosporine.

Prognosis

MCD in general carries with it a good renal prognosis and ESRD is extremely rare. However, management of complications of the nephrotic syndrome (e.g., edema, infections, thrombophilia) and complications of the immunotherapy, most notably those related to corticosteroids, may prove challenging to the clinician and affect the morbidity of the patient.

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Focal Segmental Glomerulosclerosis

Pathologic Definition

Focal segmental glomerulosclerosis (FSGS) defines a characteristic pathologic pattern of glomerular injury and is not necessarily a distinct disease. The hallmark of kidney biopsy is an increased degree of scarring seen on light microscopy of some but not all of the glomeruli present (focal) that involves some but not all portions of the affected glomeruli (segmental). There are five distinct pathologic variants of FSGS. The importance of distinguishing these variants involves their different natural histories and responses to therapy. Apart from this, other nonspecific pathologic manifestations include low-level staining for immunoglobulin M (IgM) or C3 in sclerosed portions of the mesangium and fusion of epithelial foot processes in sclerosed and nonsclerosed portions of affected glomeruli. This pattern of injury can be seen as a manifestation of chronic injury induced by many different kidney disorders, and thus is regarded as secondary FSGS. For example, kidney biopsy specimens of patients with chronic vesicoureteral reflux may show FSGS-like patterns of injury. Conversely, patients with an appropriate clinical presentation (see later) lacking other identifiable kidney disorders who exhibit this pathologic pattern are correctly regarded as having idiopathic or primary FSGS. Such differentiation between primary and secondary FSGS may prove difficult at times, but is crucial when it comes to accurate treatment and prognosis.

Prevalence and Risk Factors

Primary FSGS is one of the two most common causes of idiopathic glomerular disease in adults, accounting for up to 25% to 35% of cases of nephrotic syndrome in all adults.¹¹ There is a two to four times higher prevalence of the disease in African Americans compared with whites. It is the most common primary glomerular disorder to cause ESRD in the United States, accounting for approximately 2.3% of the ESRD population.¹²

Pathophysiology and Natural History

Similar to MCD, primary FSGS is believed to occur as a result of a T-cell disorder resulting in the production of a circulating permeability factor, the identification of which has proven elusive, but may be a cytokine or lymphokine. This permeability factor is believed to lead to glomerular injury and proteinuria, hyperfiltration, and scarring. A small fraction of primary FSGS cases result from an inherited disorder of structural parts of the glomerular basement membrane or podocyte that results in altered glomerular function; these are not caused by a circulating factor. Secondary FSGS is known to occur in the setting of many different renal disorders, which can be classified based on the following: those leading to reduced nephron mass and/or glomerular hyperfiltration (e.g., aplasia or dysplasia, vesicoureteral reflux, morbid obesity); inflammatory renal disorders causing glomerular epithelial cell injury and subsequent scarring (e.g., lupus, focal proliferative glomerulonephropathy, vasculitis); infectious (e.g., HIV-associated FSGS); and toxins (e.g., heroin nephropathy).

Signs and Symptoms

As with MCD, the hallmark of FSGS is the presence of proteinuria, which can vary in severity from only 1 to 2 g/day to more than 10 g/day. Unlike MCD, at presentation, patients with FSGS are more prone to have concomitant microscopic hematuria (up to 50% of the time), hypertension (33% of the time), and a depressed glomerular filtration rate leading to elevated serum creatinine levels (33% of the time). Typically, patients with heavy proteinuria present clinically with signs and symptoms of the nephrotic syndrome (see earlier). As with MCD, serum complement levels are normal.

Diagnosis

The laboratory findings in FSGS are similar to those of MCD, with the exception of a higher likelihood of patients presenting with significant azotemia. Red blood cell (RBC) casts or dysmorphic RBCs are not characteristic of FSGS; their presence should point the clinician to disorders that can manifest with the nephritic syndrome. As with MCD, a kidney biopsy is usually necessary to establish the diagnosis.

Summary

• FSGS is the most common cause of primary glomerular disease in African American adults.
• It typically manifest with the nephrotic syndrome.
• Patients are likely to present with an elevated creatinine level.
• It is the most common primary glomerular disease leading to ESRD.

