Cecil Medicine, 23rd ed.
Gerald B. Appel
Definition
Each glomerulus, the basic filtering unit of the kidney, consists of a tuft of anastomosing capillaries formed by branchings of the afferent arteriole. Approximately 1 million glomeruli account for about 5% of the kidney's weight and provide almost 2 m2 of glomerular capillary filtering surface. The glomerular basement membrane (GBM) provides both a size- and charge-selective barrier to the passage of circulating macromolecules. Renal processes that involve all glomeruli are called diffuse or generalized; if only some glomeruli are involved, the process is called focal. When dealing with the individual glomerulus, a process is global if the whole glomerular tuft is involved and segmental if only part of the glomerulus is involved. The modifying terms proliferative, sclerosing, and necrotizing are often used (e.g., focal and segmental glomerulosclerosis [FSGS]; diffuse global proliferative lupus nephritis). Extracapillary proliferation, or crescent formation, is caused by the accumulation of macrophages, fibroblasts, proliferating epithelial cells, and fibrin within Bowman's space. In general, crescent formation in any form of glomerular damage conveys a serious prognosis. Scarring of tissue between the tubules and glomeruli, or interstitial fibrosis, is also a poor prognostic sign in every glomerular disease.
Epidemiology
At present, 20 million people in the United States have proteinuria or renal dysfunction, and many, if not most cases are caused by glomerular diseases. By 2002, the U.S. Renal Data System documented that more than 430,000 persons were in end-stage renal disease (ESRD) programs with an annual cost to the government of billions of dollars, largely as a result of renal involvement by glomerular diseases. Diabetic renal damage alone affects many millions of persons and is the major cause of ESRD in the United States ( Chapter 125 ). Worldwide, glomerular diseases associated with infections such as malaria and schistosomiasis are major health problems. The emergence of glomerular diseases linked to human immunodeficiency virus (HIV) and hepatitis B and C viruses has focused new attention on the patterns and mechanisms of glomerular injury. The manifestations of glomerular injury range from asymptomatic microhematuria and albuminuria to rapidly progressive oliguric renal failure. In some patients, massive fluid retention and edema develop at the onset of their glomerular disease, whereas others have only the slow insidious signs and symptoms of chronic renal failure.
Pathobiology
Certain common mechanisms may underlie key findings in glomerular diseases such as hematuria and proteinuria (e.g., breaks in the glomerular capillary wall and loss of glomerular size and the charge-selective barrier). Nevertheless, the nature of the processes initiating this damage differs. In some glomerular disorders, such as diabetes and amyloidosis, there are structural and biochemical alterations of the glomerular capillary wall. In others, there is immune-mediated renal injury, whether through deposition of circulating immune complexes, localization of anti-GBM antibodies, or other mechanisms.
Clinical Manifestations
Findings that indicate the presence of a glomerular origin of renal disease include erythrocyte casts or dysmorphic erythrocytes in the urinary sediment (or both) and the presence of large amounts of albuminuria. Urinary excretion of more than 500 to 1000 erythrocytes per milliliter is abnormal, and dysmorphic erythrocytes deformed during passage through the glomerular capillary wall and tubules indicate glomerular damage. Red blood cell casts, formed when erythrocytes pass the glomerular capillary barrier and become enmeshed in a proteinaceous matrix in the lumen of the tubules, are also indicative of glomerular disease.
In a normal person, urinary excretion of albumin is less than 50 mg/day. Although increases in urinary protein excretion may come from the filtration of abnormal circulating proteins (e.g., light chains in multiple myeloma) or from deficient proximal tubular reabsorption of normal filtered small-molecular-weight proteins (e.g., β2-microglobulin), the most common cause of proteinuria—and specifically albuminuria—is glomerular injury. Proteinuria associated with glomerular disease may range from several hundred milligrams to more than 30 g daily. In some diseases, such as minimal change nephrotic syndrome, albumin is the predominant protein found in urine. In others, such as focal sclerosing glomerulonephritis and diabetes, the proteinuria, though still largely composed of albumin, contains many larger-molecular-weight proteins as well.
NEPHROTIC SYNDROME
Definition
The nephrotic syndrome is defined by albuminuria in amounts of more than 3 to 3.5 g/day accompanied by hypoalbuminemia, edema, and hyperlipidemia. In practice, many clinicians refer to “nephrotic-range” proteinuria regardless of whether their patients have the other manifestations of the full syndrome because the latter are consequences of the proteinuria.
Pathobiology
Hypoalbuminemia is in part a consequence of urinary protein loss. It is also due to the catabolism of filtered albumin by the proximal tubule, as well as redistribution of albumin within the body. This in part accounts for the inexact relationship between urinary protein loss, the serum albumin level, and other secondary consequences of heavy albuminuria.
The salt and volume retention in nephrotic syndrome may occur through at least two different major mechanisms. In the classic theory, proteinuria leads to hypoalbuminemia, low plasma oncotic pressure, and intravascular volume depletion. Subsequent underperfusion of the kidney stimulates the priming of sodium-retentive hormonal systems such as the renin-angiotensin-aldosterone axis, which causes increased renal sodium and volume retention. In the peripheral capillaries with normal hydrostatic pressure and decreased oncotic pressure, the Starling forces lead to transcapillary fluid leakage and edema. In some patients, however, intravascular volume has been measured and found to be increased along with suppression of the renin-angiotensin-aldosterone axis. An animal model of unilateral proteinuria shows evidence of primary renal sodium retention at a distal nephron site, perhaps caused by altered responsiveness to hormones such as atrial natriuretic factor. In this situation only the proteinuric kidney retains sodium and volume and at a time when the animal is not yet hypoalbuminemic. Thus, local factors within the kidney may account for the volume retention of nephrotic patients as well.
Diagnosis
Epidemiologic studies clearly define an increased risk for atherosclerotic complications in patients with nephrotic syndrome. Most nephrotic patients have elevated levels of total and low-density lipoprotein cholesterol along with low or normal high-density lipoprotein cholesterol. Lipoprotein(a) levels are elevated as well and return to normal with remission of the nephrotic syndrome. Nephrotic patients often have a hypercoagulable state and are predisposed to deep vein thrombophlebitis, pulmonary emboli, and renal vein thrombosis.
Initial evaluation of a nephrotic patient includes laboratory tests to define whether the patient has primary, idiopathic nephrotic syndrome or a secondary cause related to a systemic disease, toxin, or medication. Common screening tests include the fasting blood sugar and glycosylated hemoglobin tests for diabetes, an antinuclear antibody test for collagen vascular disease, and serum complement, which screens for many immune complex–mediated diseases ( Table 122-1 ). In selected patients, cryoglobulins, hepatitis B and C serology, antineutrophil cytoplasmic antibodies (ANCAs), anti-GBM antibodies, and other tests may be useful.
