Glomerular Diseases



Glomerular Diseases

image Robert F. Reilly Jr. and Mark A. Perazella

Recommended Time to Complete: 2 Days

Guiding Questions

1. What are the clinical presentations of glomerular disease?

2. Which primary renal diseases present as the nephrotic syndrome?

3. What are the 5 clinical stages of diabetic nephropathy?

4. Can you describe the characteristic findings on urinalysis of the patient with nephritis?

5. How does rapidly progressive glomerulonephritis (RPGN) present and what are its most common causes?

6. What is the serum antineutrophil cytoplasmic antibody test and how is it interpreted?

7. Which glomerular diseases commonly present with isolated abnormalities on urinalysis?


Diseases that adversely affect the structure and function of the glomerulus present to the clinician in a limited number of ways. Glomerular diseases can be grouped into 4 clinical syndromes: the nephrotic syndrome, the nephritic syndrome, RPGN (a variant of the nephritic syndrome), and asymptomatic abnormalities on urinalysis. The differential diagnosis varies depending on the clinical syndrome.

The nephrotic syndrome is manifested by severe proteinuria (>3.0 to 3.5 g/1.73 m2/day) and hypoalbuminemia. Associated features include, to a variable degree, edema, hyperlipidemia, and lipiduria. Nephrotic syndrome results from an increase in glomerular permeability to macromolecules. Etiologies are divided into 2 broad categories: primary renal diseases and secondary forms (infection, malignancy, medications, and multisystem diseases). The pathogenesis is not well understood. Abnormalities of the immune system appear to be the predominant mechanism in man. Circulating immune complexes may deposit in glomeruli, or the antigen may be deposited or originate in the glomerular capillary wall and immune complexes (antigen–antibody) form in situ. Less-commonly inherited diseases of the podocyte cause congenital nephrotic syndrome. Mutations in genes that produce proteins critical to the maintenance of the normal structure and function of the podocyte foot processes and slit diaphragm result in proteinuria.

The nephritic syndrome is characterized by the presence of hematuria with red blood cell casts, an increased serum blood urea nitrogen (BUN) and creatinine concentration, varying degrees of hypertension, and proteinuria. Nephritic syndrome is secondary to an inflammatory disease of the glomerulus that is manifested by an increase in cellularity on light microscopy. The increased cellularity is secondary to proliferation of endothelial, epithelial, and/or mesangial cells or to glomerular infiltration with inflammatory cells.

RPGN is a variant of the nephritic syndrome. The serum BUN and creatinine concentration rise rapidly over days to weeks. The hallmark of RPGN on renal biopsy is the cellular, fibrocellular, or fibrous crescent and this disorder is also referred to as “crescentic” glomerulonephritis. A crescent is a histologic marker of severe injury. It develops when necrosis occurs and a rent or hole forms in either the glomerular capillary basement membrane or in the basement membrane of the Bowman capsule. When such a disruption occurs macrophages, inflammatory mediators, and plasma proteins gain access to the Bowman space. A crescent develops from the proliferation of macrophages, fibroblasts, and parietal glomerular epithelial cells. Crescents are often associated with visible areas of necrosis within the glomerular capillary. RPGN is important to recognize because irreversible glomerular damage occurs quickly in the absence of therapy.

Asymptomatic abnormalities on urinalysis include the discovery of hematuria or proteinuria on routine dipstick analysis of urine. Urine microscopy often reveals dysmorphic red blood cells and cellular casts. This chapter is subdivided into 4 sections based on the clinical syndromes described above. Individual glomerular diseases are discussed further based on their most common clinical presentation.


Presentation of Glomerular Diseases

1. Glomerular diseases present as 4 clinical syndromes: nephrotic syndrome; nephritic syndrome; RPGN (a variant of the nephritic syndrome); and asymptomatic abnormalities on urinalysis.

2. The nephrotic syndrome is manifested by severe proteinuria (>3.0 to 3.5 g/1.73 m2/day) and hypoalbuminemia.

3. Hematuria with dysmorphic red blood cells, red blood cell casts, an increased serum BUN and creatinine concentration, varying degrees of hypertension, and proteinuria are present in the nephritic syndrome.

4. RPGN is a variant of the nephritic syndrome in which the serum BUN and creatinine concentration rise rapidly over days to weeks. The hallmark of RPGN on renal biopsy is the cellular, fibrocellular or fibrous crescent.

