Manual of Nephrology. Diagnosis and Therapy 6e

2017-07-07 02:10:07

Editors: Schrier, Robert W.

Title: Manual of Nephrology, 6th Edition

> Table of Contents > 9 - The Patient with Glomerulonephritis or Vasculitis

The Patient with Glomerulonephritis or Vasculitis

Alexander Wiseman

Overview Glomerular diseases are most simply defined as either a primary process, in which the disease process is confined to the kidney, or a secondary process, in which a systemic disease impacts the kidney. A wide variety of incompletely understood disease processes may lead to histologic abnormalities in the mesangial region, the subepithelial space (the urinary side of the glomerular capillary basement membrane), the subendothelial space (the vascular side of the glomerular basement membrane), or any combination of the above within the glomerulus. These distinct patterns of injury seen on renal biopsy form the basis for classification of these diseases and guide therapy. Because a number of systemic vasculidites can cause small vessel inflammation, often the small vessels of the kidney and the glomerular capillaries are targets of vascular inflammation and can be recognized on renal biopsy.

Clinically, the presence of a glomerular disease should be considered when proteinuria is present; glomerulonephritis and vasculitis should be considered when hematuria and/or proteinuria are present. Thus, the approach to the patient with possible glomerular disease should begin with an assessment of the protein excretion in the urine and a microscopical analysis of the urine for dysmorphic red blood cells and/or red blood cell casts.

Proteinuria Although a number of conditions, such as interstitial nephritis, can cause proteinuria, typically the quantity of nonglomerular proteinuria is less than 1 g on a 24-hour urine collection, whereas clinically and therapeutically relevant glomerular diseases are associated with proteinuria of greater than 1.5 to 3 g per day. The clinician must assess the presence and degree of proteinuria in order to screen for possible glomerular disease.

Evaluation of proteinuria. A number of methods are utilized to assess the presence and degree of proteinuria:
- 24-hour urine collection. When done properly, the 24-hour urine collection provides the most accurate measure of urinary protein excretion. This method involves emptying the bladder and discarding the first morning urine, then collecting all urine for the subsequent 24 hours, including the first morning void the following day. The urine should be refrigerated during the collection period. If this is not possible, one cup of vinegar can be added to the collection container to act as a preservative. To ensure adequate collection, a 24-hour total creatinine excretion should be obtained on the same sample. In females under steady-state conditions of renal function, the 24-hour urinary excretion of creatinine should equal approximately 15 to 20 mg per kg of ideal body weight; in males, the excretion should be 18 to 25 mg per kg of ideal body weight.
- Urine dipstick test. As a rapid screen for the presence of albuminuria, commercially available dipsticks can provide the clinician a gross estimate of the presence and degree of proteinuria. Quantification of proteinuria, however, must be performed using a 24-hour urine collection or alternatively, multiple early morning spot urine collections for the calculation of the protein to creatinine ratio.
- Urine sulfosalicylic acid test. The urine dipstick detects albuminuria, but not smaller molecular weight proteins such as immunoglobulin light
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  chains. The urine sulfosalicylic acid (SSA) test detects the presence of all proteins in the urine, including light chains. This test is particularly helpful in patients with chronic renal insufficiency of unknown etiology, no abnormalities on urinalysis, and little or no protein detected on dipstick screening. A positive SSA test with a normal dipstick indicates the presence of nonalbumin proteins in the urine, leading to further investigation of light chain deposition disease, most frequently associated with multiple myeloma.
- Urine protein creatinine ratio. A urinary protein creatinine concentration ratio on the first voided morning urine sample can be used as a quick assessment of proteinuria, and it can be useful as a substitute for repeated full 24-hour urine collections to assess responsiveness to therapy. The normal 24-hour urine protein excretion in the adult can range from 30 to 130 mg, whereas children and adolescents may excrete as much as twice this amount. With the assumption taken that the average individual excretes approximately 1 g of creatinine per day, normal spot urinary protein creatinine ratios on random samples generally fall below 0.2 (mg protein per mg creatinine), whereas values greater than 3 suggest the presence of nephrotic-range proteinuria. This ratio should not be used as a substitute for an initial 24-hour collection in cases in which glomerulonephritis is considered or in cases in which the creatinine generation is likely greater than 1 g per day (for example, in individuals with large muscle mass).

Classification of proteinuria. As mentioned above, a number of nonglomerular diseases can lead to proteinuria. When proteinuria is identified, it is important to identify whether it is glomerular or nonglomerular in origin, because the treatments for these conditions are dramatically different. In general, proteinuria can be classified into three major categories:

Overflow proteinuria. Overflow proteinuria is caused by the filtration of an abnormally large amount of small-molecular-weight proteins from the serum (by normal glomeruli) that exceeds the capacity of normal tubules for reabsorption. Diseases associated with overflow proteinuria include rhabdomyolysis (myoglobinuria), intravascular hemolysis (hemoglobinuria), and monoclonal gammopathies (such as the light chain deposition disease seen in multiple myeloma). Evaluation of overflow proteinuria may be aided by urine protein electrophoresis (UPEP), which separates urinary proteins into five peaks based on the molecular weights of the proteins. The five peaks include albumin and ₁, ₂, , and globulins. For example, an abnormal peak or spike occurring in the region (or, less commonly, in the ₂ or region) suggests the presence of a monoclonal gammopathy.