TABLE 122-1 -- SERUM COMPLEMENT LEVELS IN GLOMERULAR DISEASES
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Treatment
Minimal Change Disease
Minimal change disease is the most common pattern of nephrotic syndrome in children and accounts for 5 to 10% of cases of idiopathic nephrotic syndrome in adults. A similar histologic pattern may be seen as an adverse reaction to certain medications (nonsteroidal anti-inflammatory drugs [NSAIDs], lithium) and in association with certain tumors (Hodgkin's disease and leukemias). Patients typically experience weight gain and periorbital and peripheral edema related to the proteinuria, which is usually well into the nephrotic range. Additional findings in adults are hypertension and microscopic hematuria, each in about 30% of patients. However, active urinary sediment with erythrocyte casts is not found. Many adult patients have mild to moderate azotemia, which may be related to hypoalbuminemia and intravascular volume depletion. Complement levels and serologic test results are normal.
In true minimal change disease, histopathologic examination typically reveals no glomerular abnormalities on light microscopy (LM) ( Fig. 122-1 ). The tubules may show lipid droplet accumulation from absorbed lipoproteins (hence the older term lipoid nephrosis). Immunofluorescence (IF) staining and electron microscopy (EM) ( Fig. 122-2 ) show no immune-type deposits. By EM the GBM is normal, and effacement, or “fusion,” of the visceral epithelial foot processes is noted along virtually the entire distribution of every capillary loop.
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| FIGURE 122-1 Unremarkable light microscopic appearance of minimal change glomerulopathy. Glomerular basement membranes are thin, and there is no glomerular hypercellularity or mesangial matrix expansion (Jones methenamine silver stain, ×300). (From Falk RJ, Jennette JC, Nachman PH: Primary glomerular disease. In Brenner BM [ed]: Brenner and Rector's The Kidney, 7th ed. Philadelphia, Elsevier, 2004.) | |
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| FIGURE 122-2 Minimal change disease. An electron micrograph shows widespread effacement of the foot processes with microvillous transformation of the visceral epithelium. No electron-dense deposits are present (uranyl acetate, lead citrate stain; original magnification ×6000). | |
The course of minimal change nephrotic syndrome is often one of remissions, relapses, and responses to additional treatment. When treated with corticosteroids for 8 weeks, 85 to 95% of children experience a remission of proteinuria. In adults, the response rate is somewhat lower, with 75 to 85% of patients responding to regimens of daily (60 mg) or alternate-day (120 mg) prednisone therapy, tapered after 2 months of treatment. The time to clinical response is slower in adults, and they are not considered steroid resistant until they have failed to respond to 16 weeks of treatment. Tapering of the steroid dose after remission should occur gradually over a period of 1 to 2 months. Both children and adults are likely to have at least one relapse of their minimal change disease once corticosteroid therapy has been discontinued. Approximately 30% of adults experience relapse by 1 year, and in 50% it occurs by 5 years. Most clinicians treat the first relapse similarly to the initial episode. Patients who relapse a third time or who become corticosteroid dependent (unable to decrease the prednisone dose without proteinuria recurring) may be treated with a 2-month course of the alkylating agent cyclophosphamide at a dose of up to 2 mg/kg/day. Up to 50% of these patients have a prolonged remission of nephrotic syndrome (at least 5 years). The response rate is lower in corticosteroid-dependent patients. A commonly used alternative for the treatment of frequently relapsing and steroid-resistant patients is low-dose cyclosporine (4 to 6 mg/kg/day for 4 months), but this therapy carries some risk for nephrotoxicity and a higher relapse rate.
Focal Segmental Glomerulosclerosis
Twenty to 25% of adults with idiopathic nephrotic syndrome are found on biopsy to have FSGS. The incidence of FSGS is increasing in all races; it is the most common form of idiopathic nephrotic syndrome in blacks. FSGS may be either idiopathic or secondary to a number of different causes (e.g., heroin abuse, HIV infection, sickle cell disease, obesity, reflux of urine from the bladder to the kidneys, and lesions associated with a single or remnant kidneys). Recent reports have documented FSGS in multiple family members as a result of genetic defects in structural components of the visceral epithelial cell. Such abnormalities include an autosomal recessive pattern of nephrotic syndrome secondary to mutations in the structural protein podocin and autosomal dominant mutations in the structural protein α-actinin 4, as well as in the TRCP6 glomerular slit diaphragm–associated channel. In general, such patients with genetic forms of the disease are steroid resistant, have a progressive course, and do not experience recurrences of FSGS when they receive a renal transplant.
Patients with idiopathic FSGS typically present with asymptomatic proteinuria or edema. Although nephrotic syndrome is present in two thirds of patients at initial evaluation, proteinuria may vary from less than 1 to more than 30 g/day. Hypertension is found in 30 to 50%, and microscopic hematuria occurs in about half of these patients. The glomerular filtration rate (GFR) is decreased at diagnosis in 20 to 30% of patients. Complement levels and other serologic test results are normal.
By LM, initially only some glomeruli have areas of segmental scarring ( Fig. 122-3 ). As renal function declines, repeat biopsy specimens show more glomeruli with segmental sclerosing lesions and increased numbers of globally sclerotic glomeruli. By IF staining, IgM and C3 are commonly trapped in the areas of glomerular sclerosis. EM shows no deposits and only effacement of visceral epithelial cell foot processes. Recently, several morphologic variants of FSGS have been shown to have either a more benign course and prognosis (e.g., the “tip lesion” variant) or a more progressive course (e.g., the “collapsing” variant).
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| FIGURE 122-3 Light micrographs and diagrams depicting patterns of focal segmental glomerulosclerosis. One pattern (A and D) has a predilection for sclerosis in the perihilar regions of the glomeruli. The glomerular tip lesion variant has segmental consolidation confined to the segment adjacent to the origin of the proximal tubule (B and E). The collapsing glomerulopathy variant has segmental collapse of capillaries with hypertrophy and hyperplasia of overlying epithelial cells (C and F) (Jones methenamine silver stain, ×100). (From Falk RJ, Jennette JC, Nachman PH: Primary glomerular disease. In Brenner BM [ed]: Brenner and Rector's The Kidney, 7th ed. Philadelphia, Elsevier, 2004.) | |
The course of untreated FSGS is usually one of progressive proteinuria and declining GFR. Only a minority of patients experience spontaneous remission of proteinuria, and ESRD eventually develops in most untreated patients 5 to 20 years after diagnosis.