Treatment

Similar to MCD, the treatment of FSGS involves conservative measures (e.g., edema control with diuretics, hypertension management, treatment of hyperlipidemia, ACEs and/or ARBs) and those that target the proposed immune basis of the disorder specifically. The former (see earlier, MCD section), is indicated for all patients with FSGS, primary or secondary, regardless of the degree of proteinuria or azotemia. The latter is reserved for those patients with primary FSGS with nephrotic-range proteinuria and the absence of advanced azotemia. The options for immunosuppressive therapy include steroids alone (prednisone, 1 mg/kg daily or 2 mg/kg every other day) or, if comorbid conditions preclude the safe use of high-dose steroids, calcineurin inhibitors such as cyclosporine, 3 to 4 mg/kg/day in divided doses, with or without low-dose steroids. Use of calcineurin inhibitors should be avoided in patients with estimated GFRs lower than 40 mL/min/1.73 m² because of the concern for nephrotoxicity associated with their prolonged use.

The success of therapy is measured by the nephrotic patient’s response in terms of proteinuria reduction: complete remission (CR), lower than 200 mg/day; partial remission (PR), 200 to 3500 mg/day; partial responder (PR), more than 50% reduction in proteinuria from baseline but still >3500 mg/day; and nonresponder (NR), less than 50% reduction in proteinuria and still >3500 mg/day. The success of therapy should not be determined for at least 4 months after initiation of therapy because of the well-described occurrence of fairly late treatment responses that may be missed if therapy is abandoned too soon after initiation. Duration of therapy should continue for 6 to 12 months after the onset of remission, with tapering prednisone doses. Patients who fail to reach a CR or PR with an adequate steroid trial are termed steroid-resistant and deserve a trial of a calcineurin inhibitor, if not contraindicated. Those who reach a CR or PR, but then subsequently develop recurrent nephrotic-range proteinuria during or shortly after steroid weaning, are termed  steroid-dependent and may be tried on cytotoxic agents, such as cyclophosphamide, or other novel agents, such as mycophenolate mofetil or sirolimus. On average, approximately 40% to 80% of patients will achieve CR or PR with therapy, although the chance of relapse is high after cessation of cyclosporine (approximately 75%).

Summary

• Prednisone therapy is used at 1 mg/kg/day for at least 4 months.
• Monitor degree of proteinuria to determine therapeutic success.
• Calcineurin inhibitors are useful for those intolerant of high-dose steroids but without advanced azotemia.

Prognosis

As noted, primary FSGS is the most common cause of any primary glomerular disease leading to ESRD. Determining a patient’s risk of this and pace of progression of azotemia is dependent on factors determined at clinical presentation (e.g., severity of proteinuria, degree of azotemia, pathologic variant, degree of interstitial disease on biopsy) and during therapy (e.g., CR vs. PR vs. NR). Regarding the former, subnephrotic patients with a normal serum creatinine level at baseline have the slowest rate of progression to kidney failure (i.e., 80% survival-free of ESRD at 10 years) compared with heavily nephrotic patients with more than 10 g/day (i.e., almost all ESRD by 3 years).^13, 14 Regarding the latter, those achieving CR or PR have a superior renal survival compared with nonresponders: less than 15% ESRD at 5 years versus 50% ESRD at 6 months, respectively.¹⁵

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Membranous Glomerular Nephropathy

Pathologic Definition

Membranous glomerular nephropathy (MGN) is a kidney disorder defined by characteristic microscopic and immunofluorescence findings. On light microscopy, there is diffuse thickening of glomerular capillary walls without associated hypercellularity. On immunofluorescence, there is diffuse granular staining of the glomerular capillary loops: typically, for IgG more than IgA or IgM, as well as C3. On electron microscopy, the pathologic hallmark confirming MGN is electron-dense deposits in the subepithelial region of the glomerular basement membrane. These deposits correspond to the immunoglobulins seen on immunofluorescence. Occasionally, these deposits are large enough that they can be seen with special stains on light microscopy directly, or may induce adjacent changes of glomerular basement membrane material, leading to a spike appearance on either side of the deposit.

Prevalence and Risk Factors

Similar to FSGS, MGN is one of the most common primary glomerular diseases to cause nephrotic syndrome, accounting for 33% of cases,¹¹ with a predominance in men older than 40. And, similar to FSGS, MGN can result as part of a multisystem disease process such as lupus or chronic hepatitis B, or as a paraneoplastic manifestation of extrarenal carcinomas, appropriately called secondary MGN. Although primary MGN can occur in children, it is typically found in adults, with a peak incidence in the fourth or fifth decade of life.