Tubular proteinuria. In contrast to overflow proteinuria, in which normal tubular reabsorption is overwhelmed by an abnormally large amount of filtered proteins, tubular proteinuria is caused by damage to the renal tubulointerstitial region, which leads to a failure to reabsorb small-molecular-weight proteins. Under normal conditions, the small amount of urinary protein is composed of filtered proteins from plasma (50%) and proteins that are secreted into the urine from urinary tract cells (50%). Filtered proteins include small amounts of albumin (approximately 15% of the total urinary protein), immunoglobulins (5%), light chains (5%), ₂ microglobulin (<0.2%), and other plasma proteins (25%). The most prevalent tubular protein (and the most abundant protein in normal urine) is Tamm-Horsfall protein, which enters the urine after synthesis in the tubular cells of the ascending limb of the loop of Henle and is secreted into the urine. Under conditions of tubulointerstitial injury, both filtered and secreted proteins are found in increased amounts in the urine, up to 1 to 2 g per day. Increases in tubular proteinuria may occur by three mechanisms. First, injured tubules are unable to reabsorb the small-molecular-weight proteins normally filtered by the glomerulus, such as
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₂ microglobulin. Second, brush border components and cellular enzymes such as n-acetylglucosamine and lysozyme are secreted into the urine under conditions of tubular injury. Lastly, increased amounts of Tamm-Horsfall protein may be secreted into the urine by injured tubular cells of the ascending limb of the loop of Henle and the distal nephron. When the source of proteinuria is unclear, urine electrophoresis (UPEP) and immunoelectrophoresis (IEP) can be utilized to aid in diagnosis. In glomerular proteinuria, a UPEP demonstrates primarily albumin rather than globulins, whereas tubular proteinuria demonstrates a predominance of small-molecular-weight proteins. IEP can quantify this distinction further if a definitive spike is not present on UPEP. A urinary albumin to ₂ microglobulin ratio of 10 to 1 is indicative of tubular proteinuria, in contrast to glomerular proteinuria, in which this ratio usually exceeds 1,000 to 1. In comparison, in normal urine, the albumin to ₂ microglobulin ratio ranges from 50 to 1 to 200 to 1.

Glomerular proteinuria. Glomerular proteinuria results from injury to the glomerulus, leading to an increase in filtered proteins. This injury may result in changes in the size-selective properties of the glomerular basement membrane, allowing the passage of larger-molecular-weight proteins or even of cells (as in crescentic glomerulonephritis), or may result in changes in the charge-selective properties of the glomerular basement membrane, permitting the ultrafiltration of negatively charged albumin (as in minimal change nephropathy). Glomerular injury may lead to a combination of defects in both size and charge selectivity (as in diabetic nephropathy). Finally, mesangial injury may also induce proteinuria via mechanisms that are not clear, perhaps by interfering with normal mesangial clearance functions.

As described, glomerular proteinuria is identified by the preponderance of albumin compared to smaller molecular weight proteins. Generally, the greater the degree of proteinuria, the worse the renal prognosis. In this regard, nephrotic-range proteinuria, defined by significant proteinuria greater than 3.0 to 3.5 g per day, often requires specific therapeutic intervention based upon the underlying disease.

Other proteinuria. Although most forms of proteinuria may be classified into overflow, tubular, or glomerular sources, two additional causes of proteinuria exist that do not fall into these categories. Benign orthostatic proteinuria is proteinuria of less than 1 gram per day without other urinary abnormalities; this is typically found in tall adolescents. When split urine collections are performed (a 12-hour overnight collection and 12-hour daytime collection), protein is found only in the daytime collection. The condition is considered to be benign and often disappears in adulthood; however, in a very small proportion, overt renal disease develops in adulthood. Proteinuria can occur with cardiac failure, fever, or heavy exercise. It is transient and disappears within hours after cessation of exercise or with recovery from the disease process. Table 9.1 lists the most common causes of nonglomerular proteinuria.