5. Glomerular disease may also present as asymptomatic abnormalities on urinalysis.


Under normal circumstances only 30 to 45 mg of protein is excreted in urine; about one-third of that total is albumin. The upper limit of normal for urinary protein excretion is 150 mg/day and this can increase to 300 mg/day with exercise. The glomerular capillary acts as a barrier to the filtration of serum proteins. This barrier consists of 3 layers: an endothelial cell, the basement membrane itself, and an epithelial cell. There is both a size barrier (small proteins are freely filtered [molecular weight (MW) 5000 Da], and large ones are restricted [MW 100,000 Da]), as well as a charge barrier (the capillary membrane is negatively charged and repels negatively charged proteins). Disorders of the filtration barrier result in proteinuria, and if severe enough, the nephrotic syndrome. Another hypothesis purports that a large glomerular leak of protein is normal and proximal tubular cells transport albumin into cells via the megalin-cubulin receptor pathway, whereupon albumin is degraded and transported back to the systemic circulation. In this paradigm, proteinuria develops when dysfunction of apical uptake of albumin exists. The accuracy of this hypothesis is currently unknown and remains to be proven.

The nephrotic syndrome is manifested by severe proteinuria (>3.0 to 3.5 g/1.73 m2/day) and hypoalbuminemia. Peripheral edema, an elevated serum cholesterol concentration and lipiduria are often present. Edema results from a change in Starling forces across the capillary wall. As serum albumin concentration falls plasma oncotic pressure decreases. There may also be an intrarenal defect resulting in increased sodium reabsorption as well. Albumin in the tubular lumen increases activity of the Na+-H+ exchanger in the proximal tubule resulting in increased sodium reabsorption. In addition, abnormal glomerular filtration of plasminogen and its conversion to plasmin activate gamma ENaC proteolytically and contribute to sodium retention and edema formation in acute proteinuric conditions. Edema should first be treated with sodium restriction. If this is ineffective then diuretics are added. Milder diuretics that block sodium reabsorption in the distal convoluted tubule or collecting duct (thiazides, triamterene, amiloride, spironolactone, and eplerenone) are often used before more potent loop diuretics.

Hypercholesterolemia is thought to result from an increase in synthesis of hepatic proteins in response to hypoalbuminemia. This is supported by animal studies showing that the degree of cholesterol elevation is inversely related to the fall in plasma oncotic pressure. Animal studies also show that raising the oncotic pressure with albumin infusion results in a fall in serum cholesterol concentration toward normal. If the serum cholesterol concentration is elevated and the patient does not have hypoalbuminemia, the increase is probably not caused by the nephrotic syndrome. There is also a decrease in lipoprotein catabolism. Lipoprotein lipase is decreased as is lecithin-cholesterol acyltransferase (esterifies cholesterol to high-density lipoprotein [HDL]). Downregulation of lipoprotein lipase and the very-low-density lipoprotein (VLDL) receptor results in elevated triglycerides and VLDL.

A variety of coagulation abnormalities are often present in the nephrotic syndrome. Levels of factors V, VIII, α-macroglobulin, and fibrinogen are increased, while X, XI, and XII, plasminogen activator inhibitor (PAI), and antithrombin III are decreased. The platelet count tends to be increased, as is platelet aggregation. Also, the clot formed in this setting has an altered structure (closed), which makes it more resistant to fibrinolysis. The end result is that patients are hypercoagulable, and have an increased incidence of both arterial and venous thrombi. Patients at highest risk for thrombosis are the elderly and those with a serum albumin concentration less than 2.5 mg/dL. Renal vein thrombosis occurs in 5% to 35% and is more commonly associated with membranous glomerulonephritis. The presentation can be acute or chronic. Acute renal vein thrombosis is manifested by flank pain, hematuria, and a decrease in glomerular filtration rate (GFR). Chronic renal vein thrombosis is often silent and can present as a pulmonary embolus. As antithrombin III concentration is low, these patients may be relatively heparin resistant and require more heparin than usual to raise the partial thromboplastin time (PTT) into the therapeutic range.

The risk of infection with encapsulated organisms is increased possibly a result of the loss of complement factor B (alternate pathway) and γ-globulin in urine. Patients should be immunized with pneumococcal vaccine.


Minimal Change Disease

Minimal change disease, also known as nil disease or lipoid nephrosis, derives its name from the fact that the light microscopic appearance of the glomerulus is normal (Figure 17.1) and the tubules may become vacuolated with lipids as a result of hyperlipiduria. I immunofluorescence (IF) studies are also negative. On electron microscopy (EM) podocyte epithelial foot processes are fused (Figure 17.2). Some patients have mesangial deposits of immunoglobulin (Ig) M and C3. Heavy deposition of IgM (IgM nephropathy) associated with mesangial hypercellularity may carry a worse prognosis. This is thought to represent an intermediate lesion along a path of progression toward focal and segmental glomerulosclerosis (see below). Acute tubular necrosis is seen in a subgroup of patients with minimal change disease.


FIGURE 17-1. Minimal change disease (light microscopy). The glomerulus on light microscopy in minimal change disease is normal.