Pathophysiology and Natural History

The cause of immunoglobulin deposition in the subepithelial location of the glomerular basement membranes in MGN, and its subsequent damage and altered structure, function, or both, are not completely known. It is believed that antigen-antibody complexes form in situ in the subepithelial space, possibly as a result of a freely circulating antibody recognizing and binding to a resident antigen within the glomerulus. Whatever the antigen stimulus may be, when the complex is formed, it is believed that complement activation occurs that produces toxic substances (e.g., the C5b-9 membrane attack complex); these directly induce damage to nearby cells and lead to the pathologic changes seen on biopsy and to the clinical manifestation of proteinuria or azotemia, or both. In the absence of other causes, which can accelerate the rate of loss of renal function (e.g., superimposed drug-induced acute interstitial nephritis, bilateral renal vein thrombosis), chronic kidney disease progression in MGN patients is slow in those who remain free of remission, with progression rates to ESRD averaging 30% to 40% at 10 to 15 years.¹⁶ Clinical factors associated with an increased risk of this include age older than 50 years, male gender, proteinuria higher than 8 g/day, an elevated creatinine level at presentation, and higher scores of tubulointerstitial damage seen on biopsy. However, there is a well- documented occurrence of spontaneous remission of proteinuria in those with MGN who initially presented as nephrotic, ranging in up to 50% of cases, if followed untreated long enough: at least 5 years.¹⁷

Signs and Symptoms

Although patients with MGN may present with asymptomatic proteinuria, most present with signs and symptoms typical of the nephrotic syndrome. Up to 50% of patients may have some degree of hypertension at the onset of the disease. Rarely, patients will present with symptoms attributable to the hypercoagulability that may accompany nephrotic syndrome, most notably lower extremity venous thrombi causing pain or renal vein thrombosis with flank pain. Renal function is usually preserved at presentation unless MGN has gone undiagnosed for many years. Although only 3.5 g of proteinuria/day is sufficient to be regarded as in the nephrotic range, patients with MGN commonly have massive proteinuria, exceeding 10 to 20 g/day. Microscopic hematuria is seen in up to 50% of cases, although as with FSGS, RBC casts or dysmorphic RBCs should not be present. Although known as an immune complex disease, serum complement levels of C3 and C4 are normal.

Diagnosis

Adults presenting with the nephrotic syndrome and a relatively normal serum creatinine level are likely to have MGN in the absence of signs or symptoms suggestive of a systemic disease process. As noted, a kidney biopsy is necessary to delineate the pathology from the other disorders mentioned. However, given that MGN may be the presenting manifestation of a yet undiagnosed systemic disease, combined with the clinical importance of diagnosing such diseases early, all adults diagnosed with MGN on biopsy deserve a dedicated evaluation of secondary causes. This includes a remote hepatitis panel, VDRL, serologic markers of autoimmune disorders (e.g., lupus or mixed connective tissue disease), and age-appropriate cancer screening.

Summary

• MGN is one of the two most common primary glomerular diseases to cause nephrotic syndrome in adults.
• Severe proteinuria of more than 10 g/day and relatively normal serum creatinine level at presentation are not uncommon.
• Normal C3 and C4 levels are present, despite immune complex deposition seen pathologically on biopsy specimens.

Treatment

Given the relatively benign course in remission-free patients, together with a moderate chance of spontaneous remission without specific therapy, much controversy exists regarding the appropriate intensity of treatment for MGN. All patients deserve the conservative treatment of blood pressure control to lower than 130/80 mm Hg, ACE or ARB use, or both, and treatment of lipid disorders. Regarding the use of immunosuppressive therapy, however, scrutiny must be given to the risk of such treatment versus a potential benefit over the long term. This risk-to-benefit ratio only favors intense treatment for those patients who have a high likelihood of faster progression of kidney disease, which may be predicted by the presence of additive clinical risk factors present at diagnosis (see earlier). For those patients deemed high risk and in need of dedicated immunotherapy, treatment options include steroid-only regimens (e.g., prednisone at a dose of 2 mg/kg on alternate days for at least 8 weeks), alkylating agent-based regimens (e.g., 6 months of alternating steroids and cyclophosphamide),¹⁸ and cyclosporine-based regimens (e.g., 6 months of twice-daily cyclosporine, targeting a trough level of 150 μg/L, plus low-dose prednisone).¹⁹ Remission (complete or partial) rates vary among the treatment protocols, from 20% to 40% for steroid alone to almost 67% for alkylating agent or cyclosporine-based regimens, although the latter is complicated by a significantly higher relapse rate.

Summary

• Immunosuppressive therapy is controversial, given the relatively benign course and moderate chance of spontaneous remission.
• Immunosuppressive therapy is reserved only for those at highest risk for faster progression to ESRD.
• Steroid-only, alkylating agent–based, or cyclosporine-based regimens are all used, with varying degrees of success.

