Introduction to Renal Biopsy

Prebiopsy Studies

Complete clinical forms are recommended to accompany the kidney biopsy ( Figure 7-1 as an example). The patient’s medical history, family history, physical examination results, laboratory data concerning renal function, and appropriate serologic studies are important information, not only for the nephrologists but also for the pathologist who interprets the kidney biopsy ( Table 7-1 ).

Clinical Settings in Which the Kidney Biopsy Is Used

Proteinuria

One of the major clinical manifestations of glomerular disease is proteinuria, which is defined as the loss of greater than 150 mg protein in 24 hours. Proteinuria may result from:

• An increase in plasma protein (e.g., Bence Jones proteins)

• Altered tubular reabsorption

• Addition of protein to tubular fluid (Tamm-Horsfall protein)

• Altered glomerular permeability

Proteinuria can be subnephrotic (<3 g/day) or in the nephrotic range (>3 g/day). Nephrotic range proteinuria may be associated with nephrotic syndrome (NS; Tables 7-2 and 7-3 and Fig. 7-2 ). Isolated subnephrotic proteinuria is a common clinical problem. Little evidence suggests that these patients will have progression to renal failure or be candidates for a specific therapy; however, some of these patients have diagnoses of membranous glomerulopathy; early idiopathic, familial, or secondary focal segmental glomerulosclerosis; immunoglobulin A (IgA) nephropathy; metabolic disorders (e.g., diabetes); or hereditary disorders (e.g. Fabry disease or Alport disease; see Table 7-3 ).

TABLE 7-2

Differential Diagnosis of Nephrotic Syndrome

Podocytopathies

A. Minimal change disease (MCD) Idiopathic Genetically determined Secondary B. Focal segmental glomerulosclerosis (FSGS) Idiopathic Genetically determined Secondary C. Mesangial sclerosis Idiopathic Genetically determined D. Collapsing glomerulopathy (CG) Idiopathic Genetically determined Secondary

Immune-Complex Glomerular Diseases

A. Membranous glomerulopathy (MGN) Primary Idiopathic Secondary (autoimmune, infection, cancer) B. C1q nephropathy C. Others

Generalized Systemic Diseases

A. Diabetes B. Amyloid C. Systemic lupus erythematosus D. Henoch-Schönlein purpura

TABLE 7-3

Differential Diagnosis of Nonnephrotic Range Proteinuria

Focal Segmental Glomerulosclerosis

A. Early idiopathic B. Associated with a monogenetic disorder (inherited podocyte disease) C. Secondary Hyperfiltration (hypertension, obesity, loss of renal parenchyma) Metabolic disorders (Fabry disease, I-cell disease, lecithin cholesterol acyltransferase) Collagen type IV disorders (Alport disease)

Immune-Complex–Mediated and Complement-Mediated Diseases

A. Immunoglobulin A nephropathy B. Glomerulonephritis with proliferative pattern Immune-complex–mediated Idiopathic Secondary (lupus, hepatitis C, hepatitis B, cryoglobulinemia, postinfectious) Complement-mediated C3 glomerulopathy

Generalized Systemic Diseases

A. Preeclampsia B. Diabetes C. Amyloid D. Systemic lupus erythematosus E. Henoch-Schönlein purpura

Tubular Damage

A. Acute tubular injury

Hematuria

Hematuria can originate from any segment of the urinary tract. Glomerular hematuria is generally accompanied by red blood cell casts. It may be isolated or found in association with nephritic syndrome ( Figs. 7-3 and 7-4 ). Hematuria can be detected with or without proteinuria. When causes of nonglomerular hematuria are excluded, a renal biopsy is needed to evaluate the nature of the causing glomerular disease (see Fig. 7-3 ).

Acute Renal Failure

Acute renal failure (ARF) is defined as rapidly increasing serum creatinine levels. It can be accompanied by abnormal urine sediment (RBCs, white blood cells [WBCs], RBC casts, WBC casts, or epithelial casts). Approximately 25% of inpatients have ARF develop, and morphologic evaluation is necessary to discriminate between acute tubular injury/acute tubular necrosis, interstitial nephritis, vasculitic processes, thrombotic microangiopathy, and proliferative and crescentic glomerulonephritis ( Fig. 7-5 ).

Light Microscopy

Paraffin-embedded biopsies are sectioned, with 10 to 12 levels obtained. Each slide or level should contain two to three serial sections that are 2 to 3 μm thick. One sectioning protocol is as follows: stain levels 1, 6, and 12 with hematoxylin and eosin (H&E); levels 2 and 11 with Jones silver stain; levels 3 and 8 with periodic acid–Schiff (PAS); and level 7 with trichrome. The intervening unstained slides can be used for additional studies as needed.