Table 9-1. Common Causes of Nonglomerular Proteinuria


Overflow	Tubular	Other

Rhabdomyolysis	Polycystic kidney disease	Benign orthostatic proteinuria
Hemoglobinuria	Pyelonephritis	Transient proteinuria (cardiac failure, fever, heavy exercise)
Monoclonal gammopathy (light chain deposition disease)	Obstruction
	Vesicoureteral reflux
	Medications (chronic lithium exposure, analgesic nephropathy, aminoglycosides)
	Metabolic defects (oxalosis, cystinosis, hypercalcemia, hypercalciuria, hyperuricemia)
	Trace metals (lead, mercury, cadmium)

Clinical assessment of proteinuria. The clinical approach to a patient with proteinuria identified on a screening test (such as a urine dipstick or spot urine protein measurement) should be tailored to assess the presence of concurrent renal injury and the potential for future renal damage. A 24-hour urine protein measurement and a serum creatinine measurement should first be obtained, and the urine should be evaluated for the presence of red blood cells and casts (described in III.A). If renal function is normal, no red cells are present, and proteinuria is less than 200 mg per day, the renal injury sustained from a potential low-grade glomerular disease is minimal, and the risk of future renal injury is low if diabetes and/or hypertension are not present. Proteinuria in the range of 200 mg per day to 2 g per day with no hematuria and normal renal function can be caused by
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glomerular lesions, but is more likely to be related to tubular abnormalities; investigation should be directed accordingly, because a glomerular disease in this clinical scenario carries a good prognosis if blood pressure is adequately controlled. Proteinuria greater than 2 to 3 grams per day needs further evaluation for the presence of glomerular injury regardless of renal function. This evaluation is outlined in section IV. Any presentation in which red blood cell casts or dysmorphic red blood cells are present, regardless of the degree of renal function or proteinuria, must be further evaluated for the presence of a glomerulonephritis or vasculitis.

Hematuria. The pathognomonic finding of glomerular injury is the presence of dysmorphic red blood cells or red blood cell casts in the urine. This finding is a hallmark of glomerular capillary injury and limits the differential diagnosis significantly. However, care must be taken to rule out other causes of hematuria that produce red blood cells in the urine that are of normal morphology and do not form casts (typical of lower urinary tract abnormalities) and positive dipstick hematuria due to myoglobinuria or hemoglobinuria.
- Evaluation and classification of hematuria. The initial evaluation is typically provoked either by macroscopic hematuria (visible discoloration of the urine) or by incidental findings on dipstick. Similar to the evaluation of proteinuria, hematuria can either be due to a glomerular disorder or to a nonglomerular source. Glomerular bleeding should be suspected if dysmorphic urinary red blood cells, red blood cell casts, and proteinuria are present. Nonglomerular hematuria is characterized by the presence of isomorphic urinary erythrocytes without red blood cell casts or significant proteinuria. Hematuria secondary to nonglomerular causes can be differentiated by the three-glass test. In this procedure, an inital stream, mid-stream, and end-stream sample of urine (10 to 15 mL each) is collected in three separate containers. A urethral site of bleeding is likely if the hematuria predominates in the inital sample, whereas a bladder origin is suggested if hematuria is predominately identified in the final sample. Ureteral and renal sources are suspected if hematuria is present in all three collection samples.
- Clinical assessment of hematuria. The initial evaluation of the patient with gross or microscopic hematuria should be focused upon differentiating
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  glomerular from nonglomerular causes. If microscopy suggests a glomerular cause, with dysmorphic red blood cells and red blood cell casts, patients should be further evaluated for renal dysfunction and glomerulonephritis as described in section IV.C. Nonglomerular hematuria typically entails an evaluation for the possibility of a urogenital malignancy, infection, stone, or cystic disease. In this regard, the history and review of systems should focus upon the frequency and nature of hematuria (gross or microscopic), pain, burning with urination, increased frequency of urination, fever, weight loss, and passage of stones. Medications that may lead to hematuria should be reviewed, including oral contraceptives and analgesics, particularly in patients with diabetes. Other causes of hematuria, including trauma, coagulation disorders, and family history of renal disease should be considered. The physical examination can identify certain causes of hematuria, such as renal bruits suggestive of arteriovenous fistulae; an enlarged prostate or nodules suggestive of hypertrophy, prostatitis, or malignancy; or enlarged kidneys on abdominal palpation, suggestive of polycystic kidney disease.
  
  The diagnostic evaluation of nonglomerular hematuria should include urine culture for bacterial infection, and if suspected, mycobacterial and mycoplasma infection. Once a UTI has been excluded, the urinary tract anatomy should be evaluated via radiologic imaging or direct visualization to rule out malignancy, stone disease, and hereditary renal disease. The upper tract (the kidneys and ureters) can be evaluated by either a renal ultrasound, computed tomography (CT) scan, or intravenous pyelography (IVP), whereas the lower tract (bladder and urethra) is best evaluated by cystoscopy. Urine cytology can serve as an additional test to screen for the abnormal cellularity suggestive of urogenital malignancy. At the discretion of a urologist, a combination of the above tests should be performed in the patient with unexplained hematuria.
  