Prognosis

As noted, the prognosis of MGN is diverse and varied, based on pertinent clinical factors at presentation and the occurrence of remission, whether it is spontaneous or induced by specific immunotherapy. In general, those patients free of remission typically have a slow progressive loss of renal function, leading to ESRD. A pertinent caveat of MGN is the higher degree of hypercoagulability with the nephrotic syndrome compared with other primary glomerular disorders. Although any venous thrombosis event appears to be more likely in patients with MGN compared with other primary glomerular diseases, a significant consideration that may significantly affect renal and patient survival is the development of renal vein thrombosis, which may occur in approximately 15% of cases.

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Immunoglobulin a Nephropathy

Pathologic Definition

The hallmark of IgA nephropathy (IGAN) is the presence of IgA deposits, predominantly in the mesangium, on biopsy specimens. Other immunoglobulins may also be present to a lesser degree, such as IgG or IgM. On light microscopy, pathologic findings may vary, from completely lacking to a severe diffuse proliferative glomerulonephritis, depending on the severity of clinical presentation. Typically, mesangioproliferative and focal proliferative findings are evident. The most severe cases will show diffuse proliferation as well as more than 50% of glomeruli with cellular crescents. Electron microscopic findings include electron-dense deposits in an expanded sclerotic mesangium.

Prevalence and Risk Factors

IGAN is believed to be the most common primary glomerular disease worldwide, but its incidence is likely underestimated by a bias against doing a biopsy in patients with a relatively benign presentation and clinical course. This is seen by the discrepancy in prevalence rates in Asia (>40% of biopsy specimens), where patients are more likely to receive a kidney biopsy with any urine sediment alterations as opposed to North America, where biopsies are typically reserved for patients with heavier degrees of proteinuria accompanying hematuria.²⁰ Although seen at all ages, it is predominant in the second and third decades of life, with a male predominance.

Pathophysiology and Natural History

Although not exactly known, it is believed that IGAN represents abnormal polyclonal IgA production as part of mucosal host defense, specifically a post-translational glycosylation defect of that protein. This abnormal glycosylation impairs the normal clearance from the bloodstream of the circulating IgA molecules, as well as predisposing their deposition within the kidneys. Given the inability of IgA molecules to fix complement once it is deposited, the mechanism of renal injury is poorly understood. In the absence of a severe presentation of IGAN, with heavy proteinuria and azotemia, most patients have a favorable renal course. Most will have one or a few intermittent episodes of IGAN that spontaneously resolve, without long-term effects on renal function. Indeed, only 1% to 2% of patients will develop ESRD as a result of IGAN. However, with extended follow-up of higher risk patients, especially those with persistent microscopic hematuria and heavier proteinuria, up to 20% to 30% will develop ESRD two decades after diagnosis.²¹

Signs and Symptoms

Patients with IGAN present on a wide spectrum, from asymptomatic microscopic hematuria to rapidly progressive renal failure, with heavy degrees of proteinuria. Knowing how IgA production is related to a mucosal host defense mechanism, it has been found that many patients present with abnormal urine findings soon after a current or recently resolved upper respiratory tract infection.

The most common presentation (40%-50% of cases) of IGAN is a single or sparsely recurrent episodes of gross hematuria at the time of or soon after a respiratory infection; this occurs more in children than in adults. Patients may also complain of dysuria and be mistakenly diagnosed with a urinary tract infection or with fevers and myalgias, and deemed to have a nonspecific viral syndrome. Such patients typically present with normal renal function and dysmorphic RBC, or RBC casts may be present.

The next most common presentation of IGAN (40% of cases), and the most predominant in adults, is asymptomatic microscopic hematuria with dysmorphia or RBC casts, with or without concomitant proteinuria or intermittent gross hematuria. Renal function is typically normal at baseline, although it may worsen slowly over time.

The final 20% of patients with IGAN present with hematuria and the nephrotic syndrome or, rarely, with the nephritic syndrome and rapidly progressive renal failure because of a crescentic glomerulonephritis.

Diagnosis

Given the appropriate clinical scenario—new hematuria in the setting of an upper respiratory tract infection with no significant proteinuria and normal renal function—many clinicians would opt for expectant management and reserve kidney biopsy for those with persistent abnormal urine findings, significant proteinuria (>500 mg/day), or an abnormal serum creatinine level. Serum IgA levels may be modestly elevated, although this usually is not helpful in the diagnosis. As expected, serum complement levels are normal.

