Glomerular and Tubulointerstitial Disease

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[edit] Glomerular and Tubulointerstitial Disease

Paul G. Schmitz

[edit] ETIOLOGIC CLASSIFICATION

Glomerular and tubulointerstitial diseases are the most common causes of chronic renal insufficiency.A precise understanding of the relationship between clinical features and histopathologic features is necessary to classify glomerular and tubulointerstitial renal disease correctly.

[edit] Glomerular Disease

The clinical hallmark of glomerular disease is proteinuria, hematuria, or both conditions.Proteinuria in the nephrotic range or the presence of red blood cell (RBC) casts in the urine sediment is virtually pathognomonic for glomerular disease.More important, most glomerular diseases can be conveniently classified into those with a “nephrotic” urine sediment vs.those with a “nephritic” urine sediment (Figs.148-1 and 148-2).Thus examination of the urine is a crucial initial step in the clinical evaluation of glomerular disease.Glomerular disease can be further classified into primary(idiopathic) and secondary (e.g., systemic lupus erythematosus [SLE], amyloidosis) causes.Since the clinical presentation may not accurately predict the underlying histologic features, a renal biopsy is often indicated in the evaluation of suspected glomerular involvement.

Figure 148-1 Clinical approach to the patient with proteinuria.

Figure 148-2 Clinical approach to the patient with hematuria.

[edit] Tubulointerstitial Disease

Although scarring of the tubules and interstitium often occurs with glomerular disease, primary tubulointerstitial injury can occur as the principal manifestation of a variety of toxic, metabolic, and genetic diseases (Fig.148-3).Acute tubular necrosis secondary to ischemic or toxic injury is the most common cause of hospital-acquired acute renal insufficiency.Other common causes include drug-induced interstitial nephritis, cystic kidney disease, infectious pyelonephritis, and urinary tract obstruction.In contrast to glomerular involvement, tubulointerstitial disease is characterized by mild proteinuria (usually less than 1 gm/24 hr) and impaired distal or proximal tubular function (renal tubular acidosis, glucosuria, aminoaciduria, defective urinary concentration).Although acute tubulointerstitial injury is often characterized by an active urine sediment (white blood cells [WBCs], WBC casts, and RBCs), a “bland” urinalysis is the rule in chronic tubulointerstitial disease.

Figure 148-3 Clinical approach to the patient with suspected tubulointerstitial disease.

[edit] PATHOPHYSIOLOGY

[edit] Normal Anatomy and Function

The glomerulus is a specialized vascular structure that functions as the basic filtering unit of the kidney (Fig.148-4).Glomerular cells are composed of endothelial cells, visceral epithelial cells (podocytes), mesangial cells, and resident macrophages.These cells have different functions, including regulation of renal blood flow and intraglomerular pressure, synthesis and degradation of extracellular matrix, modulation of glomerular permeability for various macromolecules, and phagocytosis.An important function of the normal glomerulus is to restrict passage of certain plasma constituents while allowing filtration of endogenous waste products.The glomerular filtration barrier is composed of three layers: an inner fenestrated endothelium, a middle basement membrane, and an outer visceral epithelial cell.These elements form a physical barrier limiting the passage of molecules with molecular weights exceeding 50,000 daltons.Moreover, the visceral epithelial cell and basal lamina contain negatively charged sialoglycoproteins, which impede the filtration of negatively charged substances (e.g., albumin).

Figure 148-4 Normal glomerular anatomy.

The renal interstitium is composed of interstitial cells embedded within the extracellular matrix.Interstitial cells provide physical support for the renal tubules embedded within the interstitium.Moreover, peritubular interstitial fibroblasts are believed to secrete endogenously produced erythropoietin.Toxins (lead), drugs (antibiotics), and genetic diseases (polycystic kidney disease [PKD]) may produce interstitial injury and progressive loss of renal function.

[edit] Pathogenesis of Glomerular and Tubulointerstitial Injury

A variety of factors have been implicated in the initiation and progression of glomerular and tubulointerstitial disease.^[1] Glomerular injury is frequently associated with the deposition of immunoglobulins within the glomerulus.Antibody deposition presumably leads to the recruitment of inflammatorycells and the release of serum complement components and other mediators of cell injury (interleukins, chemokines, reactive oxygen metabolites) (Fig.148-5).The direct activation of the T-lymphocytes may also contribute to glomerular injury.Two mechanisms may give rise to antibody deposition within the glomerulus: (1) circulating antibody bound to a fixed glomerular antigen and (2) passive glomerular entrapment of circulating immune complexes.Analogous mechanisms of renal injury have been proposed in tubulointerstitial diseases.

Figure 148-5 Pathogenesis of immune-mediated renal injury.

A variety of nonimmune mechanisms may also contribute to the initiation and progression of chronic renal insufficiency.The significance of nonimmune-mediated renal injury is underscored by the absence of immune deposits in common renal disorders such as diabetic nephropathy and hypertensive nephrosclerosis.Animal models of experimental renal disease have demonstrated that a significant reduction in nephron mass leads to adaptive changes in the remaining (remnant) nephrons that may potentiate the progression of renal disease.For example, the removal of five sixths of the renal mass ina rat results in glomerular capillary hypertension and progressive renal injury.Several studies have demonstrated that a dietary reduction in protein as well as converting-enzyme inhibition (e.g., captopril) attenuate the glomerular hemodynamic and ultrastructural changes occurring in remnant nephrons.^[2][3] Although hemodynamic mechanisms of renal injury have received considerable attention, a variety of other factors have also been postulated to be important in the progression of renal injury (Fig.148-6).These include (1) proteinuria, (2) abnormalities in circulating lipids and hormones, (3) enhanced renal synthesis of eicosanoids, (4) mesangial cell proliferation, (5) enhanced extracellular matrix deposition, and (6) secretion of growth factors and other cytokines (transforming growth factor-β).Treatment strategies aimed at correcting these factors may provide a novel approach to treating medical renal disease.