  In the presence of a normal or near-normal glomerular filtration rate (GFR), intravenous urography is the most useful diagnostic radiologic procedure available for defining renal anatomy. It should disclose the
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  presence of renal cysts (hereditary and acquired); calculi; papillary necrosis; medullary sponge kidney; renal, pelvic, and ureteral tumors; and ureteral strictures. In the event of a nondiagnostic intravenous urographic study, cystoscopy can be performed to more definitively examine the bladder for the presence of tumors or infectious (inflammatory/interstitial) cystitis and the urethra for the presence of urethritis, strictures, or both. A nondiagnostic cystoscopic examination can be followed, if clinically indicated, by arteriography to pursue the possibility that hematuria is secondary to ureteral varices or aneurysms, arteriovenous malformations, or the loin-pain hematuria syndrome.

Glomerular hematuria and/or proteinuria. Once the evaluation of hematuria and/or proteinuria lead the clinician to consider a glomerular disease as the most likely etiology, further clinical information can assist in the classification of the renal disorder prior to invasive testing. Although it is often difficult to predict the histologic pattern of injury in a patient with glomerular disease, one can first consider if a pattern of injury exists that may be segregated based upon two general clinical presentations the nephritic syndrome and the nephrotic syndrome to assist in serologic testing.

The nephritic syndrome. This clinical syndrome typically presents with clinical findings of hematuria, proteinuria, and dysmorphic red blood cells and/or red blood cell casts. The proteinuria can range from 200 mg per day to heavy proteinuria (greater than 10 grams per day). Clinically, it is accompanied by hypertension and edema. Renal insufficiency is common and typically progressive. The term rapidly progressive glomerulonephritis refers to diseases with a nephritic syndrome that lead to a rapid deterioration in renal function, defined as a doubling of serum creatinine or a 50% decrease in glomerular filtration rate over 3 months or less.

The nephrotic syndrome. This clinical syndrome also presents with proteinuria and edema, but unlike the nephritic syndrome, proteinuria is the most prominent feature (greater than 3.5 g per 1.73 m² per day). Dysmorphic red blood cells and casts are typically absent [exceptions do exist: focal segmented glomerulosclerosis (FSGS) and IgA nephropathy, conditions that usually present with nephrotic proteinuria, also can present with hematuria]. Additional features of the nephrotic syndrome include hypercholesterolemia and hypoalbuminemia (serum albumin less than 3.0 mg per dL). The diseases that cause the nephrotic syndrome can lead to chronic, progressive renal injury, but typically are more indolent than diseases that lead to a nephritic syndrome.

Once the clinical pattern has been identified, the clinician must consider if there is a systemic process that may be causing the proteinuria. Tables 9-2 and 9-3 list systemic diseases that present with a nephritic and nephrotic syndrome, respectively, and also highlight key laboratory findings that may aid in an initial diagnosis.

Table 9-2. Systemic Diseases that Cause Glomerular Injury and a Nephritic Clinical Presentation


Disease	Specific examples	Laboratory findings

Infections	Hepatitis C (B less commonly)	Low C3, Hep C Ab, Hep C viral PCR, cryoglobulins
	Post-streptococcal GN	Low C3, Anti-streptolysin Ab
	Bacterial endocarditis	Low C3, positive blood cultures
	MRSA infection	Low C3, positive blood cultures
Vasculidities	SLE	Low C3, ANA, anti-DNA
	Wegener's granulomatosis	c-ANCA
	Goodpasture's syndrome	Anti-GBM Ab
	Churg-Strauss syndrome	p-ANCA
	Henoch-Sh nlein purpura	IgA in skin biopsy
	Polyarteritis nodosa	ANCA in 20% (c- or p-ANCA)
	Mixed cryoglobulinemia	Rheumatoid factor, low C4
Thrombotic microangiopathy	Scleroderma renal crisis	Anti-Scl-70
	Thrombotic thrombocytopenic purpura	Low platelets, hemolysis
	Hemolytic uremic syndrome	Low platelets, hemolysis, E. coli enteritis
	Malignant hypertension

Table 9-3. Systemic Diseases that Cause Glomerular Injury and a Nephrotic Clinical Presentation


Disease state	Common stiologies	Laboratory findings

Infections	Hepatitis B (C less common)	Hep B SAg, Hep B eAg
	HIV	HIV Ab
	Syphilis	RPR
Chronic diseases	Diabetes	Elevated HgbA1c, blood glucose
	Amyloidosis	UPEP/IEP (when associated with light chains)
	Sickle cell disease	Hemoglobin electrophoresis
	Obesity
Malignancies	Multiple myeloma	SPEP, UPEP
	Adenocarcinoma (lung, breast, colon most common)	Abnormal cancer screening studies (usually clinically evident tumor burden)
	Lymphoma
Rheumatologic	Systemic lupus erythematosus	ANA, anti-dsDNA Ab
	Rheumatoid arthritis	Rheumatoid factor
	Mixed connective tissue disease	Anti-RNP Ab
Medications	NSAIDs
	Bucillamine
	Penicillamine
	Lithium
	Ampicillin
	Captopril
	Probenecid
	Gold

In the absence of evidence of systemic disease, the clinician must consider primary (or islolated) glomerular diseases in the differential diagnosis. Histologically, these primary diseases are not distinct from the injury pattern seen in systemic diseases. The primary glomerulopathies are recognized by the histologic pattern defined by light microscopy, immunofluorescent staining for immunogloulins, and the characteristics and location of immune deposits on electron microscopy. The primary glomerular diseases are listed in Table 9-4, with the prominent histologic findings on biopsy that define the disorder.