Although there have been few randomized, controlled trials in adults with FSGS, in general, patients with a sustained remission of their nephrotic syndrome are unlikely to progress to ESRD, whereas those with unremitting nephrotic syndrome are likely to progress. Studies using more intensive and more prolonged immunosuppressive regimens (6 to 12 months) consisting of corticosteroids and cytotoxic agents have achieved up to a 40 to 60% remission rate of nephrotic syndrome with preservation of long-term renal function. Cyclosporine, 4 mg/kg/day for 4 to 6 months, has been associated with greater remissions of nephrotic syndrome and less long-term renal failure in a blinded, randomized controlled trial involving patients who were resistant to steroids and frequently cytotoxic agents. Recent studies are evaluating the role of mycophenolate mofetil in the treatment of FSGS. Focal sclerosis recurs in the transplanted kidney in up to 30% of cases, often in association with elevated levels of a circulating permeability factor. Younger patients, those with a rapid course to renal failure, and patients with a previous recurrence are more likely to have FSGS recur in the allograft.
Membranous Nephropathy
Membranous nephropathy is the most common pattern of idiopathic nephrotic syndrome in white Americans. It may also be associated with infections (syphilis, hepatitis B and C), systemic lupus erythematosus (SLE), certain medications (gold salts, NSAIDs), and certain tumors (solid tumors and lymphomas). It is typically manifested as proteinuria and edema. Hypertension and microhematuria are not infrequent findings, but renal function and GFR are usually normal at diagnosis. Despite the finding of complement in the glomerular immune deposits, serum complement levels are normal. Membranous nephropathy is the most common pattern of the nephrotic syndrome to be associated with a hypercoagulable state and renal vein thrombosis. The presence of sudden flank pain, deterioration of renal function, or symptoms of pulmonary disease in a patient with membranous nephropathy should prompt an investigation for renal vein thrombosis and pulmonary emboli.
On LM, the glomerular capillary loops often appear rigid or thickened ( Fig. 122-4 ), but there is no cellular proliferation. IF and EM show subepithelial immune-type dense deposits all along the glomerular capillary loops ( Fig. 122-5 ).
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| FIGURE 122-4 Light micrograph of a glomerulus with stage II membranous glomerulopathy demonstrating spikes along the outer aspects of the glomerular basement membrane (see Fig. 122-1 ). These spikes correspond to projections of basement membrane material between the immune deposits (Jones methenamine silver stain, ×300). (From Falk RJ, Jennette JC, Nachman PH: Primary glomerular disease. In Brenner BM [ed]: Brenner and Rector's The Kidney, 7th ed. Philadelphia, Elsevier, 2004.) | |
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| FIGURE 122-5 Membranous glomerulopathy. On ultrastructural examination there are numerous, closely apposed epimembranous electron-dense deposits separated by basement membrane spikes (uranyl acetate, lead citrate stain; original magnification ×2500). | |
In most large series the renal survival rate is higher than 75% at 10 years, with a spontaneous remission rate of 20 to 30%. Both the slow progression and the spontaneous remission rate have confounded clinical treatment trials. A number of studies using corticosteroids to treat membranous nephropathy have given conflicting results; proof of their benefit is lacking. In general, older patients, males, and those with heavy persistent proteinuria are most likely to progress to renal failure and hence to benefit from therapy. Controlled trials of alternating months of corticosteroid therapy and oral cytotoxic therapy (either cyclophosphamide or chlorambucil) over a 6-month period have achieved greater numbers of total remissions and better preservation of renal function. Meta-analyses have confirmed beneficial results from the use of cytotoxic agents for idiopathic membranous nephropathy. In randomized controlled trials, cyclosporine has led to increased remissions of nephrotic syndrome. Other agents used successfully in uncontrolled trials of membranous nephropathy include mycophenolate mofetil, pentoxifylline, and the monoclonal anti-CD20 antibody rituximab.
Membranoproliferative Glomerulonephritis
Idiopathic type I membranoproliferative or mesangiocapillary glomerulonephritis (MPGN) is an uncommon primary glomerular disease that is found in only a small percentage of renal biopsy specimens. However, by LM, similar patterns of glomerular damage have commonly been seen in association with certain infectious agents (hepatitis C), autoimmune disease (SLE), and diseases of intraglomerular coagulation. All of these stimuli have been proposed to incite the glomerular mesangial cells to grow out along the capillary wall and split the GBM. Type II MPGN, or dense deposit disease, an even less common disease than MPGN type I, is associated with uncontrolled systemic activation of the alternative complement pathway. In most patients it is due to C3 nephritic factor, an autoantibody directed against C3 convertase of the alternative complement pathway. By preventing degradation of the enzyme, there is increased activation and consumption of complement noted in dense deposit disease. It may be associated with partial lipodystrophy.
Most patients with idiopathic MPGN are children or young adults who are initially evaluated for proteinuria or nephrotic syndrome. A low serum complement level is found intermittently in type I MPGN, whereas the C3 level is always reduced in type II MPGN (dense deposit disease). Most studies have found a similar course and prognosis for the various patterns of MPGN, with half the patients progressing to ESRD within 10 years of diagnosis. Attempts to treat MPGN have included the use of corticosteroids and other immunosuppressive medications, as well as anticoagulants and antiplatelet agents. No therapy has proved to be effective in a controlled randomized trial in adults with MPGN, although corticosteroids have had some success in children with the disease.
ACUTE GLOMERULONEPHRITIS AND THE NEPHRITIC SYNDROME
Pathobiology
Known inciting causes of acute glomerulonephritis include infectious agents such as streptococci and bacteria causing endocarditis, deposition of immune complexes in autoimmune diseases such as SLE, and the damaging effect of circulating antibodies directed against the GBM (as in Goodpasture's syndrome). Regardless of the inciting cause, acute glomerulonephritis is characterized on LM by hypercellularity of the glomerulus. It may be secondary to infiltrating inflammatory cells, proliferation of resident glomerular cells, or both. Both invading inflammatory neutrophils and monocytes, as well as resident cells, can damage the glomerulus through a number of mediators, including a host of oxidants, chemoattractant agents, proteases, cytokines, and growth factors. Some factors, such as transforming growth factor-β, have been related to eventual glomerulosclerosis and chronic glomerular damage.