Figure 148-6 Pathogenesis of nonimmune-mediated renal injury.

[edit] Pathophysiology of the Nephrotic Syndrome

The nephrotic syndrome is a urine protein excretion rate exceeding 3.5 gm/24 hr coupled with hypoalbuminemia, edema, and hyperlipidemia^[4](Fig.148-7).The mechanisms underlying the nephrotic syndrome remain poorly understood; however, an abnormality of glomerular permeability is the hallmark of this syndrome.Altered glomerular permeability may be secondary to injured epithelial cells and loss of anionic sialoglycoproteins (minimal change disease [MCD]) and/or physical disruption of the glomerular filtration barrier (necrotizing glomerulonephritis).The magnitude of proteinuria is influenced by changes in the glomerular filtration rate (GFR), plasma albumin concentration, and dietary intake of protein.

Figure 148-7 Pathophysiology of the nephrotic syndrome.

Renal sodium and water retention leading to edema formation invariably occurs in patients with the nephrotic syndrome.The mechanism of enhanced tubular sodium and water reabsorption has been attributed to a reduced effective circulating volume caused by vascular redistribution of fluid.However, recent evidence suggests that plasma volume is not contracted in the nephrotic syndrome.Furthermore, the gradient of plasma to interstitial oncotic pressure is unchanged.Other studies suggest that disturbances in intrarenal physical factors, atrial natriuretic peptides, or sympathetic nervous system activity may account for the changes in tubular sodium and water reabsorption in the nephrotic syndrome.

Since the hepatic synthesis of albumin can normally increase several-fold (exceeding 30 gm/day), the mechanism of hypoalbuminemia in the setting of nephrotic-range proteinuria continues to generate much debate.Possible factors contributing to hypoalbuminemia include (1) enhanced degradation of albumin by the kidney, (2) impaired hepatic synthesis of albumin, and (3) extrarenal changes in albumin catabolism.Hyperlipidemia also accompanies urinary loss of protein and is thought to be secondary to the increased hepatic synthesis of very-low-density lipoproteins.An increase in low-density lipoproteins is also common in patients with the nephrotic syndrome and is probably the result of the catabolism of very-low-density lipoproteins.The increased incidence of cardiovascular disease noted in patients with the nephrotic syndrome is believed to be induced by changes in serum lipid levels.Indeed, the results of preliminary studies indicate that patients with unresponsive nephrotic syndrome benefit from the treatment of hyperlipidemia.

There is an increased incidence of arterial and venous thrombosis in the nephrotic syndrome.Urinary loss of endogenous anticoagulants, particularly antithrombin III, protein C, and protein S, may account for the hypercoagulable state.Indeed, plasma levels of these substances are often decreased in patients with the nephrotic syndrome.Whether systemic anticoagulation should be initiated prophylactically in all patients with severe proteinuria remains controversial.

Finally, there is an increased incidence of infection in the nephrotic syndrome.The mechanism responsible for this phenomenon is believed to be secondary to loss of immunoglobulins in the urine.Serum immunoglobulin G (IgG) levels that remain persistently below 600 mg/dl portend a high risk of infection, which may be amenable to treatment with intravenous (IV) IgG (10 to 15 gm per month).

[edit] HISTORY AND PHYSICAL EXAMINATION

A careful history can provide important clues for ascertaining the etiology of glomerular or tubulointerstitial disease.For example, childhood nephrotic syndrome is most likely secondary to MCD, whereas adult nephrotic syndrome is often a consequence of idiopathic membranous glomerulonephritis (MGN).IV drug abuse has been described in association with focal glomerulosclerosis and the nephrotic syndrome.Eliciting information about the duration of the illness is helpful in establishing the chronicity of the process.The presence of comorbid conditions such as diabetes, cancer, SLE, or viral hepatitis may also provide an important clue to the underlying renal histology.For example, MGN has been described in various malignant disorders, particularlysolid tumors of the gastrointestinal tract.Finally, obtaining a detailed family history is an essential step in the evaluation of hereditary nephritis or PKD.

The physical examination may also provide important information in the evaluation of the patient with renal disease.Hypertension, edema, and generalized fatigue are nonspecific findings observed in a variety of renal diseases.All patients should be carefully examined for the presence of skin rashes, arthritic changes, lymphadenopathy, and peripheral neuropathy.The presence of a malar rash in a patient with renal insufficiency, proteinuria, and hematuria strongly suggests renal involvement secondary to SLE.In contrast, peripheral neuropathy in an elderly patient with proteinuria and an elevated serum globulin level should prompt an investigation for systemic amyloidosis.The presence of livedo reticularis in a patient recently undergoing cardiac catheterization should raise the possibility of cholesterol embolization.Abdominal pain and a purpuric rash in an adolescent with renal failure would strongly support the diagnosis of Henoch-Schönlein purpura.In addition, palpation of the abdomen may reveal the presence of irregular or enlarged kidneys consistent with PKD or renal cell carcinoma.

[edit] LABORATORY STUDIES AND DIAGNOSTIC PROCEDURES

Patients with clinically significant renal disease most often have an abnormal urinalysis (hematuria, proteinuria, casts), a decline in GFR, or both problems.Therefore examination of a freshly voided urine specimen and determination of the serum creatinine level provide the basis for the initial evaluation of renal disease.Isolated or transient abnormalities in the urinalysis must be distinguished from abnormalities secondary to glomerular or tubulointerstitial disease.^[5] Moreover, false-positive elevations in the serum creatinine level must be differentiated from a true reduction in GFR.