FIGURE 17-2. Minimal change disease (electron microscopy). The arrow shows fusion of the foot processes of podocytes. This is the only abnormality seen on the renal biopsy of a patient with minimal change disease.

The pathogenesis may be secondary to a defect in cell-mediated immunity, because in vitro T-cell function abnormalities are described and minimal change disease can occur in association with Hodgkin disease, nonsteroidal antiinflammatory drugs (NSAIDs) and the treatment of malignant melanoma with interferon. T-cell cultures derived from patients with minimal change disease release a vascular permeability factor. Minimal change disease may result from the production of a lymphokine that is toxic to the glomerular epithelial cell. The toxin reduces the anionic charge barrier of the membrane and injures podocyte foot processes, causing albuminuria. In adults, minimal change disease is the cause of 10% to 15% of cases of nephrotic syndrome. In children, it is the most common cause of nephrotic syndrome, with a peak incidence between ages 2 and 3 years. It accounts for more than 90% of cases of nephrotic syndrome in the pediatric population. The urine sediment is generally unremarkable, although microscopic hematuria may be present in 20% of patients. Lipiduria with free lipids, oval fat bodies (cells containing lipid), and lipid casts may be seen with severe nephrosis. Proteinuria is “selective,” consisting almost entirely of albumin, suggesting that the abnormality in the glomerular basement membrane (GBM) is an alteration in the charge barrier. Hypertension is generally absent. Minimal change disease responds well to corticosteroids (within 4 weeks), although relapses are the rule. Relapses may be provoked by an upper respiratory infection. Patients with frequent relapses or those who are steroid-dependent may be treated with cyclophosphamide, chlorambucil, cyclosporine, tacrolimus, or levamisol. Oral cyclosporine and tacrolimus carry the risk of nephrotoxicity, especially in those treated for longer periods of time. The long-term prognosis with respect to the maintenance of renal function is good.

Focal Segmental Glomerulosclerosis (Focal Sclerosis)

Focal segmental glomerulosclerosis (FSGS) is characterized by sclerosing lesions associated with hyaline deposits involving parts (segmental) of some glomeruli (focal). The sclerosis results from glomerular capillary collapse with an increase in mesangial matrix (Figure 17.3). Mild-to-moderate mesangial hypercellularity may be seen. On EM subendothelial deposits and foot process fusion are present in involved glomeruli. Capillary collapse and folding and thickening of the basement membrane are present in sclerotic glomeruli. IF reveals nonspecific trapping of IgM and C3 in the sclerotic mesangium. As the disease progresses, tubular atrophy, interstitial fibrosis, and global glomerular sclerosis occur. Increasing degrees of interstitial fibrosis (>20% of biopsy surface area) is associated with a poorer prognosis. Juxtamedullary nephrons are affected initially.


FIGURE 17-3. FSGS. The left half of this glomerulus is sclerotic (arrow) and the right half is normal hence the term segmental in FSGS. In the sclerotic region, there is glomerular capillary collapse and an increase in mesangial matrix.

The Columbia pathologic classification of primary FSGS describes 5 histopathologic types of glomerular lesions. The variants include (a) classic FSGS or not otherwise specified (NOS); (b) tip lesion; (c) cellular; (d) perihilar; and (e) collapsing (Figure 17.4). In general, the tip and cellular variants of FSGS are more steroid responsive and have a better prognosis, whereas classic and collapsing FSGS are poorly responsive to steroids and have a poor renal prognosis.


FIGURE 17-4. Collapsing FSGS (light microscopy). The glomerular tuft is retracted and covered by visceral epithelial cell hypertrophy (arrow). (Courtesy of Glen S. Markowitz.)

The etiology of primary FSGS is unknown but humoral factors, glomerular hypertrophy and hyperfiltration, and injury to glomerular cells are postulated. Inherited forms of FSGS are caused by mutations in genes that encode podocyte proteins α-actinin 4, podocin, nephrin, transient receptor potential channel, subfamily 6 (TRPC6), and inverted formin-2 (IFN2). Focal sclerosis can also be secondary to vesicoureteral reflux, morbid obesity, multiple myeloma, urinary tract obstruction, analgesic nephropathy, chronic renal transplant rejection, heroin nephropathy, human immunodeficiency virus (HIV) infection, and substantial loss of nephron mass. Drugs, such as pamidronate, interferon, and anabolic androgenic steroids, are also associated with FSGS.