Patients with acute glomerulonephritis often have a nephritic picture characterized by a decreased GFR and azotemia, oliguria, hypertension, and an active urinary sediment. The hypertension is caused by intravascular volume expansion, although renin levels may not be appropriately suppressed for the degree of volume expansion. Patients may note dark, smoky, or cola-colored urine in association with the active urinary sediment. This sediment is composed of erythrocytes, leukocytes, and a variety of casts, including erythrocyte casts. Although many patients with acute glomerulonephritis have proteinuria, sometimes even in the nephrotic range, most patients have lesser degrees of albumin leakage into urine, especially when the GFR is markedly reduced.
IgA Nephropathy
IgA nephropathy was originally thought to be an uncommon and benign form of glomerulopathy (Berger's disease). It is now recognized as the most frequent form of idiopathic glomerulonephritis worldwide (15 to 40% of cases of primary glomerulonephritides in parts of Europe and Asia) and that up to 30% of patients will progress to ESRD in 10 years. In geographic areas where renal biopsy is commonly performed for milder urinary findings, a higher incidence of IgA has been noted. In the United States, some centers report this diagnosis in up to 20% of all cases of primary glomerulopathy. Males outnumber females, and the peak occurrence is in the second to third decades of life.
The diagnosis of IgA nephropathy is established by finding glomerular IgA deposits as either the dominant or codominant immunoglobulin on IF microscopy. Deposits of C3 and IgG are also found frequently. The LM picture varies from the most common situation of mild mesangial proliferation to severe crescentic glomerulonephritis. By EM, immune-type dense deposits are typically found in the mesangial and paramesangial areas. In IgA nephropathy, the predominant antibody is composed of polymeric IgA1, but the antigen—whether infectious, dietary, or other—to which it is directed is unknown in the vast majority of cases. The pathogenesis may involve abnormal O-linked galactosylation of the IgA molecule at the hinge region, which allows abnormal binding of IgA complexes to the glomerular mesangial cells.
IgA nephropathy is frequently manifested either as asymptomatic microscopic hematuria or proteinuria or both (most common in adults) or as episodic gross hematuria after upper respiratory tract infection or exercise (most common in children and young adults). The course is variable, with some patients showing no decline in the GFR over decades and, in others, nephrotic syndrome, hypertension, and renal failure. Hypertension is present in 20 to 50% of all patients. Increased serum IgA levels, noted in a third to half of cases, do not correlate with the course of the disease. Serum complement levels are normal.
Factors predictive of a poor outcome in patients with IgA nephropathy have included (1) older age at onset, (2) absence of gross hematuria, (3) hypertension, (4) persistent proteinuria greater than 1 g/day, (5) male sex, (6) an elevated serum creatinine level, and (7) the histologic features of severe proliferation and sclerosis or tubulointerstitial damage and crescent formation, or both. Renal survival rates are estimated at 80 to 90% at 10 years and 70 to 80% at 20 years. A significant percentage of patients who have undergone renal transplantation have a morphologic recurrence in the allograft, but graft loss as a result of the disease is uncommon.
Because the pathogenesis of IgA nephropathy is thought to involve abnormal antigenic stimulation of mucosal IgA production and subsequent immune complex deposition in the glomeruli, treatment has been directed at these sites. Efforts to treat the disease by preventing antigenic stimulation, including broad-spectrum antibiotics (e.g., doxycycline), tonsillectomy, and dietary manipulations (e.g., gluten elimination), have generally been unsuccessful. Most physicians choose to treat only patients at high risk for progression to renal failure. Trials using fish oils to decrease proteinuria and slow progressive disease have provided conflicting results. Controlled studies suggest that glucocorticoids may decrease proteinuria and progressive renal failure in some patients. The benefit of immunosuppressive agents (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil) is far from clear. For the few patients with crescentic IgA nephropathy, cytotoxic agents have been used. Certain antihypertensives, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, have been shown to reduce proteinuria and the progression of renal disease in almost every trial studied.
Henoch-Schönlein Purpura
Henoch-Schönlein purpura (HSP) is characterized by small vessel vasculitis with arthralgias, skin purpura, and abdominal symptoms, along with a proliferative acute glomerulonephritis that has histopathologic features similar to those of IgA nephropathy. HSP is predominantly a disease of childhood, although it does occur in adults. Despite the finding of circulating IgA-containing immune complexes, no infectious agent or allergen has been defined as causative, and serum complement levels are normal.
The renal histopathology of HSP is similar to that of IgA nephropathy. In the skin there is small vessel vasculitis, a leukocytoclastic angiitis with immune deposition of IgA. The clinical manifestations of HSP ( Chapter 291 ) include dermatologic, gastrointestinal, rheumatologic, and renal findings. Skin involvement typically starts with a macular rash coalescing into purpuric lesions on the ankles, legs, and occasionally, the arms and buttocks. Gastrointestinal symptoms include cramps, diarrhea, and less frequently, nausea and vomiting. Melena and bloody diarrhea are present in the most severely involved cases. Although arthralgias of the knees, wrists, and ankles are common, true arthritis is uncommon. Symptoms of involvement of different organ systems may occur concurrently or separately, and recurrent episodes are not uncommon during the first year.
Like IgA nephropathy, HSP has no proven therapy. Episodes of rash, arthralgias, and abdominal symptoms usually resolve spontaneously. Some patients with severe abdominal findings have been treated with short courses of high doses of corticosteroids. Patients with severe glomerular involvement may benefit from modalities used to treat patients with severe IgA nephropathy. Although most patients with HSP recover fully, patients with a more severe nephritic or nephrotic manifestation and more severe glomerular damage on renal biopsy have an unfavorable long-term prognosis.
Poststreptococcal Glomerulonephritis
Acute poststreptococcal glomerulonephritis (PSGN) may be manifested as an acute nephritic syndrome or as isolated hematuria and proteinuria. It may occur in either an epidemic or sporadic form. PSGN is largely a disease of childhood, but severe disease in adults has been well documented. The disease is most common after episodes of pharyngitis, but it can follow streptococcal infections at any site, and subclinical cases greatly outnumber clinical cases.
PSGN is an acute immune complex disease characterized by the formation of antibodies against streptococci and localization of immune complexes with complement in the kidney. PSGN occurs only after infection with certain nephritogenic strains of group A β-hemolytic streptococci.
On LM, glomeruli are markedly enlarged and often fill Bowman's space. They exhibit hypercellularity because of an infiltration of monocytes and polymorphonuclear cells and a proliferation of glomerular cellular elements. The capillary lumens are often compressed by the glomerular hypercellularity. Some cases demonstrate extracapillary proliferation with crescent formation. By IF microscopy there is coarse granular deposition of IgG, IgM, and complement, especially C3, along the capillary wall. EM shows large dome-shaped, electron-dense subepithelial deposits resembling the humps of a camel at isolated intervals along the GBM.