[edit] Examination of Urine

Transient proteinuria may occur in up to 10% of otherwise healthy individuals.The magnitude of proteinuria is typically mild but can rarely be severe (more than 3 gm/24 hours).Transient proteinuria is particularly common in patients with congestive heart failure, infection, and other stress-related illnesses.The mechanism responsible for transient proteinuria in these settings is poorly understood but may involve changes in the circulating levels of stress hormones (angiotensin II, epinephrine).These hormones alter glomerular permeability for protein and modulate intrarenal blood flow and glomerular pressure.More important, transient episodes of proteinuria are not associated with the presence of significant glomerular diseases and thus are considered benign.

Postural, or orthostatic, proteinuria is noted only during upright posture and not during recumbency.The magnitude of proteinuria is generally mild (less than 1 gm/day) but can rarely exceed 3 gm/day.It is more common in adolescents and is rare in patients over 30 years of age.The diagnosis rests on establishing the relationship of posture to the presence of protein in the urine.However, postural changes in urine protein excretion can sometimes occur in serious renal diseases.Therefore benign orthostatic proteinuria should be diagnosed only when the recumbent protein excretion rate is less than 50 mg/day.

In contrast to proteinuria, hematuria can arise anywhere within the urinary tract.The most common cause of hematuria in an adult is urinary tract disease (e.g., prostatitis, renal calculi, cystitis).In the absence of RBC casts or a rising creatinine level, a thorough urologic evaluation (IV pyelography, renal ultrasonography, and cystoscopy) should be performed.RBC morphology has been used to distinguish renal parenchymal from lower urinary tract causes of hematuria.Typically, extrarenal hematuria is characterized by uniform RBC morphology, whereas glomerular hematuria is usually accompanied by dysmorphic RBCs as a result of their passage through the renal tubule and the hypertonic medullary interstitium.

[edit] Measurement of Glomerular Filtration Rate

The hallmark of significant renal disease is a reduction in GFR.At steady state the serum creatinine measurement inversely correlates with GFR.Thus a doubling of the serum creatinine value indicates a 50% reduction in the GFR.The clearance of endogenous creatinine is the most widely used method of determining GFR.(See Chapter 144 for a detailed discussion on GFR.)

[edit] Serologic Studies

Determination of serum complement components (C₃, C₄, CH₅₀) constitutes an important step in the evaluation of patients with suspected glomerular disease (see Fig.148-2).Other serologic markers useful in the evaluation of glomerular disease include serum cryoglobulin levels (essential mixed cryoglobulinemia), hepatitis B and C serologic tests (MGN and membranoproliferative glomerulonephritis [MPGN]), human immunodeficiency virus (HIV) testing (focal glomerulosclerosis), serum and urine immunoelectrophoresis (myeloma, amyloidosis), and quantitative determination of antinuclear antibodies (lupus nephritis).

In addition the presence of circulating antibodies to specific cytoplasmic antigens (antineutrophil cytoplasmic antibodies [ANCAs]) has been described in association with renal vasculitis.^[6] These antibodies possess several different antigenic specificities, although two major classes are routinely reported using indirect immunofluorescence staining.Antibodies with a cytoplasmic pattern of staining (C-ANCA) are directed toward proteinase-3 and are commonly found in granulomatous vasculitis (Wegener's granulomatosis).In contrast, antibodies with specificity to myeloperoxidase demonstrate a perinuclear staining pattern (P-ANCA).P-ANCAs are often noted in patients with systemic vasculitis (microscopic polyangiitis) (Fig.148-8).These antibodies have also been described in several nonrenal diseases such as inflammatory bowel disease and therefore cannot be considered absolutely specific for renal disease.Antiglomerular basement membrane antibodies (anti-GBMAb) are found in Goodpasture's syndrome and are sometimes noted in association with circulating ANCAs, implying a nonspecific disturbance in immune regulation.

Figure 148-8 Incidence of C-ANCA and P-ANCA in the two principal types of renal vasculitis.

[edit] Radiologic Studies

Ultrasonic determination of kidney size can be useful in the evaluation of unexplained renal insufficiency.Kidneys measuring less than 10 cm in length are highly suggestive of a chronic process and would tend to mitigate against further evaluation.An asymmetric kidney size suggests the possibility of renal vascular disease.Abnormal renal scintigraphy is seen in virtually all patients with significant glomerular or tubulointerstitial disease and thus adds little in establishing the correct diagnosis.Magnetic resonance imaging (MRI) may be used to evaluate the renal artery and veins (e.g., renal vein thrombosis).The use of computed tomography (CT) is particularly beneficial in the evaluation of suspected analgesic nephropathy, showing microcalcifications at or near the papillary tip.

[edit] Renal Biopsy

The renal biopsy remains the “gold standard” for establishing the diagnosis of glomerular and tubulointerstitial renal disease.Often the clinical description and laboratory features of renal disease may be insufficient to arrive at a definitive diagnosis.In these circumstances, a renal biopsy is necessary for delineating the underlying disease.

[edit] DIFFERENTIAL DIAGNOSIS

[edit] Glomerular Disease Associated With a Nephrotic Pattern

Classifying glomerular disease according to the urinary findings (nephrotic vs.nephritic) is a useful strategy for formulating a differential diagnosis (see Figs.148-1 and 148-2).Five clinical entities account for most cases of the nephrotic syndrome in an adult: (1) diabetic nephropathy, (2) MGN, (3) focal segmental glomerulosclerosis (FSGS), (4) amyloidosis, and (5) MCD.

[edit] Diabetic Nephropathy.