Summary

• IGAN is the most common primary glomerular disorder worldwide.
• It involves the temporal relation of hematuria to an upper respiratory tract infection.
• Intermittent macroscopic hematuria, without proteinuria, and persistent microscopic hematuria, with or without proteinuria, are the most common presentations.

Treatment

Treatment of IGAN nephropathy is dictated by the clinical presentation of the patient and, if obtained, the pathologic changes seen. Those patients with isolated or recurrent gross hematuria following a respiratory tract infection, without alteration in renal function or significant proteinuria, may be observed without specific treatment. Similarly, patients with isolated microscopic hematuria, or with minimal proteinuria and favorable pathologic changes on biopsy, may be observed without specific treatment. In patients with significant proteinuria or azotemia, treatment with ACEs or ARBs is warranted, with blood pressure targeted at lower than 130/80 mm Hg. One study used ACEs plus ARBs, with favorable results on long-term renal function compared with either agent alone.²² Controversy exists about whether treatment with fish oil in such patients is beneficial but, because of apparently little toxicity with their use, this is reasonable to try in patients at risk for progressive disease. Immunosuppressive therapy should be reserved for patients with the most severe clinical presentation or biopsy findings, or both. Patients with nephrotic syndrome may be tried on steroid-only regimens, such as prednisone, 2 mg/kg every other day for 3 months, tapered off over 3 months. For the most severe cases of rapidly progressive crescentic glomerulonephritis, a combined regimen of oral or intravenous cyclophosphamide along with steroids should be used for 3 months, followed by a prolonged steroid taper.

Summary

• Treatment is dictated by clinical presentation and biopsy findings.
• Moderate-risk patients should receive ACE inhibitors or ARBs, or both, statins, and possibly fish oil therapy.
• Severe cases are treated with steroids, with or without cyclophosphamide.

Prognosis

Generally, the long-term renal prognosis of IGAN is favorable. The most common clinical and most benign course is isolated events of macroscopic hematuria without proteinuria and normal renal function. These patients do well over time, without significant renal events. Patients with persistent urine abnormalities, especially those with higher degrees of proteinuria, are at risk for progression of renal disease over time, although the pace may be significantly slowed by the treatment regimens discussed. The worst prognosis is limited to those with crescentic glomerulonephritis, as would be expected.

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Membranoproliferative Glomerulonephritis

Pathologic Definition

Biopsy specimens from patients with membranoproliferative glomerulonephritis (MPGN) are characterized by global capillary wall thickening and glomerular hypercellularity. The increased cellular content occurs because of proliferation of resident glomerular cells, as well as infiltrating mononuclear cells and neutrophils. Often seen, but not necessarily specific to MPGN, is double contouring or splitting of the glomerular capillary basement membranes. A subset of patients with MPGN may exhibit cellular crescents within Bowman’s space. Immunofluorescence studies demonstrate diffuse granular or bandlike intense staining of capillary loops and mesangium with C3, and to a lesser extent IgG and IgM. MPGN pathognomonic changes on electron microscopy are subendothelial and mesangial electron-dense deposits; the former are found in an expanded subendothelial region of the glomerular basement membrane formed by projections of mesangial cytoplasm. Some subepithelial deposits may also been seen, but they are not as prominent as in cases of MGN. A subset of MPGN cases (type II MPGN) have a different hallmark electron microscopic finding than the discrete subendothelial deposits (type I MPGN). In the former, a bandlike, almost continuous, ribbon of the electron-dense material is found in the subendothelial space.

Prevalence and Risk Factors

MPGN is a rare primary glomerular disorder and appears to be decreasing in frequency. A possible reason for this is correction of what used to be known as primary MPGN, but actually was a renal manifestation of hepatitis C virus infection and mixed essential cryoglobulinemia. Such cases are now correctly defined as secondary MPGN. Primary MPGN is a disease mostly found in children, with more than 75% of cases diagnosed between ages 8 and 16 years.²³ It accounts for approximately 10% of biopsy specimens of primary glomerular disorders.

Pathophysiology and Natural History

Similar to MGN, MPGN is classified as an immune complex disease and the presumptive pathophysiologic mechanism is the inappropriate production of antibodies recognizing a nephritogenic antigen. Unlike MGN, in which it is believed that antigen is inherent in the glomerular structure itself, MPGN is believed to occur as a result of deposition of circulating antigen-antibody complexes. These traverse the large pores found between glomerular endothelial cells and deposit between them and the glomerular basement membrane. Complement activation results from the deposition of these antigen-antibody complexes and results in a cascade of proinflammatory signals that stimulate local cell proliferation and recruitment of circulating immune cells, which augments the inflammatory reaction. This ongoing inflammation is believed to be the major reason for the ensuing renal damage.