Table 9-4. Primary Glomerular Diseases, Defined by Histology


Nephritic	Histologic findings	Nephrotic	Histologic findings

Renal-limited vasculitis/microscopic polyangiitis	Necrotizing capillary lesions, crescents; negative IF, EM	Minimal-change disease	Normal light microscopy, effaced foot processes on EM
Anti-glomerular basement membrane disease	Linear IgG staining along glomerular basement membrane	Membranous nephropathy	Subepithelial spikes on light, IF, EM
Essential cryoglobulinemia	Fibrils on electron microscopy	Membranoproliferative glomerulonephritis	Thickened mesangial matrix, splitting ( double contour ) of the glomerular basement membrane, C3 granular staining on IF
		Focal segmental glomerulosclerosis	Sclerosis in portions of glomeruli, C3 in areas of sclerosis on IF
		IgA nephropathy	IgA in mesangium on IF
		Fibrillary glomerulonephritis	Fibrillar deposits in mesangium, negative congo red staining on IF

Clinical assessment of glomerular disease

The nephritic syndrome. In cases in which the nephritic syndrome is the predominant clinical presentation, a search for systemic diseases is warranted. The history and physical exam should particularly focus on the assessment of rashes, lung disease, neurologic abnormalities, evidence of viral or bacterial infections, and musculoskeletal and hematologic abnormalities. Laboratory assessment should be tailored to the clinical

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findings in the history and physical examination. A complete blood count (CBC), electrolyte panel, 24-hour urine collection for protein and creatinine clearance, and liver function tests should be obtained initially. Serum complement (C3) levels are often clinically helpful to assist in the diagnosis of a specific renal disease (Table 9-5). Further laboratory assessment may be performed based on these findings, and may include an anti-streptolysin (ASO) titer, antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, and/or an anti-GBM antibody. These early assessments may provide a presumptive diagnosis and should lead the clinician to an appropriate therapeutic intervention while awaiting renal biopsy results. These laboratory assessments should not substitute for the renal biopsy; only with a tissue diagnosis that confirms the clinical findings and provides information regarding the acuity and chronicity of the disease process can a glomerular disease can be properly managed.

Table 9-5. Clinical Approach to Glomerulonephritis Based Upon Serum Complement Level


Low serum complement level		Normal serum complement level

Systemic diseases	Primary renal diseases	Systemic diseases	Primary renal diseases
SLE	Post-streptococcal glomerulonephritis	Polyarteritis nodosa	IgA nephropathy
Subacute bacterial endocarditis	Membranoproliferative glomerulonephritis (MPGN)	Hypersensitivity vasculitis	Idiopathic rapidly progressive glomerulonephritis (anti-glomerular basement membrane disease, pauci-immune glomerulonephritis, immune complex disease)
	Type 1
	Type 2
Shunt nephritis		Wegener's granulomatosis
Cryoglobulinemia		Henoch-Sch nlein purpura
		Goodpasture's syndrome
		Visceral abcess

(Adapted from Madaio MP, Harrington JT. Current concepts. The diagnosis of acute glomerulonephritis. N Eng J M 1983;309:1299, with permission.)

The nephrotic syndrome. With the identification of significant proteinuria, with or without other features of the nephrotic syndrome, secondary causes of proteinuria should be assessed. History and physical examination should evaluate for the presence of viral and bacterial infections, malignancies (particularly lung, breast, and lymph node), chronic diseases (such as diabetes), and medications should be reviewed for their potential to cause glomerular proteinuria. Laboratory assessment initially includes CBC, electrolyte panel, 24-hour urine collection for protein and creatinine clearance, liver function tests, and a cholesterol panel. Further assessment may include hepatitis and human immunodeficiency
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virus (HIV) serologies, ANA, rapid plasma reagin (RPR), and serum and urine electropheresis. Renal biopsy should be performed in all cases in which no cause is evident, or to determine the extent of renal disease to guide therapy or prognosis.

Therapy for glomerulonephritis. The management of systemic diseases that cause secondary glomerular injury is rapidly changing (for example, new antiviral therapies for HIV and Hepatitis B and C, and clinical trials using chemotherapeutic regimens for malignancies and vasculidities), thus the reader is encouraged to refer to recent disease-specific reviews of the literature for current management strategies for these systemic diseases. This chapter reviews the treatment of the most frequent systemic diseases that cause glomerular injury. The treatment of glomerular disorders can be approached by general management of the nephrotic syndrome and proteinuria, and immunomodulating therapies for specific glomerular diseases and vasculidities.