Diabetic nephropathy accounts for the majority (up to 40%) of patients receiving dialysis for end-stage renal disease (ESRD).The incidence of diabetic renal disease is greater in Mexican-Americans and African-Americans and in some Native American populations in North America.Microalbuminuria (30 to 300 mg/day of albumin in the urine) is the hallmark of incipient diabetic renal disease and is predictive of progression to ESRD (Fig.148-9).^[7]“Hyperfiltration” (GFR >140 ml/min) is frequently observed in insulin-dependent diabetes mellitus(IDDM) in the early stages of the disease; however, microalbuminuria develops in less than 40% of these patients.The identification of specific risk factors for the development of microalbuminuria in patients with IDDM has remained uncertain; however, poor glycemic control, abnormal intrarenal hemodynamics, and hyperlipidemia have been implicated in the progression of latent hyperfiltration to overt proteinuria.With the onset of microalbuminuria, renal function slowly deteriorates over 15 to 20 years, ultimately progressing to ESRD.Uncontrolled hypertension and poor glycemic control accelerate the progression to ESRD.Recent evidence suggests that patients with non-IDDM evolve through similar stages of hyperfiltration and microalbuminuria, although the incidence of nephropathy in non-IDDM is less well established.Indeed, the incidence of nephropathy may be similar to that of IDDM, although many patients die because of other clinical disorders with advancing age.Nephropathy is strongly associated with other complications of diabetes (retinopathy, neuropathy).Indeed, in the absence of retinopathy, the clinician should question the diagnosis of diabetic nephropathy.

Figure 148-9 Clinical course of diabetic nephropathy.Note that microalbuminuria precedes overt proteinuria by 5 to 10 years.Once proteinuria is diagnosed based on dipstick testing, renal function slowly declines over 10 to 15 years.

Systemic hypertension plays an important role in the progression of diabetic nephropathy, since antihypertensive therapy can significantly attenuate the progression of renal disease.Angiotensin-converting enzyme inhibitors ameliorate renal injury and proteinuria in humans independent of alterations in systemic blood pressure.In patients intolerant of converting-enzyme inhibitors, the use of nondihydropyridine calcium channel antagonists and possibly angiotensin receptor antagonists may provide reasonable alternatives based on several preliminary reports.A protein-restricted diet (0.6 gm/kg/day) also slows the rate of progressive renal disease in diabetic nephropathy.However, many patients find these diets unpalatable, and frequent assessment of nutritional status is necessary.

[edit] Membranous Glomerulonephritis.

As many as 40% of adults with the idiopathic nephrotic syndrome are found to have MGN.The pathologic hallmark of MGN is the presence of glomerular subepithelial immune deposits on electron microscopic examination.A variety of underlying conditions have also been described in association with this clinicopathologic syndrome.These include chronic hepatitis B and C, SLE (lupus nephritis type V), malignancies, and some drugs (gold, penicillamine).For unknown reasons, the incidence of thrombotic events is more common in MGN than in other causes of the nephrotic syndrome.The natural history of MGN varies depending on the underlying cause, but in idiopathic MGN, up to 50% of patients remain in partial or complete remission 10 to 15 years after the original diagnosis.Less than 25% of cases progress to ESRD.Because of the variable clinical course, controversy exists regarding the optimal treatment for these patients.Some series report striking benefits with a combination of chlorambucil and prednisone, whereas other investigators have been unable to confirm these findings.

[edit] Focal Segmental Glomerulosclerosis.

FSGS accounts for up to 10% to 15% of cases of adult nephrotic syndrome.Unfortunately, many cases progress to ESRD within 5 years of the diagnosis.Although most appear to be idiopathic, many cases have been reported in patients after IV drug abuse (heroin) and with HIV infection.HIV nephropathy differs from idiopathic FSGS in that it typically follows a more virulent course, frequently progressing to ESRD in a matter of months.Although some investigators recommend a course of steroid administration in patients with idiopathic FSGS, definitive studies regarding the optimal treatment for these patients do not exist.

[edit] Amyloidosis.

Renal amyloidosis accounts for a small percentage of cases of adult nephrotic syndrome.Massive proteinuria (>10 gm/day), severe edema, and hypoalbuminemia are frequently noted on clinical presentation.In some patients, multiorgan involvement, as well as hepatosplenomegaly, congestive heart failure, peripheral neuropathy, macroglossia, and carpal tunnel syndrome, is present.The overall prognosis is poor, and often the mean survival time is less than 1 year, with most patients dying from renal failure or infection.Light-chain deposition disease (LCDD) involves a similar pathogenesis; however, the fibrils detected on electron microscopy are distinct from those of amyloid.More than 80% of patients with renal amyloidosis or LCDD demonstrate a circulating or urinary monoclonal protein.Thus serum and urine immunoelectrophoresis is invaluable in establishing the proper diagnosis.The diagnosis can be made with a rectal biopsy (60%) or a transcutaneous fat aspiration (90%).Up to 25% of patients with renal amyloidosis or LCDD demonstrate the presence of a malignant plasma cell clone (e.g., myeloma).Melphalan and prednisone appear to offer promise in the management of these patients, even in the absence of a plasma cell malignancy.^[8]

Chronic inflammatory disorders such as rheumatoid arthritis may occasionally be complicated by renal deposition of amyloid.The amyloidogenic protein in these disorders is distinct from light chains and appears to be derived from a circulating protein synthesized in the liver.Treatment for these conditions is directed at the underlying disease process.

[edit] Minimal Change Disease.