Signs and Symptoms

Patients with MPGN may present with different clinical syndromes. Approximately 50% exhibit signs and symptoms typical of the nephrotic syndrome, whereas 25% of patients only present with asymptomatic hematuria and proteinuria. The remaining 25% present more severely, with the acute nephritic syndrome. Although 50% of all patients may have some degree of azotemia at presentation, those exhibiting a nephritic as opposed to a nephrotic picture tend to have more depressed renal function at baseline, which declines rapidly.

Diagnosis

As with all glomerular diseases, one must be cognizant of systemic processes in which MPGN may be a common renal manifestation. These include autoimmune diseases such as lupus, viral infections such as hepatitis C or B, and chronic bacterial infections such as endocarditis or chronic abscesses. Rarely, MPGN may represent a paraneoplastic manifestation of solid or liquid malignancies. Correct identification of a systemic disease leading to MPGN is critical because treatment of the underlying disorder, and not the renal lesion itself, is appropriate. Beyond the typical findings of the nephrotic or nephritic syndrome, few other symptoms may aid the clinician in distinguishing primary MPGN from other primary glomerular disorders. However, the urine sediment becomes a valuable tool in this setting. Unlike the other primary glomerular diseases that cause nephrotic syndrome, patients with MPGN exhibit an active sediment, defined by hematuria with associated dysmorphic RBCs (e.g., acanthocytes) as well as RBC casts. Additionally, because the inflammatory reaction induced by the deposition of the immune complexes is in the subendothelial space and directly in contact with circulating complement, which they can fix and activate, hypocomplementemia is characteristic of all types of MPGN. C3 and C4 levels are more equally depressed in type I MPGN because of activation of the classic complement pathway as opposed to type II MPGN, in which C3 levels are lower than C4 because of preferential activation of the alternative complement pathway.

Summary

• MPGN is more prevalent in children and young adults.
• The clinical presentation may be nephrotic syndrome, nephritic syndrome, or asymptomatic hematuria and proteinuria.
• An active urine sediment and hypocomplementemia in the absence of systemic diseases are useful clinical clues.

Treatment

Patients with MPGN follow the rule of thirds. That is, approximately one third will have a spontaneous remission, one third will have persistent manifestations that intermittently wax and wane, and one third will have a progressive decline to ESRD. Factors that may predict the latter include heavier degrees of proteinuria or the nephrotic syndrome, or both, hypertension, advanced azotemia at baseline, and a nephritic presentation, especially with crescents on biopsy. After excluding important secondary causes of MPGN, most notably hepatitis C infection, immunosuppressive therapy should be tried for these patients, in addition to conservative management. Most data on treatment have come from pediatric studies,²⁴ but a potential adult regimen includes prednisone, 2 mg/kg every other day for 3 to 12 months, depending on the rate of response. If a significant response is seen, with a decline in proteinuria, stabilization of serum creatinine level, and improvement in activity of the urine sediment, the steroids may be tapered to 20 mg every other day and maintained for another few years. Other therapies, in addition to steroids, such as antiplatelet agents (e.g., aspirin, dipyridamole), with or without cytotoxic agents, have not convincingly proven to be of benefit.

Summary

• Restrict immunosuppressive patients to those at highest risk for progression-heavier proteinuria, nephritic syndrome, elevated creatinine level at baseline, and crescents on biopsy.
• It is crucial to exclude secondary causes, most notably hepatitis C, before initiating immunosuppressive therapy.
• Prednisone, 2 mg/kg every other day for many months, tapered to 20 mg every other day for several years, may be given.