General management of the nephrotic syndrome and proteinuria. Four general treatment strategies should be considered in the patient with nephrotic syndrome: managment of edema, management of proteinuria, mangagement of hyperlipidemia, and management of hypercoagulability. Management of edema should initially focus on sodium restriction and diuretics. Thiazides are a reasonable treatment choice for patients with mild edema and normal renal function; however, the majority of patients will require a loop diuretic such as furosemide for adequate sodium balance. The cornerstone to management of proteinuria is the inhibition of the renin-angiotensin system using either angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). Using these medications, intraglomerular pressure is reduced due to efferent arteriolar vasodilation, thus resulting in a reduced amount of protein filtrated. In diabetes, ACEi have been shown to be critical in slowing the development of overt diabetic nephropathy in patients with type 1 diabetes and microalbuminuria (30 to 300 mg per day), and reducing the incidence of end-stage renal disease (ESRD) and overall mortality in patients with type 1 diabetes and overt diabetic nephropathy (urine protein excretion greater than 300 mg per day). ARBs have shown similar benefits in patients with type 2 diabetes with either microalbuminuria or overt nephropathy. In nondiabetic proteinuric renal disease, ACEi also significantly reduces the risk of developing ESRD. The maximal therapeutic dose of single agent, and the role a combination of ACE and ARB for treatment of significant proteinuria and progression of renal disease remains unknown. Proteinuria may also be reduced by lowering patients' mean arterial pressure to levels lower than 92 mm Hg, independent of the class of antihypertensive agents used to achieve this target. Finally, dietary protein restriction in the range of 0.6 to 0.8 g per kg per day has been suggested, both to slow the rate of loss of renal function and as a further means of diminishing proteinuria. Long-term studies regarding nutritional safety are still necessary before this strategy should be advocated in patients, particularly those with heavy proteinuria (i.e., more than 10 g per day).

Control of hyperlipidemia often can be accomplished with use of the HMG-CoA reductase inhibitors or agents such as gemfibrozil. The issue of anticoagulation arises due to a hypercoagulable state induced by nephrotic proteinuria. Protein losses include the loss of antithrombotic factors such as antithrombin III, leading to an increased frequency of renal vein thrombosis and, less commonly, arterial thrombosis or pulmonary emboli. Long-term anticoagulation for the duration of the nephrotic syndrome is recommended for patients with documented thrombotic episodes. Debate still exists regarding prophylactic anticoagulation for all patients with nephrotic syndrome.

Therapies for specific glomerular diseases. The specific management of glomerular diseases may be initiated following renal biopsy. Histologically, glomerular disorders associated with the nephrotic syndrome fall into five

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general categories: minimal-change glomerulopathy, membranous nephropathy, mesangial proliferative glomerulonephritis (MPGN), focal and segmental glomerulosclerosis, and IgA nephropathy. Glomerular disorders with a nephritic clinical presentation typically show disruption of the glomerular basement membrane with cellular crescent formation in Bowman's space on renal biopsy (crescentic glomerulonephritis). These disorders generally fall into three histologic categories defined by the immunofluorescence patterns of immune deposits within the glomerulus (Table 9-6): linear immunofluorescence, granular immunofluorescence, and absent immunofluoresence. This categorization is a generalization, since aggressive forms of IgA nephropathy and MPGN may clinically appear nephritic and may be associated with glomerular crescents.

Table 9-6. Histologic Classification of Crescentic (or Rapidly Progressive) Glomerulonephritis


Linear immunofluorescence	Granular immunofluorescence	Absent (pauci-immune) immunofluorescence

Goodpasture's disease	SLE	ANCA-associated vasculitis:
		Wegener's granulomatosis,
		Churg-Strauss syndrome,
		microscopic polyangiitis
Anti-GBM disease	Henoch-Schonlein purpura, IgA nephropathy
	Cryoglobulinemia

Minimal-change glomerulopathy. Approximately 15% of cases of idiopathic nephrotic syndrome in adults, and 85% in children, are due to minimal-change disease (MCD). Light microscopy is normal, and in combination with findings of effacement of foot processes on electron microscopy, is diagnostic of MCD on renal biopsy. IgM deposits may be seen in the mesangium on immunofluorescence, which may protend a poorer prognosis. In addition to the conservative managment of nephrotic syndrome, high-dose prednisone (1 mg per kg, maximum, 80 mg) is used as primary therapy for at least 12 weeks. Whereas greater than 90% of children with MCD will have a complete remission of proteinuria within 2 months of starting steroid therapy, in adults this figure is approximately 50% to 60%. Extending the duration of high-dose prednisone to 5 to 6 months increases the rate of complete remission to 80%. Prednisone should then be slowly tapered over approximately 4 months. For relapsing cases and cases in which steroids cannot be tapered (steroid dependence), recycling of steroids with or without the addition of cytotoxic agents (e.g., cyclophosphamide or chlorambucil), cyclosporine A, or possibly mycophenolate mofetil, may be effective.