Most cases are diagnosed by detecting hematuria, proteinuria, and hypertension, with only some of the findings of nephritic syndrome detected after a latency period of 10 days to several weeks following a streptococcal infection. Throat and skin cultures of suspected sites of streptococcal involvement may often not be positive for group A β-hemolytic streptococci. A variety of antibodies (e.g., antistreptolysin O [ASLO]), antihyaluronidase [AHT]) and a Streptozyme panel of antibodies against streptococcal antigens (including ASLO, AHT, antistreptokinase, and anti-DNase) often show high titer, but a change in titer over time is more indicative of a recent streptococcal infection. More than 95% of patients with PSGN secondary to pharyngitis and 85% of patients with streptococcal skin infections have positive antibody titers. Serum total hemolytic complement levels and C3 levels are decreased in more than 90% of patients during the episode of acute glomerulonephritis.
With a classic acute nephritic episode following a documented streptococcal infection and associated with a change in streptococcal antibody titer and a depressed serum complement level, renal biopsy adds little to the diagnosis. In other cases, biopsy may prove necessary to confirm or refute the diagnosis. In most patients, PSGN is a self-limited disease, with recovery of renal function and disappearance of hypertension in several weeks. Proteinuria and hematuria may resolve more slowly over a period of months. Therapy is symptomatic and directed at controlling the hypertension and fluid retention with antihypertensive agents and diuretics.
Glomerulonephritis with Endocarditis and Visceral Abscesses
Various glomerular lesions have been found in patients with acute and chronic bacterial endocarditis ( Chapter 76 ). Although embolic phenomena can lead to glomerular ischemia and infarction, a common finding is immune complex glomerulonephritis. In the pre-antibiotic era, with most cases of endocarditis being due to Streptococcus viridans, both focal and diffuse forms of proliferative glomerulonephritides were common. Recently, with an increased incidence of Staphylococcus aureus endocarditis, 40 to 80% of these patients have clinical evidence of an immune complex proliferative glomerulonephritis. Glomerulonephritis is now more common with acute than with subacute bacterial endocarditis, and the duration of illness is not an important determinant of the renal disease.
Patients often have hematuria and erythrocyte casts in their urinary sediment, proteinuria ranging from less than 1 g/day to nephrotic levels, and progressive renal failure. Serum total complement and C3 levels are usually reduced. Renal insufficiency may be mild and reversible with appropriate antibiotic therapy, or it may be progressive and lead to dialysis and irreversible renal failure.
A proliferative immune complex glomerulonephritis has also been noted in patients with deep visceral bacterial abscesses and infections such as empyema of the lung and osteomyelitis. With appropriate antibiotic therapy, most patients' glomerular lesions heal and renal function is restored. Immune complex forms of acute glomerulonephritis have also been noted in patients with pneumonia associated with many bacterial organisms, as well as Mycoplasma. Patients with chronically infected cerebral ventriculoatrial shunts for hydrocephalus may have similar glomerular pathology. Many have nephrotic-range proteinuria and only mild renal dysfunction.
Rapidly Progressive Glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) comprises a group of glomerular diseases that progress to renal failure in a matter of weeks to months along with the presence of extensive extracapillary proliferation (i.e., crescent formation). RPGN thus includes renal diseases with different causes, pathogeneses, and clinical manifestations ( Table 122-4 ). Patients with primary RPGN have been divided into three patterns defined by immunologic pathogenesis: type I, with anti-GBM disease (e.g., Goodpasture's syndrome); type II, with immune complex deposition (e.g., SLE, HSP, poststreptococcal); and type III, without immune deposits or anti-GBM antibodies, so-called pauci-immune. Most of the last group fall into the category of ANCA-positive RPGN. In the past, with the exception of postinfectious RPGN, the prognosis was generally poor for most patients regardless of the pathogenesis. This prognosis has dramatically changed for some patterns of RPGN.
TABLE 122-4 -- CLASSIFICATION OF RAPIDLY PROGRESSIVE (“CRESCENTIC”) GLOMERULONEPHRITIS
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Anti–Glomerular Basement Membrane Disease
Anti-GBM disease ( Table 122-5 ) is caused by circulating antibodies directed against the noncollagenous domain of the α3-chain of type 4 collagen that damage the GBM. Such injury leads to an inflammatory response, breaks in the GBM, and the formation of a proliferative and often crescentic glomerulonephritis. If the anti-GBM antibodies cross-react with and damage the basement membrane of pulmonary capillaries, pulmonary hemorrhage and hemoptysis develop, an association called Goodpasture's syndrome. The disease has two peaks of occurrence: in men in the third decade of life and in women older than 60 years. These patients initially have a nephritic picture. Renal function may deteriorate from normal to dialysis-requiring levels in a matter of days to weeks. Patients with pulmonary involvement may have life-threatening hemoptysis with dyspnea and diffuse alveolar infiltrates on chest radiographs. The course of the disease, once it has progressed to dialysis levels, is usually one of permanent renal dysfunction. If treatment is started before severe renal failure develops, most patients regain considerable kidney function.
TABLE 122-5 -- COMMON RENAL DISEASES WITH ASSOCIATED PULMONARY DISEASES
| Disease | Marker |
| Goodpasture's syndrome | +Anti–glomerular basement membrane antibodies |
| Wegener's granulomatosis, polyarteritis | +Antineutrophil cytoplasmic antibodies |
| Systemic lupus erythematosus | +Anti-DNA antibodies, low complement |
| Nephrotic syndrome, renal vein thrombosis, pulmonary embolus | +Lung scan |
| Pneumonia with immune complex glomerulonephritis | -Low complement, circulating immune complexes |
| Uremic lung | -Elevated creatinine level |
The pathology of anti-GBM disease shows a proliferative glomerulonephritis, often with severe crescentic proliferation in Bowman's space. There is linear deposition of immunoglobulin (usually IgG) along the GBM by IF ( Fig. 122-6 ), but EM does not show any electron-dense deposits.
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| FIGURE 122-6 Anti–glomerular basement membrane (GBM) glomerulonephritis. An immunofluorescence micrograph of a portion of a glomerulus with anti-GBM glomerulonephritis shows linear staining of GBMs for IgG (fluorescein isothiocyanate anti-IgG stain, ×600). (From Falk RJ, Jennette JC, Nachman PH: Primary glomerular disease. In Brenner BM [ed]: Brenner and Rector's The Kidney, 7th ed. Philadelphia, Saunders/Elsevier, 2004.) | |
Although treatment of this rare disease has not been studied in large controlled trials, intensive immunosuppressive therapy with cyclophosphamide and corticosteroids to reduce the production of anti-GBM antibodies, combined with daily plasmapheresis to remove circulating anti-GBM antibodies, has been successful in many patients. Rapid treatment is necessary to prevent irreversible renal damage and pulmonary hemorrhage. Patients already requiring dialysis support at the time of treatment generally do not regain renal function despite aggressive therapy.