Prognosis

Given the rule of thirds, the renal prognosis of patients with MPGN depends exactly on presentation. Those with asymptomatic hematuria and non-nephrotic proteinuria have a relatively benign course, whereas those with more severe presentations who fail to remit spontaneously or with therapy will progress to ESRD faster. On average, progression to ESRD 10 years after diagnosis will occur in is 35% to 60% of patients with MPGN.^25, 26

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Special Cases of Crescentic Glomerulonephritis

Pathologic Definition

As discussed for MPGN and IGAN, there are some severe forms of primary glomerular diseases that manifest clinically, with rapid deterioration of renal function associated with diffuse cellular crescents on biopsy. However, there are other forms of primary crescentic glomerular diseases pathologically distinct from those discussed that also lead to rapidly progressive glomerulonephritis (RPGN). Anti–glomerular basement membrane (anti-GBM) disease refers to cases of RPGN characterized by linear staining, as opposed to granular patterns (as in MPGN or IGAN) of IgG along the glomerular basement membranes, almost always in the presence of cellular crescents and fibrinoid necrosis, but usually in the absence of significant hypercellularity. Although most cases of anti-GBM disease occur as part of a systemic process involving other systems—most notably the lungs in the form of Goodpasture’s syndrome, with pulmonary hemorrhage—idiopathic anti-GBM disease can occur as a renal-limited disorder.

Pauci-immune antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis is characterized by a necrotizing, hypercellular, crescentic, glomerular lesion similar to that in anti-GBM disease that lacks any significant immunoglobulin staining in a granular or linear pattern. Again, although usually occurring with multisystem small-vessel ANCA-associated vasculitis syndromes (e.g., Wegener’s granulomatosis, Churg-Strauss syndrome), patients can present with a renal-limited pauci-immune glomerulonephritis. Rarely, there are some forms of crescentic glomerulonephritis with granular immunoglobulin staining similar to but not completely classifiable as other lesions, such as IGAN or MPGN, and are thus known as idiopathic immune complex glomerulonephritis.

Prevalence and Risk Factors

Anti-GBM disease is rare, accounting for less than 20% of all cases of crescentic glomerulonephritis,²⁷ and has a bimodal distribution, the first in the second to third decade of life and the second in the sixth and seventh decades. Pauci-immune ANCA-associated crescentic glomerulonephritis, renal-limited or as part of a systemic vasculitis syndrome, is the most common cause of RPGN in older adults, with a predominance in whites observed.²⁸

Pathophysiology and Natural History

Although many antigens have been described to which the IgG of anti-GBM disease binds, 90% of the time they are directed toward a mutated α₃ chain of type IV collagen, which is a predominant component of the GBM. It is believed that once bound, these IgG molecules stimulate a T lymphocyte-dependent inflammatory reaction that leads to the pathologic and clinical findings observed, including crescent formation and rapid deterioration of renal function. In cases of pauci-immune glomerulonephritis, because of the absence of immunoglobulin deposition, it is believed that the ANCAs directly stimulate a neutrophilic inflammatory process and subsequent damage. If left untreated, both syndromes will lead to complete loss of renal function over a short period of time, in weeks to months).²⁹

Signs and Symptoms

Patients with crescentic glomerulonephritis syndromes in the absence of systemic processes present with the nephritic syndrome with varying degrees of proteinuria, hematuria with dysmorphic RBCs and RBC casts, hypertension, and some degree of azotemia at the time of diagnosis. Patients may also exhibit concomitant or subsequent extrarenal signs and symptoms if the anti-GBM disease is present as part of Goodpasture’s syndrome (e.g., hemoptysis or frank pulmonary hemorrhage, respiratory failure), or if the pauci-immune glomerulonephritis is part of systemic small-vessel vasculitis syndromes (e.g., recurrent sinusitis, hemoptysis, abdominal pain, arthralgias, mononeuropathies).

Diagnosis

Although pathologic determination is necessary to classify the exact glomerular syndrome, patients exhibiting the nephritic syndrome should also undergo a serologic workup, including determination of complement levels, which are normal in anti-GBM or pauci-immune cases but are usually depressed in cases of idiopathic immune complex glomerulonephritis. Additionally, the presence of circulating anti-glomerular basement antibodies or ANCAs (e.g., c-ANCA against proteinase-3 antibodies or p-ANCA against myeloperoxidase) should be investigated. However, because significant time may elapse before the results of these assays are available, combined with the rapid deterioration of renal function if appropriate therapy is delayed, the clinician should not delay pursuing a renal biopsy if clinical suspicion is high.

Summary

• These rare disorders can manifest with the nephritic syndrome as a renal-limited process or as part of a multisystem disease.
• Although serologic markers are specific, the delay in obtaining the results of such assays should not postpone a kidney biopsy for a definitive diagnosis if clinical suspicion is high.
• Immunofluorescence staining is necessary to differentiate between specific causes, which affect the correct treatment modality to be used.