Immunofluorescence

Tissues for IF studies should contain renal cortex and can be received in the renal laboratory in saline solution or in transport medium. IF can be performed on frozen (ideal) or on paraffin sections.

• A.

  Standard IF panel: Indication: frozen tissue from native kidney biopsies and transplant biopsies (when recurrent or de novo glomerular disease is suspected). The most commonly used panel includes IgG, IgA, IgM, C3, C1q, fibrinogen, albumin, and kappa (κ) and lambda (λ) light chains. Staining with Abs against κ and λ light chains is recommended; not only are they useful internal controls, but they also allow early diagnosis of monoclonal gammopathies or primary amyloidosis.

• B.

  IgG subgroups: Immunofluorescence stain for IgG subgroups is helpful to discriminate between idiopathic/primary and secondary forms of membranous glomerulopathy. It is also useful for the diagnosis of fibrillary glomerulopathy, especially in the absence of electron microscopy, although alone, it may not be sufficient to fully confirm the diagnosis.

• C.

  IF on paraffin sections: Indication: no frozen tissue available or absence of glomeruli in the frozen tissue. Paraffin sections are first treated with pronase and then incubated with antibodies against IgG, IgA, IgM, and C1q.

• D.

  Amyloid panel: Indication: cases with positive Congo red. If IF for κ and λ light chain is negative, secondary amyloidosis should be suspected and IF should be performed with antibodies against amyloid fibril protein (AA).

• E.

  Alport panel: Indication: presence of thin basement membranes or irregular texture of the glomerular basement membranes (GBMs) on EM in patients with hematuria or hematuria and proteinuria. It includes IF staining with Abs against collagen type IV alpha 1, 3, and 5 alpha chains. A positive control (normal kidney) should be stained simultaneously to compare the intensity of the staining.

• F.

  When antibody-mediated rejection is suspected, C4d staining can be performed on frozen tissue, preferably medulla to preserve the cortex for microscopic evaluation. A positive control should be stained simultaneously. As a positive control, tissue from a transplant nephrectomy with acute rejection or a lupus membranous glomerulopathy can be used.

Immunohistochemistry on Paraffin Sections

• A.

  Amyloid panel: Indication: primary amyloidosis (AL) with Abs against κ and λ light chains or secondary amyloidosis with Abs against AA. It is generally more expensive and time consuming than studies on frozen tissue.

• B.

  Evaluation of tubular casts: Indication: suspected myeloma cast nephropathy (κ and λ light chains), cases of suspected ARF from hemolysis or rhabdomyolysis (with use of Abs against hemoglobin or myoglobin).

• C.

  Alport panel: Indication: no frozen tissue available when a diagnosis of thin basement membrane disease or Alport disease is suspected. Second choice over IF on frozen tissue.

• D.

  Suspected virus infection: BK virus. Indication: transplant biopsies with atypical tubular epithelial nuclei. False negative results may result from lack of medulla, where generally the BK virus infection is more prominent. Epstein-Barr virus (EBV). Indication: posttransplant proliferative disorders. Cytomegalovirus. Indication: transplant biopsies and non–HIV-associated collapsing glomerulopathy (CG; very rare). Parvovirus B19. Indication: non–HIV-associated CG.

• E.

  Suspected antibody-mediated rejection: C4d staining can also be performed on paraffin tissue with results comparable with IF on frozen section.

• F.

  Unusual interstitial inflammatory infiltrate: Those that contain atypical lymphocytes or sheets of plasma cell should be investigated to rule out hematologic disorders.

• G.

  Membranous glomerulopathy: Immunostain for antiphospholipid A2 receptors (PLA2Rs) has been recently introduced to discriminate between PLA2R–associated, formerly known as idiopathic, membranous glomerulopathy and secondary forms.

Electron Microscopy

Whether EM should be performed in all cases of glomerular disease is controversial, although it is recommended. In most cases, EM studies provide confirmation of the diagnosis from LM and IF; but in approximately one third of the cases, the diagnosis is modified by the ultrastructural findings. Ideally, fresh tissue should be fixed in glutaraldehyde. If cortex is not available to be fixed in glutaraldehyde or does not contain glomeruli, frozen tissue or formalin fixed tissue can be reprocessed for EM. Of note: tissue received in transport medium is not well preserved and therefore is suboptimal for EM studies, and thin basement membrane nephropathy is not diagnosed reliably in deparaffinized, formalin-fixed tissue.