Immune Complex Rapidly Progressive Glomerulonephritis
Type II RPGN is associated with immune complex–mediated damage to the glomeruli and may occur with idiopathic glomerulopathies such as IgA nephropathy and MPGN or diseases of known origin such as postinfectious glomerulonephritis and SLE. Therapy for IgA nephropathy and MPGN was discussed previously. Many cases of crescentic postinfectious glomerulonephritis resolve with successful treatment of the underlying infection. Treatment of severe SLE is considered later.
Pauci-immune and Vasculitis-Associated Rapidly Progressive Glomerulonephritis
Pauci-immune type III RPGN includes patients with and without evidence of systemic vasculitis. Retrospective analyses have found no difference in prognosis between patients with or without documented true arterial vasculitis along with the crescentic and focal segmental necrotizing glomerulonephritis. Patients are often initially found to have progressive renal failure and a nephritic picture. Many patients have circulating antibodies directed against components of neutrophil primary granules (ANCA). Patients who are perinuclear ANCA positive (antibodies usually directed against granulocyte myeloperoxidase) more often have a clinical picture akin to that of microscopic polyarteritis with arthritis, skin involvement with leukocytoclastic angiitis, and constitutional and systemic signs. Patients who are cytoplasmic ANCA positive (antibodies usually directed against a granulocyte serine proteinase—anti-PR3) more often have granulomatous disease associated with their glomerulonephritis, as in Wegener's granulomatosis. There is considerable overlap between these groups. Moreover, some patients have the combination of both ANCA and anti-GBM antibodies. Although there is no direct correlation between ANCA titers and disease activity, patients with high titers (especially high anti-PR3 titers) and those with a four-fold increase in titer are more likely to have flares of their disease.
As in all forms of RPGN, renal function may deteriorate rapidly. Administration of oral cyclophosphamide in addition to corticosteroids has led to markedly improved patient and renal survival in those with Wegener's granulomatosis and polyarteritis nodosa. For example, in a series of 158 patients with Wegener's granulomatosis, more than 90% experienced marked improvement and 75% had a complete remission. These excellent results include patients with true crescentic glomerulonephritis. The use of steroids plus cytotoxic agents has produced successful results in both oliguric and dialysis-dependent patients. Several recent large randomized controlled trials and retrospective reviews have better defined high-risk populations and therapy for pauci-immune RPGN. Older patients, those with severe pulmonary involvement, and patients with severe renal failure may be at higher risk. Intravenous treatment of ANCA-positive RPGN with cyclophosphamide leads to fewer complications but perhaps a higher relapse rate than does treatment with oral cyclophosphamide. Controlled trials have shown that methotrexate is as effective as cyclophosphamide in achieving remission in early or limited disease but that the relapse rate was higher with methotrexate. In severe renal vasculitis, renal survival (but not patient survival) is improved with the addition of plasmapheresis, as opposed to methylprednisolone pulses, to a standard regimen of cyclophosphamide and corticosteroids. Finally, regimens using a long course of cyclophosphamide versus a shorter course followed by the less toxic azathioprine had equal efficacy with a trend toward fewer side effects in the azathioprine group.[1] Ongoing trials are comparing mycophenolate mofetil with azathioprine for maintenance therapy in ANCA-positive vasculitis patients, as well as the appropriate duration of maintenance therapy.
ASYMPTOMATIC URINARY ABNORMALITIES AND GLOMERULAR DISEASES ASSOCIATED WITH GENETIC DEFECTS
Some patients have the asymptomatic urinary abnormalities of microhematuria or proteinuria (or both) discovered through routine evaluations. Microscopic hematuria associated with deformed erythrocytes or erythrocyte casts is likely to be glomerular in origin. Levels of proteinuria less than the nephrotic range may be due to orthostatic proteinuria, hypertension, and tubular disease, as well as glomerular damage.
In patients with asymptomatic urinary abnormalities of glomerular origin, the underlying glomerular lesion may be the early phase of one of the progressive glomerular diseases or be due to a benign, nonprogressive glomerular lesion. Most such patients have a lesion with mild proliferation limited to the mesangial areas of the glomeruli. Some patients have mesangial IgA immune deposits and hence IgA nephropathy, whereas others have deposition of IgM or complement only. In general, for patients with less than 1 g of proteinuria daily or glomerular microhematuria, or both, if the GFR is normal, many clinicians would not proceed to a renal biopsy to establish a diagnosis. Because the vast majority of these patients need no immunosuppressive therapy, they prefer to monitor the patient closely and perform biopsy only on those with progressive proteinuria or evidence of decreasing GFR.
Some patients, often with a history of similar findings in siblings and other relatives, have a hereditary nephritis. A hereditary form of glomerulonephritis that is often accompanied by asymptomatic urinary findings is Alport's syndrome. In approximately 85% of cases it is an X-linked condition with hematuria and proteinuria, frequently in association with high-pitched hearing loss and abnormalities of the lens of the eye (lenticonus). In males, this disease often leads to progressive glomerulosclerosis and ESRD. The defect in most of these cases is localized to a mutation in the α5-chain of type IV collagen (COL4A5). Other families have different patterns of inheritance, more often with mutations in the α3- and α4-chains of type IV collagen (COL4A3, COL4A4). Although LM findings vary from mild mesangial proliferative to advanced sclerosing lesions, depending on the stage of biopsy, EM typically shows areas of thinning of the GBM and areas of splitting of the basement membrane with lamellations. Some other patients with mutations in the collagen IV gene have microhematuria and proteinuria with areas of extreme thinning of the basement membrane on EM of their biopsy specimens. This entity, thin basement membrane disease, was formerly thought to be uniformly benign, but some patients do progress to glomerulosclerosis with time.
Fabry's disease is caused by an X-linked recessive genetic defect in α-galactosidase that leads to the deposition of ceramide trihexose in the kidneys and other organs. It may result in progressive proteinuria and renal insufficiency in males and some female carriers and is associated with telangiectases of the skin, typically in the bathing suit area, acroparesthesias, cardiac abnormalities, and eye changes. Nail-patella syndrome, associated with skeletal and nail deformities, is a rare cause of nephrotic syndrome in children. It is due to an autosomal dominant mutation in the LMX1B transcription factor, which regulates collagen genes and genes for nephrin and podocin.