The most common histology detected in the childhood nephrotic syndrome is MCD, also known as lipoid nephrosis or nil disease. Up to 20% of adults with the nephrotic syndrome may also have MCD.Generally, only “fusion” of the glomerular epithelial cell foot processes is observed with electron microscopy.The results of light microscopy and immunofluorescent studies are unremarkable.The pathogenesis appears to be secondary to diffuse injury of the epithelial cell and loss of polyanionic sialoglycoproteins.Patients with this syndrome typically have edema, hypoalbuminemia, hyperlipidemia, and a normal GFR.Rarely, patients may develop acute renal failure, presumably secondary to profound volume depletion.Although most cases are idiopathic, MCD has occasionally been noted in association with hematologic malignancies (Hodgkin's disease) or drug administration (nonsteroidal antiinflammatory drugs, gold, lithium).Most patients with idiopathic MCD respond to corticosteroid therapy, although remissions are less frequent in adults.Although an excellent response is usually detected within 2 weeks of initiating therapy, some individuals may require up to 12 weeks to respond.Frequent relapses and resistance may occur in some individuals, and long-term administration of low-dose steroids (up to 1 year) may be required to induce a permanent remission.Occasionally, a patient with refractory disease may respond to immunotherapy with either cytotoxic agents (cyclophosphamide and chlorambucil) or cyclosporine.

[edit] Glomerular Disease Associated With a Nephritic Urinary Sediment(see Fig.148-2)

[edit] Hereditary Nephritis.

Hereditary nephritis, or Alport's syndrome, is characterized by lenticular opacities, renal insufficiency, and sensorineural hearing loss.Three modes of inheritance have been described: X-linked dominant, autosomal dominant, and rarely, autosomal recessive.The differing modes of inheritance are associated with the expression of different phenotypes.For example, X-linked dominant families have renal insufficiency and deafness, which is usually less severe in female patients (Lyon hypothesis).In contrast, autosomal dominant or recessive inheritance results in renal insufficiency but usually no auditory or eye involvement.The pathologic hallmark in the kidney consists of thinning and splitting (lamination) of the GBM.Urinary findings frequently include hematuria and proteinuria; the latter can be severe.Most male patients with this disorder progress to ESRD by age 40; female patients typically follow a less virulent course, although some may progress to ESRD by age 30.The pathogenesis of this disorder is poorly understood, although considerable evidence suggests that patients have a mutated GBM antigen.Unfortunately, no specific therapy exists for hereditary nephritis.

[edit] Postinfectious Glomerulonephritis.

Poststreptococcal glomerulonephritis (PSGN) is the most common form of postinfectious glomerular injury.Certain strains of “nephritogenic” streptococci (type 12 and type 49 β-hemolytic streptococci) are associated with glomerular inflammation.Electron microscopy reveals granular deposits (“humps”) of immune complexes (IgG and complement) in the subepithelial space.Affected glomeruli usually show diffuse proliferation of inflammatory cells and in some cases, crescent formation.Epidemiologic studies suggest that glomerulonephritis may occur in up to 25% of patients infected with nephritogenic strains of β-hemolytic streptococci.Serum complement components, particularly C₃, are low, and circulating antibodies to antistreptolysin O and DNAase B are usually elevated.The clinical manifestations of PSGN range from florid nephrotic syndrome to asymptomatic hematuria and proteinuria.Although most patients spontaneously recover, some may exhibit mild urinary abnormalities for several years.Sporadic reports of patients with chronic renal insufficiency and severe intrarenal scarring occurring 30 to 40 years after an acute episode have been described.The mechanism of progression to ESRD is uncertain in these patients.Other infectious causes of diffuse proliferative glomerulonephritis and immune complex deposition include infected ventriculoatrial shunts and subacute bacterial endocarditis.These disorders typically resolve after appropriate antimicrobial therapy, removal of the infected shunt, or both treatments.

[edit] Membranoproliferative Glomerulonephritis.

MPGN is often associated with a combination of nephrotic-range proteinuria and hematuria.The clinical course of renal disease ranges from a fulminant, rapidly progressive glomerulonephritis to a slowly progressive course dominated by the symptoms and signs of the nephrotic syndrome.Two histologic subtypes have been characterized: type 1 is associated with mesangial hypercellularity and interposition, resulting in the characteristic “tram track” appearance on light microscopy, whereas type 2 (dense deposit disease) is characterized by heavy deposits of immune complexes along the entire length of the GBM.Both types are associated with hypocomplementemia, although type 1 is characterized by activation of the classic pathway (low C₃and C₄values), whereas type 2 is characterized by activation of the alternative pathway (low C₃values).The latter is thought to occur as a consequence of the persistent activation of C₃via an antibody (C₃nephritic factor, C₃NeF), which stabilizes and prolongs the half-life of C₃convertase.Although most cases of MPGN are idiopathic, an association with SLE, chronic hepatitis B and C, chronic lymphocytic leukemia, cryoglobulinemia, IV drug abuse, and transplant rejection has also been reported.

The treatment of idiopathic MPGN is controversial.An investigation of childhood MPGN demonstrated a beneficial effect of long-term administration of low-dose corticosteroids.However, there is no evidence in adults that steroid use is beneficial.A controlled trial of aspirin and dipyridamole for 1 year in adult MPGN appeared to slow the progression of renal injury when compared with placebo.However, other studies have not confirmed the benefits of antiplatelet drugs.

[edit] Systemic Lupus Erythematosus.

Renal disease in the setting of SLE is extremely common.Approximately 90% of patients have abnormalities on a renal biopsy.In many instances, pathologic abnormalities are present in the absence of clinical or urinary findings.Five histologic subtypes of renal disease have been described in patients with SLE(Table 148-1).Hypocomplementemia frequently accompanies active lupus nephritis.Serum complement levels may be used to follow disease progression and response to treatment.Rarely, lupus nephritis may present without systemic involvement.The natural history of lupus nephritis is poorly understood.Spontaneous conversion from one histologic subtype to another is the rule rather than the exception.The uncertain natural history has complicated treatment strategies and the interpretation of interventional studies.Treatment has been best defined for the diffuse proliferative class of lupus nephritis, in which the response to combined prednisone and cyclophosphamide is clearly superior to that to placebo or steroids alone.^[9] However, it is uncertain whether treatment for other histologic subtypes of lupus nephritis offers similar benefits.