Classification

The classification of podocytopathies has evolved over the last 30 years from simple classification systems based on the presence or absence of segmental sclerosis (focal segmental glomerulosclerosis [FSGS] versus minimal change disease [MCD]) to more recent morphologic classifications that include five variants of FSGS (Columbia classification). The definition of FSGS has also changed from original descriptions, in which it was defined as a non–immune-complex–mediated and nonproliferative disease, to the Columbia classification, in which sclerosing segmental glomerular damage and proliferative features are grouped under the common name of FSGS. Morphologic classifications, however, do not account for the complexity of diseases that present with proteinuria and nephrotic syndrome, and the underlying mechanisms and etiologies for diseases with similar morphology are numerous. Similarly, monogenetic disorders, for example, can present with more than one pattern of glomerular injury. Thus it has been suggested that MCD and FSGS should no longer be considered diseases but rather lesions associated with multiple diseases.

A different approach has been taken with the taxonomy of podocytopathies, where morphologic features are integrated with etiology for the classification of nephrotic syndrome. On the basis of morphologic features, four categories of diseases can be identified: (1) normal histology and extensive foot process effacement ( Fig. 7-8 ); (2) diffuse mesangial sclerosis (rare); (3) segmental solidification of the glomerular tuft ( Fig. 7-9 ); and (4) segmental or global collapse of the glomerular tuft with podocyte hypertrophy and hyperplasia ( Fig. 7-10 ). Each category is further subclassified based on etiology or podocyte phenotype ( Table 7-5 ). The three most common forms of podocytopathies, minimal change disease, focal segmental glomerulosclerosis, and collapsing glomerulopathy (CGP), are discussed here.

Epidemiology

MCD is the most common form of nephrotic syndrome in children, although it may also occur in adults. In children, peak occurrence is between 2 and 6 years with a male predominance. It may occur in association with ARF after the intake of NSAIDs or secondary to hemodynamic effects of the NS.

Clinical Features

The classic presentation is rapid development of NS with selective proteinuria (albumin and low– molecular-weight proteins). Renal function and serum complement levels are generally normal (if not associated with ARF). Serology is negative.

Pathologic Features

Ancillary Studies

Differential Diagnosis

The main clinical problem is discrimination between MCD and FSGS. Morphologically the distinction is not difficult if a segmental solidification of the tuft is present; however, in some cases, the segmental sclerosis is very focal and may not be present in the first set of slides examined. A good practice is to section the entire paraffin block to completely exclude FSGS. If foot process effacement is only focal, a diagnosis of MCD should be made with the caveat that FSGS may have been missed with sampling error. The only exception to this rule is if the patient has been already treated with steroid before the renal biopsy; in this case, partial foot process effacement may represent partial response to therapy. Experimental data show that MCD may be discriminated from FSGS based on marked reduction of podocyte dystroglycan expression in MCD versus normal positive staining in FSGS. The differential diagnosis is also with IgM nephropathy, as discussed previously, and IgA nephropathy with minimal glomerular changes by LM. In this case, IF and EM studies are critical.

Prognosis and Treatment

The disease is often very responsive to steroid therapy; however, adults tend to have a slower response to treatment than children. Some of the patients are steroid dependent. If a patient is steroid resistant, FSGS should be suspected; often on follow-up biopsy, segmental sclerosis is present. Children with steroid-resistant nephrotic syndrome often have progression to chronic renal failure. Genetic screening is now advised for all patients in pediatric age with NS because the incidence of monogenetic mutations in NS has shown to be considerable.

Epidemiology

FSGS is the most common cause of nephrotic proteinuria in the United States (versus IgA nephropathy in Europe and Asia) and is one of the glomerular lesions that most frequently lead to chronic renal failure. Blacks are at higher risk compared with whites.

Clinical Features

Seventy percent to 80% of the patients have NS; the remaining 20% to 30% have subnephrotic or nephrotic range proteinuria. Proteinuria tends to be nonselective. Occasionally microhematuria may be present; in these cases, thin basement membrane disease or Alport disease should be excluded. Black patients with polymorphisms for APOL1 (apolipoprotein 1) have recently been shown to be at almost 10 times more increased risk for the disease.

Pathologic Features

Ancillary Studies

Differential Diagnosis

The differential diagnosis between FSGS and MCD is discussed in the MCD section. Discrimination between FSGS and segmental solidification of the tuft from other glomerulonephritis or healed necrotizing lesions is important. In cases of segmental sclerosis/scar from glomerulonephritis, deposits may be present. Moreover, these patients do not present clinically with new onset of pure NS but tend to have a history of nephritic syndrome or hematuria and subnephrotic proteinuria. Idiopathic FSGS is a diagnosis of exclusion when secondary and genetic FSGS are ruled out (see Table 7-5 ).