Focal sclerosis is the most common primary renal disease resulting in nephrotic syndrome in African Americans. Recent advances have enhanced our understanding of the common occurrence of FSGS in African Americans. An allelic varitation at the APOL-1 locus on chromosome 22 may explain the high risk of FSGS in individuals of African ancestry. APOL-1 is trypanosomolytic and this protective allelic variant has persisted over evolutionary time. Although the exact mechanism of injury is unknown, the expression of APOL-1 in podocytes is in keeping with FSGS, a disorder of podocytes. The pathogenesis of idiopathic FSGS may also be related to circulating factors that target and injure the podocyte (permeability factors). A pivotal role for soluble urokinase plasminogen activator receptor (suPAR) in idiopathic FSGS has been noted. The mechanism underlying development of FSGS with suPAR is likely related to the ability of this molecule to activate β-integrin on podocytes, which then promotes foot process effacement. Other possible circulating permeability factors include cardiotrophin-like cytokine (CLC-1) and a factor that disturbs nonmuscle myosin IIA on podocytes. With all of these molecules, the final common pathway is foot process effacement with proteinuria and eventual focal glomerular sclerosis.

In FSGS, the urinary sediment is usually remarkable for hematuria and pyuria, and up to 30% of adults may present with asymptomatic proteinuria. Blood pressure is generally elevated, GFR decreased, and the development of slowly progressive renal failure is the usual course. Approximately 50% to 60% of patients reach end-stage renal disease (ESRD) within 10 years of initial diagnosis. Patients with nonnephrotic range proteinuria have a better prognosis. The clinical course is much more rapid in patients with heroin nephropathy or HIV infection (renal failure often is present within 2 years from the time of initial diagnosis).

HIV-associated nephropathy (HIVAN) is much more common in African Americans than in whites. It generally occurs late in the course of HIV infection in patients with a higher viral titer (load) and CD4 count of less than 250 cells/mm3. Patients present with nephrotic syndrome and an elevated BUN and serum creatinine concentrations. The kidneys are enlarged on renal ultrasound with increased echogenicity of the renal cortex. On light microscopy there is glomerular collapse, extensive lymphocytic infiltration, and cystic dilation of tubules that are filled with proteinacious material (microcysts). Tubuloreticular inclusion bodies are found within glomerular and tubulointerstitial endothelial cells. Immune complex-related diseases, such as membranoproliferative glomerulonephritis (MPGN), membranous glomerulonephritis, IgA nephropathy, and a lupus-like immune complex glomeulopathy, are more common in whites with HIV infection and the nephrotic syndrome. HIV viral proteins induce podocyte injury and apotosis. Studies in HIVAN show that the decrease in GFR was slowed by combination antiretroviral therapy, angiotensin-converting enzyme (ACE) inhibitors, and prednisone. Prednisone should be reserved for those patients who are at low risk of infection as serious infectious complications may arise during its use. A collapsing FSGS is also a complication of drug therapy (pamidronate, interferon, and androgenic steroids).

Focal sclerosis is less responsive to corticosteroids. High-dose corticosteroids often must be employed for 6 to 9 months before a response is seen. If corticosteroids fail, second-line agents of choice are cyclosporine and tacrolimus, although cyclophosphamide and mycophenolate mofetil (MMF) can also be used. Rituximab is of unclear benefit in FSGS. A number of other agents are in early phase trials, including adalimumab (monoclonal tumor necrosis factor [TNF] inhibitor), fresolimumab (anti-transforming growth factor [TGF] monoclonal antibody), rosiglitazone, pirfenodone (TGF antagonist), natural adrenocorticotropic hormone (ACTH), and oral galactose. In general, approximately 30% to 50% of patients with sporadic or idiopathic FSGS are resistant to a reasonable course of steroids (at least 4 months). Relapses occur commonly in steroid-sensitive FSGS, and over time, steroid resistance can develop. Although complete remission is rare, partial remissions are common, which is opposite to what is seen with minimal change disease. Factors associated with a poorer prognosis include persistent high-grade proteinuria, diffuse mesangial IgM deposition, the extent of tubulointerstitial fibrosis and the degree of glomerulosclerosis on renal biopsy, and a higher serum creatinine concentration (not uniformly). African American race and a lack of response to corticosteroids are also predictors of poor outcome. As many as 50% of patients may develop a recurrence in the transplanted kidney, and greater than 80% in secondary grafts of patients where the initial graft was lost because of recurrent FSGS. Those patients with a rapid progression and high degrees of proteinuria are at increased risk of recurrence. Treatment of secondary causes of FSGS are directed at the underlying cause, such as repair of reflux, weight reduction (obesity), control of hyperfiltration (nephron loss), and HIVAN therapy with combination antiretroviral medications, and discontinuation of offending drugs.