Systemic Lupus Erythematosus
Renal involvement may greatly influence the course and treatment of SLE ( Chapter 287 ). Although the incidence of clinical renal disease in SLE varies from 15 to 75%, histologic evidence of renal involvement is found in the vast majority of biopsy specimens.
The new International Society of Nephrology (ISN) classification of lupus nephritis is now used widely for both clinical and research activities ( Table 122-6 ). It involves the use of LM, IF, and EM to classify each biopsy specimen by separating the milder mesangial lesions and the bland membranous lupus nephritis from true proliferative lupus nephritis. It is being used and studied as a guide for prognosis and treatment.
| Class | Clinical Features | |
| I. Minimal mesangial LN | No renal findings | |
| II. Mesangial proliferative LN | Mild clinical renal disease; minimally active urinary sediment; mild to moderate proteinuria (never nephrotic) but may have active serology | |
| III. Focal proliferative LN (<50% of glomeruli involved) | More active sediment changes; often active serology; increased proteinuria (about 25% nephrotic); hypertension may be present; some evolve into a class IV pattern. Active lesion require treatment, chronic do not | |
| | Active | |
| | A/C: active and chronic | |
| | Chronic | |
| IV. Diffuse proliferative LN (>50% of glomeruli involved); all may be with segmental or global involvement (S or G) | Most severe renal involvement with active sediment, hypertension, heavy proteinuria (frequent nephrotic syndrome), often reduced glomerular filtration rate; serology very active. Active lesions require treatment | |
| | Active | |
| | A/C | |
| | Chronic | |
| V. Membranous LN glomerulonephritis | Significant proteinuria (often nephrotic) with less active lupus serology | |
| VI. Advance sclerosing LN (>90% glomerulosclerosis) | No treatment prevents renal failure | |
| ISN = International Society of Nephrology; LN = lupus nephritis; RPS = Renal Pathology Society. |
In general, patients with ISN class I and II have mild lesions that require no therapy directed at the kidney. All patients with class IV lesions on biopsy deserve some form of vigorous therapy for their lupus nephritis. Many class III patients (especially those with active necrotizing lesions and large amounts of subendothelial deposits; Fig. 122-7 ) also benefit from such therapy. The optimal therapy for class V patients is less clear; some clinicians treat all membranous lupus nephritis patients vigorously, whereas others reserve such therapy for those with serologic activity or more severe nephrotic syndrome. Vigorous lupus nephritis therapy has included corticosteroids, as well as immunosuppressive therapy, usually with oral or intravenous cyclophosphamide in the past. A series of well-performed randomized studies at the National Institutes of Health (NIH) found that patients treated with cytotoxic agents had less renal failure at 10 years than did those treated with corticosteroids. Intravenous cyclophosphamide appeared to be an effective therapy with fewer side effects than with oral cyclophosphamide. Other NIH studies have documented the superiority of regimens with monthly high-dose intravenous cyclophosphamide therapy (0.5 to 1 g/m2) for 6 months over monthly pulse methylprednisolone in preventing renal progression and flares of disease. Another controlled trial found that combination therapy with monthly cyclophosphamide along with methylprednisolone was more effective in preventing renal failure than either drug regimen was alone, with no increased long-term side effects.
| | |
| FIGURE 122-7 Lupus nephritis. At the ultrastructural level, wire loop deposits correspond to large subendothelial electron-dense deposits (uranyl acetate, lead citrate stain; original magnification ×5000). | |
Recent studies have tried to match the efficacy of cyclophosphamide with newer immunosuppressive agents that have a better safety profile. In recent trials, daily oral mycophenolate mofetil appeared to be equally effective in inducing remissions of severe lupus nephritis but had a better safety profile in several populations, including those at high risk for progressive renal disease (e.g., African Americans). Likewise, in another trial, maintenance therapy with mycophenolate proved to be more effective as cyclophosphamide and was associated with fewer infections and hospitalizations.[2] The precise role of mycophenolate as induction and maintenance therapy in patients with severe lupus nephritis versus cyclophosphamide and the less expensive and relatively nontoxic azathioprine will be decided by future studies. Newer agents such as rituximab, an anti-CD20 monoclonal antibody, and blockers of costimulatory molecules are also currently being studied.
Many patients with lupus nephritis (40 to 50%) produce autoantibodies against certain phospholipids, including anticardiolipin antibodies. Some of these patients have coagulation in the glomeruli and arterioles and require treatment with anticoagulation or antiplatelet agents, or both, as well as immunosuppressive medications.
Diabetes Mellitus
Diabetic nephropathy is the most common form of glomerular damage seen in developed countries. In 2002, it was the most frequent diagnosis in new patients with ESRD in the United States ( Chapter 125 ). Nephropathy develops in 20 to 30% of all patients with type 1 or type 2 diabetes, with a much higher percentage of those with type 1 disease progressing to ESRD. However, because of the much greater prevalence of type 2 disease, the majority of diabetics starting dialysis have this form of the disease.
The histopathologic changes in the kidneys of diabetics involve all components of the kidney, including the glomeruli, vessels, tubules, and interstitium. Changes in the glomeruli consist of thickening of the GBM, mesangial sclerosis, nodular intercapillary glomerulosclerosis (so-called Kimmelstiel-Wilson nodules), lesions caused by insudation of plasma proteins along the glomerular capillary walls, and microaneurysms of the glomerular capillaries.
A current goal of treatment in diabetics is to prevent diabetic renal failure by controlling hyperglycemia and blood pressure, reducing intracapillary glomerular pressure, and preventing the deleterious effects of growth factors and angiotensin II on the kidney. The superiority of ACE inhibitors over other antihypertensive agents in preventing the progression of renal disease and renal morbidity and mortality in type 1 diabetics has been documented in controlled trials. In type 2 diabetics with microalbuminuria, ACE inhibitors and angiotensin II receptor blockers also prevent the appearance of clinical proteinuria and progression of renal dysfunction. Studies have documented the efficacy of angiotensin II receptor antagonists in preventing progression of renal disease in type 2 diabetics. In controlled, randomized, double-blind trials, proteinuria is reduced, doubling of creatinine is decreased, and progression to ESRD is diminished by the use of angiotensin II receptor blockers in addition to conventional blood pressure therapy versus conventional therapy alone. Although survival is improving for diabetic patients maintained on dialysis, it is still inferior to that of nondiabetic ESRD patients. Survival in diabetics after living related donor renal transplantation is approaching that of the nondiabetic population.