Prognosis and Treatment

FSGS is a progressive disease. Patients reach end-stage renal disease within a few years. Negative prognostic factors are widespread glomerular and tubulointerstitial damage, high serum creatinine values, severe proteinuria, steroid resistance, and black race. FSGS may recur in approximately 30% of transplants.

Epidemiology

CGP was first described in association with HIV infection (called HIV-associated nephropathy [HIVAN] ); in 1986, Weiss described the first few cases of non-HIV CGP (idiopathic CG) . Virus-associated and idiopathic CGPs are generally more frequent in the black population, with a slight male predilection. Other forms of CGP can also occur in Asians and whites and are associated with use of medications such as pamidronate and interferon, vascular damage (severe hyalinosis and thrombotic microangiopathy), myeloma, or other conditions. Idiopathic and virus-associated forms are frequent in young adults or in middle age. Other forms have no predilection for any age.

Clinical Features

CGP is characterized by severe proteinuria or NS with rapid increase of serum creatinine levels.

Pathologic Features

Ancillary Studies

Differential Diagnosis

The CGP lesions are often accompanied by segmental and global sclerosis, and some authors consider CGP as part of the spectrum of FSGS (Columbia classification). Regardless of the amount of sclerosis, the diagnosis of CGP is made if at least one glomerulus contains a segmental collapse with pseudocrescents. Pseudocrescents can be difficult to discriminate from real crescents. In general, pseudocrescents are formed by podocytes only and are located around the collapsed glomerular tuft and separated from parietal cells and Bowman capsule by the urinary space; real crescents contain epithelial cells but also inflammatory cells, fibrin, and occasional fibroblasts, and they tend to grow from the Bowman capsule toward the glomerular tuft, from which they are separated by the urinary space ( Table 7-6 ).

Prognosis and Treatment

Idiopathic and virus-associated CGPs generally have a poor prognosis. Idiopathic and HIV-associated forms may respond to steroids and cyclosporin. For other forms of CGP, therapy should target the cause of the disease.

Epidemiology

MGN is one of the most common causes of NS in adults and elderly without diabetes. It is rare in children.

Clinical Features

Patients generally present with severe proteinuria and NS.

Pathologic Features

Microscopic Findings

In early stages of the disease, glomeruli may appear unremarkable on light microscopy. The most characteristic feature is uniform thickening of the glomerular capillary walls as a result of the deposition of immune complexes in the subepithelium. The trichrome stain may sometimes reveal fuchsinophilic subepithelial deposits. In intermediate stages of the disease, the silver stain, which stains extracellular matrix black, reveals spikes and holes in the GBM. The spikes represent the interposition of newly formed extracellular matrix in between the deposits (optically clear on silver staining). As the disease progresses, holes in the GBM are more prominent; the holes represent the deposits fully immersed in the extracellular matrix. In later stages, the deposits are reabsorbed and the GBM remodeled. If there is concomitant mesangial expansion or hypercellularity, the possibility of secondary MGN should be investigated ( Fig. 7-11 , A ).

Ancillary Studies

Differential Diagnosis

The most important differential diagnosis between idiopathic MGN is with secondary MGN. The presence of mesangial expansion and mesangial deposits may suggest secondary MGN; however, idiopathic MGN can be diagnosed if all other conditions are clinically excluded.

Prognosis and Treatment

MGN is a slowly progressive disease. Bad prognostic features include high blood pressure, severe proteinuria, and the presence of associated segmental sclerosis and interstitial fibrosis. MGN can recur in renal transplants.

Epidemiology

Diabetes is the most common cause of end-stage renal disease in the United States.

Clinical Features

Microalbuminuria starts to develop, and with time, proteinuria becomes more severe, up to nephrotic range. The disease is often accompanied by the presence of hypertension. Evaluation of the retina is a good indicator of progression of the disease at the level of the microvasculature. In the absence of retinopathy and the presence of proteinuria, renal biopsy is indicated to rule out other causes of glomerular disease.