Mesangial Proliferative Glomerulonephritis

Mesangial proliferative glomerulonephritis generally presents with isolated microscopic hematuria or proteinuria although nephrotic syndrome is also seen. On light microscopy there is an increase in mesangial cell number. Mesangial deposits of immunoglobulin and complement are present on EM. Treatment is often supportive focusing on blood pressure control and proteinuria reduction with drugs that modulate the renin-angiotensin-aldosterone system (RAAS) such as ACE inhibitors and angiotensin receptor blockers (ARBs). Initial treatment is generally with corticosteroids. Nonresponders or partial responders often do not respond to cyclosporin. Deposition of IgM in the mesangium and lack of response to corticosteroids are associated with a poor prognosis.

Membranous Glomerulonephritis

Membranous glomerulonephritis is characterized by uniform, diffuse thickening of the glomerular capillary wall without cellular proliferation (Figure 17.5). The most characteristic feature is the presence of subepithelial immune deposits on EM (Figure 17.6). The electron-dense deposits are formed in situ in the GBM. The M-type phospholipase A2 receptor (PLA2R) appears to be the human glomerular target antigen in primary membranous glomerulonephritis. Thus, antibodies formed in the circulation may bind the PLA2R, form antigen–antibody (Ag-Ab) complexes that then initiate a cascade of events causing glomerular capillary loop injury. The development of glomerular injury is complement-dependent and is related to the formation of the membrane attack complex (C5b-C9). The membrane attack complex induces matrix production, release of oxidants, and podocyte injury. GBM accumulates between the deposits, which creates the appearance of spikes. With time, the basement membrane extends over the deposits, forming domes. IF microscopy shows a granular pattern (Figure 17.7). In the idiopathic lesion mesangial deposits are usually absent and IgG subtype 4 is present. In membranous glomerulonephritis from secondary causes, mesangial deposits greater than 8 polymorphonuclear cells per glomerulus and tubuloreticular inclusions are generally present, depending on the cause. Subendothelial deposits, tubulointerstitial deposits, the presence of all Igs in deposits, and mesangial or endocapillary proliferation are suggestive of a secondary cause. Many of these patients have evidence of circulating immune complexes. Histologic changes associated with a poor prognosis include interstitial fibrosis and segmental glomerulosclerosis.


FIGURE 17-5. Membranous glomerulonephritis (light microscopy). Shown by the arrows are the diffusely thickened glomerular capillary loops characteristic of this lesion. There is no increase in cellularity.


FIGURE 17-6. Membranous glomerulonephritis (EM). Immune deposits in the glomerular basement membrane are shown by the arrow. They are found in the subepithelial space.


FIGURE 17-7. Membranous glomerulonephritis (IF microscopy). The staining pattern is granular and corresponds to the punctate accumulation of immune deposits in the glomerular basement membrane (arrow) and mesangium.

Membranous glomerulonephritis is the most common primary renal disease that causes nephrotic syndrome in white adults. Nephrotic syndrome is present in 80% of cases. Hypertension is usually absent and the urinary sediment may show hematuria in approximately half of patients. A serum test measuring the M-type PLA2R antibody may become a diagnostic test to identify idiopathic membranous nephropathy (MN). The initial study demonstrated that anti-PLA2R antibodies were present in 82% of patients with idiopathic MN, but in very few secondary causes of MN such as systemic lupus erythematosus (SLE) nephritis, cancer-related MN, and hepatitis B-related MN. This antibody test may be useful in diagnosis, as well as in monitoring of disease activity and response to therapy. However, the absence of antibodies does not preclude response to therapy and the presence of antibodies does not absolutely exclude the presence of a secondary cause of MN.

As described above, this lesion is also seen in collagen vascular diseases (SLE, mixed connective tissue disease, and rheumatoid arthritis), infections (hepatitis B, malaria, secondary and congenital syphilis, leprosy, schistosomiasis, and filariasis), drugs (NSAIDs, gold, penicillamine, mercury, probenecid, captopril, and bucillamine), neoplasia (lung, colon, stomach, breast, cervix, and ovary), and miscellaneous disorders (sickle cell disease, thyroiditis, and sarcoid).