Table 148-1 Classification, Prognosis, and Therapy for Lupus Nephritis

✢Prognosis (untreated): +, worst; ++++, best.

[edit] Rapidly Progressive Glomerulonephritis.

The pathologic hallmark of rapidly progressive glomerulonephritis (RPGN) is the presence of cellular crescents in more than 60% of the glomeruli examined in a renal biopsy specimen.Three major subtypes of RPGN have been described based on the pathologic distribution of immune deposits.

Type 1 RPGN has linear deposits of IgG along the glomerular capillary basement membrane.Anti-GBM Ab are also detected in serum.Pulmonary hemorrhage may also occur (classic Goodpasture's syndrome), or the immune deposits may be limited to the kidneys.

Type 2 RPGN is characterized by immune complex deposition along the glomerular capillary basement membrane.In most cases the inciting antigen is unknown; however, some individuals may have an underlying immune complex disorder (e.g., SLE, PSGN).

Type 3 RPGN (pauci-immune) is characterized by the absence of immune deposits within the kidney.Many patients have an underlying vasculitis.Interestingly, type 3 RPGN is frequently associated with the presence of circulating ANCAs.Serologic evaluation in patients with RPGN can provide an important clue to the pathogenesis of the underlying disease process.

The prognosis and treatment for all three subtypes of RPGN are similar.Early initiation of cytotoxic therapy (2 to 4 mg/kg/day of oral cyclophosphamide) and prednisone (1000 mg methylprednisolone IV each day for 3 days, followed by 1 mg/kg oral prednisone daily) leads to dramatic improvement in renal function and overall mortality rates.However, response rates are substantially less when treatment is delayed (creatinine level >5.0 mg/dl).Plasma exchange therapy may be beneficial in patients with high titers of circulating anti-GBM Ab.

[edit] IgA Nephropathy.

IgA nephropathy is the most common cause of glomerulonephritis worldwide.Its pathogenesis remains poorly understood, but the presence of increased circulating levels of IgA suggests increased synthesis or decreased degradation of IgA.Although elevations in circulating levels of IgA are found in as many as 50% of affected patients, the nonspecific nature of this finding precludes its usefulness as a diagnostic test.The presence of mesangial deposits of IgA is pathognomonic.Gross or microscopic hematuria is the most common presenting feature and is often preceded by a viral syndrome.Most patients have normal renal function, and their disease follows a benign course.However, progression to ESRD with nephrotic-range proteinuria may occur in up to 20% of affected individuals.Treatment remains controversial, although some studies suggest that sustained use of angiotensin-converting enzyme inhibitors may be helpful.A large multicenter trial assessing the efficacy of fish oils (ω-3 fatty acids) in IgA nephropathy suggests that these agents ameliorate the progression of renal disease.^[10]

[edit] Systemic Vasculitis.

The classification of vasculitis is frequently perplexing, largely because of the varying causes of this syndrome and a lack of understanding of the underlying pathophysiologic mechanisms.A reasonable classification system is based on the size of the artery involved (Fig.148-10).Although systemic vasculitis can present with multiorgan involvement, renal-limited forms have been recognized.The vasculitides can be conveniently classified into three major categories: (1) large vessel, (2) medium vessel, and (3) small vessel.Renal involvement is more common when small or medium-sized vessels are involved.The most common disorders associated with renal injury are Wegener's granulomatosis and microscopic polyangiitis.

Figure 148-10 Classification of renal vasculitides based on the size of the vessel involved. (From Jennette JC, Falk RJ:N Engl J Med 337:15121523, 1997.)

Wegener's granulomatosis affects the small and medium- sized arteries and is associated with granuloma formation in the respiratory tract.A sinus biopsy in a patient with sinusitis and renal disease can often yield a diagnosis.Renal biopsy specimens are characterized by segmental necrotizing glomerulonephritis with or without crescent formation.Immune deposits are conspicuously absent.Affected patients may have either renal-limited disease or pulmonary hemorrhage and/or sinusitis.Response rates as high as 90% are obtained with a combination of cyclophosphamide and prednisone.Microscopic polyangiitis is a systemic vasculitis that typically involves the small arterioles and capillaries.The clinical presentation is similar to that of Wegener's granulomatosis without granuloma formation and sinus involvement.

Other causes of small-vessel vasculitis include Henoch- Schönlein purpura, essential mixed cryoglobulinemia, and serum sickness.Henon-Schönlein purpura is characterized by purpuric lesions of the upper and lower extremities, arthralgias, abdominal pain, and renal failure.Classically, this syndrome is seen in children and resolves spontaneously with supportive care.Adults appear to have less favorable outcomes.Deposits of IgA in the mesangium and mesangial cell proliferation are the hallmarks of this disorder.

Essential mixed cryoglobulinemia is characterized by the presence of circulating cryoglobulins.These complexesconsist of an antigen, an antibody of the IgG type to the antigen, and a rheumatoid factor IgM antibody to the IgG.The inciting event that stimulates the synthesis of these antibodies is uncertain.In many cases, there is an underlying hepatitis B or C infection.A recent report also implicated HIV.Up to 60% of patients with circulating cryoglobulins have renal involvement.Characteristic findings include arthralgias, fatigue, purpuric rash, lymphadenopathy, Raynaud's phenomenon, and hepatosplenomegaly.Hypocomplementemia frequently accompanies disease activity.Pathologically, essential mixed cryoglobulinemia is characterized by the presence of intraluminal thrombi of precipitated cryoglobulins in the kidney.Treatment is similar to that for other vasculitis syndromes (cytotoxic agents and corticosteroids) but may also include plasmapheresis to remove circulating cryoglobulins.The administration of interferon-α to treat hepatitis B or C may result in a renal remission.