Amyloidosis
Renal amyloid deposits—whether caused by AL or AA amyloid—are predominantly found within the glomeruli and often appear as amorphous eosinophilic extracellular nodules ( Chapter 296 ). They stain positively with Congo red and, under polarized light, display apple-green birefringence. By EM, amyloid appears as nonbranching rigid fibrils 8 to 10 nm in diameter.
Although almost 80% of patients with AL amyloid have renal disease, amyloidosis is a disease with multisystemic involvement, and hence patients may have symptoms referable to cardiac or neural involvement, as well as renal symptoms. The diagnosis may be made from organ biopsy other than the kidney (e.g., gingival biopsy, rectal biopsy, or fat pad biopsy). Common renal manifestations are albuminuria and renal insufficiency, which are found in almost half of patients. Approximately 25% of patients with AL amyloid are initially found to have nephrotic syndrome, and it eventually develops in up to half the patients. Amyloid is rarely found in association with light chain cast nephropathy. Treatment strategies for renal amyloidosis have focused on combined therapy with melphalan, prednisone, and colchicines. Studies involving stem cell or bone marrow transplantation and ablative therapy to destroy the clone of abnormal plasma cells leading to amyloid production have produced promising results in select patients.
Light Chain Deposition Disease
Light chain deposition disease (LCDD), like AL amyloidosis, is a systemic disease caused by the overproduction and extracellular deposition of a monoclonal immunoglobulin light chain ( Chapter 198 ). However, the deposits do not form β-pleated sheets, do not stain with Congo red, and are granular rather than fibrillar. Most patients with LCDD have a lymphoplasmacytic B-cell disease similar to multiple myeloma. On LM, most glomeruli have eosinophilic mesangial glomerular nodules. Some biopsy specimens from patients with LCDD have associated light chain cast nephropathy with eosinophilic laminated casts obstructing the tubules, as seen in myeloma. By IF, a single class of immunoglobulin light chain (κ in 80% of cases) stains in a diffuse linear pattern along the GBMs, in the nodules, and along the tubular basement membranes, with little or no staining for complement components.
Albuminuria is common, and nephrotic syndrome is found in half the patients at initial evaluation, often accompanied by hypertension and renal insufficiency. Treatment of most patients with LCDD is chemotherapy, similar to that for myeloma, which has led to significant renal and patient survival, although marrow and stem cell transplantation is being tried in select cases.
Fibrillary Glomerulopathy–Immunotactoid Glomerulopathy
Some patients with renal disease have glomerular lesions with deposits of nonamyloid fibrillar proteins ranging in size from 12 to larger than 50 nm. In the past, these lesions were called fibrillary glomerulopathy, immunotactoid glomerulopathy, amyloid-like glomerulopathy, Congo red–negative amyloid-like glomerulonephritis, and nonamyloiditic fibrillary glomerulopathy. Patients with these lesions have been divided into two groups: those with fibrillary glomerulonephritis with fibrils 20 nm in diameter and those with immunotactoid glomerulonephritis, a rare disease often associated with lymphoproliferative disorders in which the fibrils are much larger (30 to 50 nm). Proteinuria is found in almost all patients, and hematuria, nephrotic syndrome, and renal insufficiency are eventually detected in the majority. There is no proven therapy for fibrillary glomerulopathy at this time.
Human Immunodeficiency Virus–Associated Nephropathy
Infection with HIV ( Chapter 407 ) has been associated with a number of patterns of renal disease, including acute renal failure and a unique form of collapsing focal sclerosis now called HIV-associated nephropathy (HIVAN).
Although a number of histologic patterns of glomerulopathy may be seen in HIV-infected patients, by far the most common is HIVAN. HIVAN is characterized by heavy proteinuria and rapid progression to renal failure. The use of ACE inhibitors and highly active antiretroviral therapy (HAART) may slow the progression to renal failure and decrease proteinuria. Studies show that corticosteroid use in selected patients with HIVAN may be beneficial.
The pathology of HIVAN shows features distinct from those of classic FSGS, including, on LM, diffuse global collapse of the glomerular tufts, severe tubulointerstitial changes with interstitial inflammation, edema, microcystic dilation of tubules, and severe tubular degenerative changes and, on EM, tubuloreticular inclusions in the glomerular endothelium.
Mixed Cryoglobulinemia
Cryoglobulinemia is caused by the production of circulating immunoglobulins that precipitate on cooling and resolubilize on warming. Cryoglobulinemia may be found in association with many types of disease, including infections, collagen vascular disease, and lymphoproliferative diseases such as multiple myeloma and Waldenström's macroglobulinemia ( Chapter 198 ). Many patients with what was originally described as glomerulonephritis secondary to essential mixed cryoglobulinemia have been found to have hepatitis C–associated renal disease. An acute nephritic picture with acute renal insufficiency develops in some patients. Most patients have proteinuria, and about 20% of patients are initially found to have nephrotic syndrome. The majority with renal disease have a slow, indolent renal course characterized by proteinuria, hypertension, hematuria, and renal insufficiency. Hypocomplementemia, especially of the early components Clq to C4, is a characteristic and often helpful finding in cryoglobulinemic glomerulonephritis, whether related to hepatitis C or idiopathic.
A number of systemic diseases, including HUS, thrombotic thrombocytopenic purpura, and the antiphospholipid syndrome ( Chapter 181 ), as well as microangiopathy associated with drugs such as mitomycin and cyclosporine, are characterized by microthromboses of the glomerular capillaries and small arterioles. The renal findings may be dominant or only part of a more generalized picture of microangiopathy.
The histologic findings in all of the microangiopathies resemble each other. Glomerular capillary thromboses are noted in some glomeruli, whereas others downstream from thrombosed arterioles may have only ischemic damage. Arterioles and small arteries show intimal proliferation with luminal narrowing by thrombus. Renal manifestations of the thrombotic microangiopathies may include gross or microscopic hematuria, proteinuria that is typically less than 2 g/day but may reach nephrotic levels, and renal insufficiency. Patients may have oliguric or nonoliguric acute renal failure. In all thrombotic microangiopathies, treatment includes correcting hypovolemia, controlling hypertension, and providing dialytic support for those with severe renal failure. In thrombotic thrombocytopenic purpura associated with an acquired or hereditary deficiency of the von Willebrand convertase ADAMTS-13 and in some other cases, infusion of fresh plasma with or without plasmapheresis has been beneficial. In the antiphospholipid syndrome, anticoagulation with heparin and then warfarin (Coumadin) has been useful.
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