Therapy remains controversial because of the high spontaneous remission rate. Without treatment, generally one-third of patients spontaneously remit, one-third progress to renal failure, and one-third remain unchanged. Factors associated with an increased frequency of progression to renal failure include male sex, age older than 50 years, high-grade persistent proteinuria, hypertension, and an elevated serum creatinine concentration. Excretion of IgG and α1-microglobulin is a predictor of response to therapy, progression to renal failure, and the extent of tubulointerstitial damage on renal biopsy. An initial study suggested that corticosteroids alone decrease the rate of decline in renal function but this was not borne out by subsequent trials. The combination of alternating monthly courses of either corticosteroids and chlorambucil or corticosteroids and oral cyclophosphamide increase the rate of remission of nephrotic syndrome and the probability of survival without renal failure. The majority of therapeutic trials were conducted, however, in patients with serum creatinine concentration equal to or less than 1.7 mg/dL. Uncontrolled trials were carried out in patients with serum creatinine concentrations between 2 and 3 mg/dL. The combination of prednisone and cyclophosphamide lowered serum creatinine concentration in the short-term. It is unclear whether patients with serum creatinine concentration equal to or greater than 3 mg/dL benefit from therapy. Cyclosporine was used in patients who failed steroid therapy. The rate of remission of nephrotic range proteinuria is increased but conflicting data exist as to whether one can slow progression of disease. MMF was employed successfully in small numbers of patients. Synthetic ACTH has been noted to reduce proteinuria and induce remission of membranous glomerulonephrtitis in small studies. Rituximab has also been used successfully to induce remission of proteinuria in 60% of patients, but is expensive and complicated by infection and progressive multifocal leukoencephalopthy. Intravenous rituximab has been used to treat MN with some success. However, this drug’s efficacy for MN requires comparison with cyclosporine in a randomized controlled trial.

Because of the high spontaneous remission rate, some authors recommend treating only patients with elevated serum creatinine concentration, progressive declines in GFR, and symptomatic nephrotic syndrome, as well as those patients who are at high risk for progression and patients with thromboembolic disease. Because of the association with renal vein thrombosis and thromboembolic events some recommend treating patients with profound hypoalbuminemia with anticoagulants. Patients who experience a thromboembolic event should be anticoagulated as long as they remain nephrotic.

Membranoproliferative Glomerulonephritis

MPGN is characterized by diffuse proliferation of mesangial cells with the extension of mesangial matrix or cytoplasm into the peripheral capillary wall, giving rise to a thickened and reduplicated appearance. This gives rise to the double contour or “tram-track” appearance of the GBM. There is mixed mesangial and endothelial cell proliferation that results in a lobular distortion of the glomerulus (lobular accentuation) (Figure 17.8). MPGN is divided into several types based on EM.


FIGURE 17-8. MPGN (light microscopy). There is an increase in both cellularity (proliferation of endothelial and mesangial cells) and mesangial matrix. Open capillary loops are difficult to visualize as a result of endothelial proliferation. The lobules of the glomerulus are distorted (lobular accentuation).

Type I MPGN, which is the most common form of the disease, is associated with subendothelial electron-dense deposits and marked peripheral capillary interposition of mesangial cell cytoplasm and matrix. IF microscopy reveals glomerular deposition of immunoglobulin, C3, and C4. Patients may present with the nephrotic syndrome, nephritic syndrome, an overlap of these 2 syndromes, RPGN, or with asymptomatic hematuria and proteinuria. Episodic macroscopic hematuria may also occur. Blood pressure is generally increased, GFR reduced, and anemia is present disproportionate to the degree of azotemia. Complement concentrations are low especially in type II MPGN. The classical complement pathway is activated in type I MPGN resulting in a decrease in C4 concentration. Glomerular crescents, hypertension, decreased GFR, and heavy proteinuria are poor prognostic signs. Infection (shunt nephritis, malaria, endocarditis, hepatitis B and C, and HIV), B-cell lymphomas, SLE, mixed connective tissue disease, sickle cell disease, monoclonal immunoglobulin deposition diseases (amyloidosis, light-/heavy-chain deposition disease), and α1-antitrypsin deficiency are also associated with MPGN type I. Infection with hepatitis C is the most common cause.

Type II MPGN is characterized by intramembranous electron-dense deposits and is often called dense deposit disease. There are dense ribbon-like confluent deposits in the basement membranes of the glomeruli, tubules, and vasculature. In type II MPGN the alternative complement pathway is activated decreasing C3 concentration. Peripheral catabolism of C3 is increased by a circulating IgG known as C3 nephritic factor. This results in an increase in C3 degradation products especially C3c. C3c has an affinity for the lamina densa of the GBM and is deposited there. The depressed complement concentrations do not correlate with disease activity. These patients are generally resistant to therapy.

Subendothelial and subepithelial immune deposits and marked fragmentation of the GBM are found in type III MPGN. It is associated with IgA nephropathy and Henoch-Schönlein purpura (HSP) and is rarely a result of hepatitis C infection. This lesion is not corticosteroid-responsive.

More recently, given the role of the alternative pathway of complement in MPGN, a more practical approach is to reclassify this entity as immune complex-mediated and complement-mediated MPGN. Using this paradigm, immune complex-mediated MPGN occurs when there are increased circulating immune complexes (infection, autoimmune, dysproteinemia), and complement-mediated MPGN occurs when there is a disease with dysregulation of the alternative complement pathway (mutations or antibodies to complement factors or complement-regulating proteins). Examples of complement-mediated MPGN (Ig-C3+ IF staining) are classical intramembranous dense deposit disease (type II MPGN) and C3 glomerulopathy.