Treatment

Once the specific type of crescentic glomerulonephritis is determined by kidney biopsy, appropriate treatment should be instituted immediately to preserve renal function and optimize patient survival. Anti-GBM disease treatment includes daily or alternate-day plasmapheresis for 2 to 3 weeks and immunosuppressive therapy with steroids and a cytotoxic agent, such as cyclophosphamide. The goal of the former is to remove the pathologic circulating anti-GBM antibody and the latter is to decrease its production. A typical daily regimen is 1 mg/kg of prednisone plus 2 mg/kg of oral cyclophosphamide. The duration of cyclophosphamide therapy is usually 3 months, with a slow taper of the prednisone over a 6- to 9-month period after cessation of the cytotoxic agent.³⁰

In general, all patients with anti-GBM should be treated, but some caveats do exist. In patients requiring dialysis, the chance of renal recovery is sufficiently low that the potential toxicity outweighs the chance of success and should be avoided.³⁰ A possible exception to this involves patients with crescentic glomerulonephritis who have circulating anti-GBM antibodies and ANCAs. In such cases, cytotoxic therapy may lead to a late renal recovery, despite early dialysis requirements, and so its use should at least be contemplated.³¹ Similarly, those patients who present with pulmonary hemorrhage should undergo treatment regardless of their renal status because patient, and not just renal, survival takes precedence in this situation.

Optimal treatment for pauci-immune ANCA-associated crescentic glomerulonephritis is different than that for anti-GBM disease. In this case, plasmapheresis has not shown to add any advantage to a combination of cytotoxic and steroid therapies unless the patient also has hemoptysis or anti-GBM antibody present. Initial steroid dosing should be more aggressive in the form of pulse intravenous high doses, such as methylprednisolone, 1000 mg daily for 3 consecutive days, followed by oral prednisone at a dosage of 1 mg/kg daily. Cytotoxic therapy should accompany this steroid therapy, typically either 2 mg/kg of oral cyclophosphamide daily, or monthly intravenous pulse cyclophosphamide. Typical duration of therapy is 6 to 12 months, depending on how quickly the patient has entered remission. Patients who need dialysis should still be treated unless contraindicated, because the chance for renal recovery is higher than with anti-GBM disease, although adjusting down the dose of cyclophosphamide is necessary.

Summary

• Early institution of plasmapheresis and cytotoxic therapy is essential in anti-GBM disease, because there is a small chance of renal recovery when progression to dialysis dependence has occurred.
• Steroid dosing should be more aggressive in patients with pauci-immune crescentic glomerulonephritis and cytotoxic therapy should be used, even for patients requiring dialysis, unless otherwise contraindicated.

Prognosis

The renal and patient prognoses of untreated crescentic glomerulonephritis are dismal and bely the aggressiveness of treatment. In general, with early intervention, patient response to therapy is good, with renal and patient survival approaching 70% and 90%, respectively. Relapses can occur and, when present, adversely affect overall outcome. As expected, success of treatment and prognosis is highly dependent on the degree of renal dysfunction at the time of diagnosis.

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Suggested Readings

• Cattran DC, Appel GB, Hebert LA, et al: Cyclosporine in patients with steroid-resistant membranous nephropathy: A randomized trial. Kidney Int 2001;59:1484–1490.
• Couser WG: Rapidly progressive glomerulonephritis: Classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis 1988;11:449–464.
• Haas M, Meehan SM, Karrison TG, et al: Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976–1979 and 1995–1997. Am J Kidney Dis 1997;30:621–631.
• Hogan SL, Muller KE, Jennette JC, et al: A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis 1995;25:862–875.
• Jennette J, Mandal A: The nephrotic syndrome. In: Mandal A, Jennette J (eds): Diagnosis and Management of Renal Disease and Hypertension. Durham, NC, Carolina Academic Press, 1994, pp 235–272.
• Kitiyakara C, Eggers P, Kopp JB: Twenty-one-year trend in ESRD because of focal segmental glomerulosclerosis in the United States. Am J Kidney Dis 2004;44: 815–825.
• Korbet SM: Primary focal segmental glomerulosclerosis. J Am Soc Nephrol 1998;9:1333–1340.
• Nakao N, Yoshimura A, Morita H, et al: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial. Lancet 2003;361:117–124.
• National Heart, Lung and Blood Institute: Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), 2003. Available at www.nhlbi.nih.gov/guidelines/hypertension.
• Nolasco F, Cameron JS, Heywood EF, et al: Adult-onset minimal change nephrotic syndrome: A long-term follow-up. Kidney Int 1986;29:1215–1223.
• West CD: Childhood membranoproliferative glomerulonephritis: An approach to management. Kidney Int 1986;29:1077–1093.

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