Serum sickness is rarely observed in clinical practice.Classically reported after the administration of heterologous antisera, most cases occur after the administration of an antibiotic (commonly a penicillin) or an acute viral syndrome.For example, acute viral hepatitis has been associated with a serum sickness–like syndrome.Circulating antibody-antigen complexes are the hallmark of these disorders.Clinical manifestations include fever, urticaria, rash, and lymphadenopathy.When the kidneys are involved, the urinalysis is dominated by red blood cells and cellular casts.Infrequently a rapidly progressive glomerulonephritis may ensue.Virtually all patients respond to removal or treatment of the inciting event (e.g., discontinuance of drugs, resolution of viremia, effective treatment of viral hepatitis).

[edit] Renal Atheroemboli.

Renal atheroembolic disease may occur in association with invasive angiographic procedures.Virtually all patients with atheroemboli also have an ulcerated atherosclerotic aorta.Clinical findings that distinguish renal atheroemboli from contrast nephropathy include embolic findings in the lower extremities, livedo reticularis, hypocomplementemia, and peripheral eosinophilia.Many individuals also experience labile hypertension.The mechanism of hypertension appears to be renin mediated, perhaps because of the occlusion of small renal vessels.A biopsy of the affected tissue may disclose the presence of a microthrombus, with needle-shaped crystals representing dissolved cholesterol.Occasionally, examination of the retina reveals refractile bodies consistent with cholesterol embolization.Systemic anticoagulation may exacerbate atheroemboli and thus should be avoided.

[edit] Thrombotic Microangiopathies.

The thrombotic microangiopathies are characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal insufficiency.In adults, neurologic complications secondary to thrombotic occlusion of the cerebral vessels may also occur (thrombotic thrombocytopenic purpura).In contrast, renal insufficiency is typically severe in the childhood form of the disease (hemolytic uremic syndrome).Indices of disseminated intravascular coagulation (thrombin time, fibrin split products, fibrin monomers, prothrombin time, partial thromboplastin time) are not increased in these syndromes.

Thrombotic microangiopathy may occur spontaneously or in association with cyclosporine administration, combination chemotherapy (especially mitomycin C), malignant hypertension, vasculitis, postpartum acute renal failure, and HIV infection.Recent outbreaks of hemolytic uremic syndrome have been associated with verotoxin-producing Escherichia coli(serotype 0157:H7).The pathologic hallmark of these syndromes includes endothelial cell injury and swelling(endotheliosis) with platelet and fibrin thrombi of the microvasculature.The pathogenesis remains poorly understood, but recent studies suggest that endothelial injury results in abnormalities in circulating von Willebrand's factor that predispose to platelet aggregation.Children with the disorder frequently recover spontaneously with supportive care alone.In adults or children who do not recover within 1 to 2 weeks, treatment should be initiated without delay because the mortality rate can exceed 90%.Infusions of fresh-frozen plasma alone can induce a remission in up to 50% of patients.If no response is noted within 24 hours, plasma exchange therapy should be instituted.Occasionally, patients with refractory disease respond to IV infusions of IgG; the administration of aspirin, dipyridamole, or corticosteroids; and rarely, splenectomy.

[edit] Tubulointerstitial Disease

Tubulointerstitial disease represents a broad group of renal diseases that predominantly affect the tubules and interstitium (see Fig.148-3).In contrast to glomerular disease, heavy proteinuria (more than 2 gm/day), RBC casts, lipiduria, and oval fat bodies are usually not found.More often, either the urine sediment is normal or it demonstrates pyuria with or without WBC casts (allergic or infectious interstitial nephritis).In some instances, discrete tubular defects such as renal tubular acidosis may be the presenting feature (e.g., multiple myeloma).

[edit] Allergic Interstitial Nephritis.

The most common cause of tubulointerstitial disease is drug-induced allergic interstitial nephritis (AIN).A variety of drugs have been implicated in the pathogenesis of AIN, although the exact mechanism responsible for renal injury is uncertain (Box 148-1).An immune basis for injury seems likely because antibody deposition, complement activation, and infiltration of inflammatory cells (especially eosinophils) are frequently noted in the renal interstitium.The clinical features of AIN include peripheral eosinophilia, rash, fever, renal insufficiency, and pyuria.The urine sediment may also demonstrate WBC casts and hematuria.The presence of eosinophils in the urine can be helpful in establishing the correct diagnosis.In this regard, Hansel's stain of the urine sediment appears to offer greater sensitivity for detecting the presence of eosinophils (about 90%) compared with the traditional Wright's stain (about 25%).Although a renal biopsy may be required for a definite diagnosis, in many patients with AIN the classic symptoms of a rash, fever, eosinophilia, and renal insufficiency after exposure to a known offending agent are sufficiently diagnostic to obviate the need for a renal biopsy.Unfortunately, the classic clinical syndrome is noted in fewer than 60% of patients with AIN.Gallium scintigraphy has been used to noninvasively determine the presence of interstitial inflammation.However, radiologic evaluation of AIN with gallium is highly subjective, and considerable overlap exists among various renal diseases.Nonetheless, it is imperative to establish the proper diagnosis of AIN, since the clinical and laboratory findings are largely reversible on removal of the offending agent.Several uncontrolled trials suggest more rapid resolution of symptoms and improved recovery of renal function with corticosteroid therapy.However, randomized controlled clinical trials have yet to establish the role of corticosteroids in the treatment of AIN.