C3 glomerulopathy has subendothelial dense deposits that resemble type I MPGN on EM, but has only C3 staining without Ig on IF. Patients typically present with proteinuria, often in the nephrotic range (sometimes with nephrotic syndrome), hematuria, variable degrees of hypertension and kidney failure. C3 levels are usually low, C4 levels are normal, and some patients have a C3 convertase stabilizing autoantibody called C3 nephritic factor, which is also seen in dense deposit disease. Progression to ESRD occurs and this glomerulopathy can recur following kidney transplantation. Some patients develop hematuria after an upper respiratory infection (URI), leading to a presumptive clinical diagnosis of IgA nephropathy or postinfectious glomerulonephritis. Six of 9 patients who developed hematuria following a URI and glomerulonephritis on renal biopsy had mesangial C3 deposits, four of which had associated hypocomplementemia. This suggests that a form of C3 glomerulopathy occurred in these patients. Thus, this entity must be included in the differential diagnosis of acute glomerulonephritis following a URI.


Diabetes Mellitus

Diabetic nephropathy is the single most common cause of the nephrotic syndrome and ESRD in the United States. Type I diabetics with nephropathy have a 50-fold increase in mortality compared to those without nephropathy. Nephropathy in type I diabetes mellitus rarely develops before 10 years’ disease duration, and approximately 40% of type I diabetics have proteinuria within 40 years after the onset of disease. The annual incidence of diabetic nephropathy peaks just before 20 years’ disease duration and declines thereafter. Those patients who survive 30 years of diabetes mellitus without developing nephropathy are at extremely low risk of doing so in the future.

The glomeruli in patients with diabetic nephropathy may exhibit a form of nodular glomerulosclerosis known as Kimmelstiel-Wilson disease (Figure 17.9). The nodules form in the peripheral regions of the mesangium and can be single or multiple. They may result from accumulation of basement membrane or injury from microaneurysmal dilation of the glomerular capillary. Nodular glomerulosclerosis can occur in association with diffuse glomerulosclerosis. Diffuse glomerulosclerosis, which is universally present, results from widening of the mesangial space by an increase in matrix production. Glomerular injury in diabetes mellitus is related to the severity and duration of hyperglycemia and may be related to advanced glycosylation end-products (AGEs). Elevation of serum glucose concentration leads to glycosylation of serum and tissue proteins resulting in AGE formation that can crosslink with collagen. In animal models, administration of AGEs induces glomerular hypertrophy and stimulates mesangial matrix production. Upregulation of TGF-β1 and its receptor likely play an important role in renal cell hypertrophy and stimulation of mesangial matrix production. Altered vascular endothelial growth factor (VEGF) homeostasis in the podocyte may also play a role in the pathogenesis of diabetic nephropathy. VEGF expression is increased early in diabetic nephropathy, potentially causing capillary injury, but over time, with ongoing injury and loss of podocytes, there is a decline in VEGF. This may lead to an insufficient capillary repair and a reduction in nephrin expression in podocytes and proteinuria. In addition to glomerular changes, there is diffuse accumulation of hyaline material in the subendothelial layers of the afferent and efferent arterioles.


FIGURE 17-9. Diabetic glomerulosclerosis (light microscopy). The arrow shows an area of nodular glomerulosclerosis (Kimmelstiel-Wilson disease). Note also the diffuse increase in mesangial matrix throughout the glomerulus (diffuse glomerulosclerosis).

The natural history of diabetic nephropathy is divided into 5 stages: (a) time of initial diagnosis; (b) the first decade (characterized by renal hypertrophy and hyperfiltration); (c) the second decade manifested by glomerulopathy (microalbuminuria) in the absence of clinical disease; (d) clinically detectable disease (the hallmarks of this stage are dipstick-positive proteinuria, hypertension, and a progressive decline in renal function); and (e) ESRD.

Stage I—At the onset of diabetes mellitus virtually all patients experience functional changes, such as increased kidney size, microalbuminuria that reverses with the control of blood glucose concentration, and an increased GFR that decreases with initiation of insulin therapy in most patients.

Stage II—GFR may be increased in Stage II, and it is postulated that this finding predicts the later development of nephropathy, but this remains controversial. The pathogenesis of the hyperfiltration is unclear but may be partly caused by hyperglycemia and activation of the RAAS. At the onset of diabetes mellitus the renal biopsy is usually normal. Within 1.5 to 2.5 years, GBM thickening begins in nearly all patients. No correlation exists between GBM thickening and clinical renal function. Mesangial expansion begins approximately 5 years after the onset of disease.