Membranous nephropathy. Approximately 30% to 40% of cases of idiopathic nephrotic syndrome in adults are due to membranous nephropathy. Typically, this disease is slowly progressive and frequently patients may have spontaneous remissions, particularly female patients. However, certain patients are at high risk for progressive renal injury. Clinical risk factors associated with progression include heavy proteinuria greater than 8 g per day; hypertension; diminished GFR (creatinine greater than 1.2 for women, greater than 1.4 for men), male gender, and a greater than 20% tubulointerstitial fibrosis on renal biopsy. For these patients, steroids combined with a cytotoxic agent (either chlorambucil or cyclophosphamide) alternating monthly for 6 months appears to be more effective than steroids alone in inducing a complete or partial
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remission. Preliminary data suggest that mycophenolate therapy also may be effective in the management of low- to moderate-risk patients.

MPGN. Idiopathic MPGN can be subcategorized to two types, type 1 (immune complex-mediated) and type II (thought to be complement-mediated). Both types, however, appear similar on light microscopy with expansion of the mesangial matrix. On electron microscopy, type II MPGN shows dense longitudinal deposits within the GBM versus the dense subepithelial deposits seen in type 1 MPGN. Together, these entities make up 5% of idiopathic nephrotic syndrome in adults, and they tend to carry a poor renal prognosis. Of patients with type 1 MPGN and nephrotic proteinuria, 60% will progress to ESRD in 10 years. Unfortunately, no established therapy exists for MPGN. Despite conflicting data regarding its efficacy, long-term alternate-day prednisone is the current therapy of choice, particularly for children and teenagers. In any case of MPGN, secondary causes must be fully evaluated, because diseases such as chronic bacterial infection, Hepatitis C infection, and cryoglobulinemia, as well as leukemias and lymphomas all have therapies that may lead to remission of the renal disease.

Focal and segmental glomerulosclerosis. Approximately 20% of cases of idiopathic nephrotic syndrome in adults is due to focal segmental glomerulosclerosis (FSGS). FSGS may represent a more severe form of minimal-change disease, because glomerular epthelial cell foot process effacment is present on electron microscopy. Unlike MCD, however, focal areas within the kidney demonstrate sclerosis in segments of individual glomeruli. Previously considered an untreatable renal lesion, recent evidence suggests that with prolonged courses (at least 6 months) of high-dose corticosteroid therapy approximately 30% of patients will acheive remission of the nephrotic syndrome. The remaining 70% who fail to respond to steroids may occasionally experience remission on cytotoxic agents such as cyclosporin, cyclophosphamide, or chlorambucil.

IgA nephropathy (Berger's disease). IgA nephropathy is the most common form of primary glomerular disease in the world. It is particularly prevalent in Asia and Australia (perhaps due to sampling bias resulting from a more frequent biopsy rate in these regions), and rare in African-Americans. Although generally considered to be a slowly progressive renal disease, with ESRD occuring in 20% to 40% of patients by 20 years, a minority of patients may experience a rapidly progressive glomerulonephritis with crescent formation on biopsy. Occasionally, reversible acute renal failure occurs, particularly in association with gross hematuria. Treatment of IgA nephropathy remains controversial, because no therapeutic regimen has been shown to clearly affect outcome. Some studies advocate the use of fish oil in slowing the progression of renal insufficiency. For crescentic disease, short-term, high-dose prednisone may be of benefit. The use of cytotoxic agents such as cytoxan remains investigational at this time.

Crescentic glomerulonephritis, linear immunofluorescence. When glomerulonephritis is accompanied by crescents, and immunofluorescent staining for IgG demonstrates a linear pattern along glomerular capillaries on biopsy, the presence of an anti-glomerular basement membrane autoantibody (anti-GBM) is the most likely etiology. Clinically, this may present either as isolated renal dysfunction (anti-GBM disease) or as renal disease in conjunction with pulmonary involvement (Goodpasture's syndrome) with IgG staining of the pulmonary capillary basement membrane. Treatment of this disorder involves the combination of high-dose steroids, cytoxan therapy, and plasmapheresis to remove the anti-GBM antibody. Patients who present with oliguria have a poor renal prognosis, but occasionally may avoid chronic dialysis with aggressive and early therapy.

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Crescentic glomerulonephritis, granular immunofluorescence. In this form of glomerulonephritis, immune complexes deposit within the glomeruli in a nonlinear fashion, giving the appearance of lumps and bumps when stained by immunofluorescent markers. Diseases within this histologic category include postinfectious GN (in which C3 and IgG stains in the subepithelial space), Henoch-Sch nlein purpura, and occasionally IgA nephropathy (in which IgA predominantly stains in the mesangial space), cryoglobulinemia (in which IgM rheumatoid factor or light chains are identified in the subendothelial space) and systemic lupus erythematosus (SLE; in which C3, IgG, IgM, IgA, and C1q all are present on immunofluorescence). In general, therapy for immune complex mediated glomerulonephritis includes high-dose corticosteroids and cytoxan, particularly for the treatment of diffuse proliferative lupus nephritis. Plasmapheresis has not been demonstrated to be of benefit in this class of renal diseases, with the exception of cryoglobulinemia.