[edit] Analgesic Nephropathy.

Analgesic-induced chronic renal insufficiency probably accounts for less than 1% of all cases of ESRD.There are geographic variations in the incidence of this disorder.In some European countries, such as West Germany, the incidence may be as high as 18%.In the southeastern regions of the United States, it may be ashigh as 10%.The specific analgesic or combination of analgesics necessary to initiate this process remains controversial.Epidemiologic data suggest that a combination of phenacetin with a nonsteroidal antiinflammatory drug such as ibuprofen or aspirin may be the most nephrotoxic combination.Most patients have ingested at least 1 gm of analgesic per day for several years before renal disease becomes apparent.Renal biopsy reveals severe interstitial fibrosis associated with mild infiltration of inflammatory cells.Papillary necrosis is the hallmark of analgesic nephropathy.Its pathogenesis is uncertain, but the inhibition of vasodilator prostaglandins may lead to ischemia of the interstitial cells and surrounding tubules.CT is useful in establishing the diagnosis, since most patients have microcalcifications in the inner medulla near the papillary tip.^[11]

[edit] Reflux Nephropathy and Chronic Pyelonephritis.

Reflux nephropathy results from the abnormal backflow of urine from the urinary bladder to the renal parenchyma.It is unclear whether the mechanism of tubulointerstitial scarring is a direct consequence of high-pressure reflux or is secondary to chronic, repeated urinary tract infections (UTIs).Children with chronic reflux usually have symptoms and signs of UTI, such as dysuria, pyuria, flank pain, and fever.In later stages, glomerular involvement may occur, manifested by focal scarring and heavy proteinuria (more than 3.5 gm/day).The diagnosis of urinary tract reflux can be established with a voiding cystourethrogram.The management of reflux nephropathy depends on the severity of the reflux.Mild abnormalities generally respond to conservative measures such as the long-term administration of low-dose antimicrobial agents.Many patients have spontaneous remission with time.More severe grades of reflux may require surgical intervention.The hallmarks of advanced reflux nephropathy are interstitial scarring, tubular atrophy, and mild inflammatory cell infiltration (e.g., chronic pyelonephritis).Although chronic pyelonephritis is most frequently described in association with chronic UTI with or without reflux, it has also been reported with chronic lithium exposure, cisplatin administration, cyclosporin use, hyperoxaluria, cadmium exposure, hypercalcemia and hypercalciuria, chronic hypokalemia, and hyperuricemia.

[edit] Polycystic Kidney Disease.

PKD is a clinical disorder with two distinct inheritance patterns.The infantile variety is transmitted via an autosomal recessive gene, whereas adult PKD is transmitted in an autosomal dominant fashion.Infantile PKD usually follows a fulminant course, resulting in ESRD early in childhood.More than 90% of patients with adult PKD have an abnormal gene on the short arm of chromosome 16 (PKD1).Most of these patients have a family history of PKD.Other forms of adult PKD (non-PKD1) also may occur.The abnormal gene in some of these variants has been localized using linkage analysis.In general, patients with non-PKD1 appear to have a more favorable prognosis than those with the PKD1 locus.The abnormal gene in PKD1 encodes for a large protein referred to as polycystin; its function, however, remains a mystery.

The mechanism of cyst formation in this disorder remains poorly understood.Cyst enlargement results in the compression of adjacent normal tissue, causing scarring and progressive renal insufficiency.The demonstration of multiple renal cysts using ultrasonography confirms the diagnosis.Most of these patients develop ESRD by age 55 to 60.Cysts may also occur in the liver, pancreas, and spleen.

Significant cystic involvement of the kidney may not be apparent until early adulthood.Thus screening high-risk patients with ultrasonography may reveal nothing early in the course of PKD.However, by age 30 virtually all patients have multiple cysts on ultrasonography.However, the natural history of this disease is quite variable and seems to depend on a combination of genetic and environmental factors.Approximately 35% of patients have hematuria.

Complications of PKD include infection and bleeding into cysts, usually accompanied by severe pain.Infections can be treated symptomatically with antimicrobial therapy, but cyst drainage may be necessary for the resolution of symptoms.The most ominous complication is a ruptured intracerebral berry aneurysm.This complication has been reported in up to 4% of affected patients.Guidelines for screening patients for intracranial aneurysms have not been clearly established, although patients with a family history of intracranial aneurysm should undergo routine testing with MR angiography.Patients at high risk for developing a ruptured aneurysm (previous rupture, large aneurysms, bleeding diathesis) should be considered for invasive repair.Other complications include renal calculi (20%), colonic diverticuli (70%), cardiac valvular abnormalities (25%), and hepatic cysts (75%).No specific therapy exists for this disorder.

[edit] MANAGEMENT

In addition to the immunosuppressive regimens outlined for specific renal syndromes, several nonspecific measures are useful in the management of patients with progressive renal injury.These include dietary protein restriction,^[2] treatment of hypertension, and management of associated metabolic disorders (hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperlipidemia).Abundant evidence indicates that angiotensin-converting enzyme inhibition lessens proteinuria and retards progression of diabetic^[3] and nondiabetic renal disease.In addition, the role of hypertension in accelerating the progression of renal disease is well established.Other metabolic complications contributing to renal injury include hyperlipidemia, hyperphosphatemia, and secondary hyperparathyroidism.The treatment of these complications may attenuate progressive renal scarring in addition to reducing the risk of various comorbid events such as atherosclerotic vascular disease and renal osteodystrophy.Since the cardiovascular risk of hyperlipidemia is well established, it seems prudent to initiate antihyperlipidemic therapy in patients with renal disease who are at high risk for cardiovascular events.

[edit] REFERENCES