Stage III—Stage III is manifested by microalbuminuria. Microalbuminuria is an albumin excretion rate between 30 and 300 mg/day (20 to 200 μg/min). This amount of albumin excretion is below the level of sensitivity of a urine dipstick. A mid-morning albumin-to-creatinine ratio above 30 mg/g correlates well with 24-hour or timed urine collections. Several groups reported that a slightly elevated urinary albumin excretion occurring in the first or second decade of diabetes mellitus is a harbinger of the later development of clinical diabetic nephropathy. These studies used thresholds ranging from 15 to 70 μg/min to classify patients. Microalbuminuria best predicts diabetic nephropathy when it is progressive over time and is associated with hypertension.

Stage IV—Stage IV is defined by the presence of dipstick positive albuminuria (>300 mg/day) and is associated with a slow gradual decline in GFR that may result in ESRD. Classically, the rate of decline of GFR was stated to be 1 mL/min/month, but this number is probably now closer to 0.5 mL/min/month or less. The rate of progression can be slowed by antihypertensive therapy. It may decline further with combined treatment with ACE inhibitors and ARBs.

Stage V—As the GFR continues to decline, ESRD may develop. Diabetic nephropathy is the most common cause of ESRD in the United States. Because of associated autonomic neuropathy and cardiac disease, diabetics often experience uremic symptoms at higher GFRs (15 mL/min) than nondiabetics.

Although the 5 clinical stages of diabetic nephropathy are best characterized in patients with type I diabetes mellitus, they are similar in patients with type II disease with the following exceptions. The ability to date the time of onset of type II diabetes mellitus is more difficult than in patients with type I disease. Therefore, one needs to be more flexible in interpreting the first decade—it may be shorter than 10 years. In virtually 100% of patients with type I diabetes mellitus and diabetic nephropathy, retinopathy is present, whereas retinopathy is present in two-thirds of those with type II disease and diabetic nephropathy. Therefore, the absence of retinopathy in a patient with type II diabetes mellitus should not dissuade one from the diagnosis in the appropriate clinical setting. On the other hand, the absence of retinopathy in a patient with type I disease would argue strongly against diabetes mellitus as a potential cause of renal disease.

The urinalysis in diabetic nephropathy is generally remarkable for proteinuria with little in the way of cellular elements present. On occasion microscopic hematuria is seen. This should prompt a workup for other causes of hematuria, such as transitional cell carcinoma in the patient who is older than age 40 years (cystoscopy). The most common cause of microscopic hematuria in the patient with diabetic nephropathy is, however, diabetic nephropathy. Macroscopic hematuria or the presence of red cell casts is suggestive of another diagnosis. Broad waxy and finely granular casts can be seen as well. The presence of nephrotic range proteinuria in the diabetic patient with a preserved GFR should also raise concern that another glomerular lesion is the cause of the nephrotic syndrome. In general, proteinuria is initially mild and progresses to the nephrotic syndrome as the GFR declines in patients with diabetic nephropathy. Treatment of diabetic nephropathy requires a multidrug regimen, including tight glucose control, blood pressure control with medications that modulate the RAAS, and statin therapy to reduce lipids. This is reviewed in more detail in Chapter 16.

Systemic Amyloidosis

More than 90% of patients with primary and secondary amyloidosis have renal involvement, approximately 60% have nephrotic syndrome. In patients older than the age of 60 years with nephrotic syndrome, 10% have amyloidosis. On light microscopy, diffuse amorphous hyaline material is deposited in glomeruli (Figure 17.10). Amyloid deposits may also be present in tubular basement membranes, arterioles, and small arteries. In more advanced cases, nodule formation occurs and the light microscopy picture can resemble advanced diabetic nephropathy. The diagnosis is confirmed by special stains (Congo red, thioflavin-T) and EM. Amyloid deposits have a characteristic apple-green birefringence under polarized light with Congo red staining. The demonstration of 8- to 12-nm nonbranching fibrils on EM is diagnostic (Figure 17.11). Patients present with nephrotic syndrome, decreased GFR, and an unremarkable urinary sediment, although oval fat bodies and lipid casts are sometimes seen with severe nephrosis. Clinically apparent extrarenal involvement is often absent. A monoclonal light chain is present in urine in approximately 90% of patients with primary amyloidosis. The combination of serum free light chains and serum immunofixation is diagnostic in 99% of patient with primary amyloidosis. Tissue diagnosis can be established on biopsy of the rectum, gingiva, abdominal fat pad and skin, as well as on renal biopsy.


FIGURE 17-10. Amyloid (light microscopy). The arrow illustrates a diffuse increase in amorphous hyaline material (amyloid) deposited in the glomerulus. (Courtesy of Gilbert Moeckel.)

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Sep 18, 2017 | Posted by in NEPHROLOGY | Comments Off on Glomerular Diseases

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