Crescentic glomerulonephritis, absent immunofluorescence. When crescentic glomerulonephritis is accompanied by necrotizing capillary lesions, but no immunofluorescent staining of immune deposits are present on renal biopsy, the differential diagnosis of pauci-immune diseases are considered. These diseases are generally considered to be secondary to antibodies to lysosomal enzymes of neutrophils (ANCA). Two ANCAs have been identified. Antibody to myeloperoxidase (MPO) results in perinuclear staining of neutrophils (p-ANCA), whereas antibody to proteinase-3 results in cytoplasmic staining of neutrophils (c-ANCA). Both systemic diseases (such as Wegener's granulomatosis, associated primarily with c-ANCA; Churg-Strauss syndrome, associated with either c- or p-ANCA; and polyarteritis nodosa) and primary renal disease (microscopic polyangiitis) can cause a pauci-immune necrotizing glomerulonephritis. Whether systemic or primary, these diseases are managed with high-dose steroids and cyclophosphamide as the therapy of choice. Oral cytoxan seems to be more effective than i.v. pulse cytoxan therapy. Eighty percent of patients respond to therapy, and unlike anti-GBM disease, patients may ultimately cease dialysis requirements, although patients with a serum creatinine of greater than 6 mg per dL at presentation are less likely to respond than patients with lower serum creatinine at the time of presentation.

The thrombotic microangiopathies: glomerular injury that masquerades clinically as glomerulonephritis. Systemic disorders that may produce a nephritic clinical presentation include a number of diseases that are not classical inflammatory diseases or vasculidities. Systemic diseases such as scleroderma, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), malignant hypertension, and antiphospholipid syndrome (APS) can present with hematuria, hypertension, and proteinuria (although usually less than 1 to 1.5 g per day), but all have renal histologic findings distinct from glomerulonephritis. Common histologic findings on renal biopsy in HUS, TTP, and APS include glomerular capillary thrombi and afferent arterioles, with fibrinoid necrosis from endothelial injury. Immunofluorescence is typically negative, with the exception of the presence of fibrinogen. Electron microscopy is also usually unremarkable, with no deposits noted. Additionally, malignant hypertension and scleroderma can cause subintimal proliferation within blood vessels, leading to an onion-skin appearance of arterioles. Microthrombi may be present as well.

The specific management of the thrombotic microangiopathies differs significantly from other disorders that lead to a nephritic clinical presentation, thus a correct diagnosis rather than empiric therapy is critical under circumstances of a nephritic presentation. For treatment of malignant hypertension and scleroderma renal crisis, blood pressure control is paramount. ACE inhibitor therapy is the first-line therapy in the setting of scleroderma, since data demonstrate improved patient survival and renal outcomes using this
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form of therapy. In HUS, the clinical picture is predominantly one of acute renal failure, thrombocytopenia, and hemolysis resulting either from verotoxin (from E. coli 0157:H7 gastrointestinal infection) or from secondary causes such as idiosyncratic reactions to medications such as cyclosporin and mitomycin, or postpartum HUS. Therapy is supportive, with dialysis and correction of electrolytes and treatment of anemia providing reasonable short-term outcomes. Ninety percent of cases of diarrhea-associated HUS will completely recover, whereas 5% die within the acute phase and 5% remain with severe renal and extrarenal complications. Long-term follow-up demonstrates a diminished GFR in 40% of these patients at 10 years. For TTP, the clinical picture is a pentad of neurologic signs, purpura, fever, thrombocytopenia, hemolysis, and renal failure that usually do not coexist but rather wax and wane. Secondary forms of TTP exist, and include pregnancy-associated, malignancy-associated, and HIV-associated causes. However, the most common cause of primary TTP is secondary to endothelial injury and the release of abnormally large von Willebrand factor (vWF) multimers into the microcirculation. This leads to platelet aggregation and thrombi formation. For this syndrome, fresh frozen plasma exchange or infusion is the most effective therapeutic intervention, although the mechanism for its beneficial effect remains under investigation. Plasma exchange should be continued until the platelet count has normalized and the serum lactate dehydrogenase (LDH) enzyme level returns to normal range. This typically takes 7 to 16 exchanges to induce remission, followed by a slow taper of therapy. Additional therapies that have been described include high dose prednisone therapy, vincristine, and other chemotherapeutic agents. The benefit of these therapies is not clear. In some patients in whom plasma exchange is only transiently effective, splenectomy may be necessary.

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