Pathologic Features

Ancillary Studies

Differential Diagnosis

Histologically, diabetic nodules have to be differentiated from idiopathic nodular sclerosis, light chain deposition disease, amyloidosis, fibrillary or immunotactoid glomerulonephritis (GN), and resolving membranoproliferative GN (MPGN). Differently from diabetic nephropathy, in idiopathic nodular glomerulosclerosis (common in nondiabetic heavy smokers), significant hyalinosis is not seen in glomeruli and arterioles. Nodules from deposition of material other than collagen do not stain black on silver staining; moreover, in light chain deposition disease and primary amyloidosis, immunofluorescence shows positive staining for only one of the light chains. In secondary amyloidosis, not only are the nodules silver negative, but they stain positive for AA amyloid or other amyloid proteins. Diabetic nodules are Congo red negative. Fibrillary and immunotactoid nodules are Congo red negative as well but generally do not stain strongly positive on silver; and on electron microscopy, the nodules are composed of fibrils that measure approximately 12 to 30 nm in diameter (fibrillary), which are positive for IgG, or organized microtubular structures that measure approximately 10 to 90 nm in diameter (immunotactoid) and are positive for Ig and either κ or λ light chains (see Table 7-6 ).

Prognosis and Treatment

Diabetic nephropathy is a slowly progressive disease. Presence of hypertension (HTN) and severe proteinuria are negative prognostic factors.

Epidemiology

IgA nephropathy is the most common glomerular disease in the world, especially in Asia and Europe; it is rare in blacks.

Clinical Features

Hematuria (microscopic and occasionally macroscopic) is always present and is sometimes accompanied by nephritic syndrome. In some cases, proteinuria (subnephrotic or nephrotic in 10% of the cases) is the presentation. Patients with HSP also have symptoms related to the vasculitis: abdominal pain, purpura, and joint pain. The renal disease is often exacerbated by infections of the respiratory or gastrointestinal tract.

Pathologic Features

Microscopic Findings

Mesangial expansion and mesangial cell proliferation is the most characteristic finding. However, the morphologic presentation is variable, and glomeruli may appear normal on light microscopy and may have lesions that resemble focal segmental glomerulosclerosis, mesangial expansion and proliferation, segmental to diffuse endocapillary proliferation with double contours, and occasionally, extracapillary proliferation and necrosis. Histologic diversity has led to several classification systems. The 2009 Oxford classification was a result of an international committee to develop an evidenced-based consensus that identified four histologic parameters: M (M0 or M1 for mesangial hypercellularity in <50% versus >50% of glomeruli), E (E0 or E1 for endocapillary hypercellularity in 0 or >1 glomerulus), S (S0 or S1 the latter for any tuft sclerosis not involving the entire glomerulus), T (T0, T1, T2 for <25%, 26% to 50%, or >50% of cortical area involved by interstitial fibrosis or tubular atrophy respectively; Fig. 7-13 , A ).

Ancillary Studies

Differential Diagnosis

IgA nephropathy can mimic a large variety of diseases morphologically, from lupus nephritis class II, to FSGS, to MPGN, and the IF is necessary to discriminate between these disorders and IgA nephropathy. IgA-dominant acute postinfectious glomerulonephritis, in particular Staphylococcus infection–associated glomerulonephritis, is a

known mimicker of IgA nephropathy. This type of glomerulonephritis mainly affects hypertensive elderly patients often with diabetes mellitus and has an abrupt onset of acute kidney injury; most patients have known positive infections.

Prognosis and Treatment

IgA nephropathy is a slowly progressive disease. Negative prognostic factors are high blood pressure, severe proteinuria, and high serum creatinine values. On the contrary, the prognosis of HSP, particularly in children, is more favorable. In approximately 50% of patients, IgA NP recurs in the transplant.

Epidemiology

Idiopathic MPGN is more common in children, whereas secondary forms, discussed subsequently, are more common in adults. Recent advances in the role of dysregulation of the alternative pathway of complement in the pathogenesis of MPGN-type patterns of glomerular injury with IF immunoglobulin negative reactivity underscore the proposed new histopathologic classification.

Clinical Features

Mixed nephrotic and nephritic syndrome is the common presentation; hypocomplementemia is almost always present. Patients with type I MPGN may also have positive serology for nephritic factor. In adult patients, secondary forms are more common, especially those associated with hepatitis C virus infection.

Pathologic Features

Microscopic Findings

MPGN patterns of glomerular injury are characterized by lobular accentuation from mesangial expansion and mesangial cell proliferation, endocapillary proliferation composed of swollen endothelial cells and variable degrees of inflammatory cells that lead to obliteration of the capillary lumina and capillary wall remodeling with double contours. Double contours are formed by interposition of mesangial cell cytoplasm and deposits between two layers of the capillary basement membrane. The outer layer represents the original GBM, and the inner layer is newly formed by the endothelium, resulting in a “tram track” appearance. Double contours are best seen on silver stain where both layers of the GBM are silver stain positive and the deposits and mesangial cell cytoplasm are silver stain negative. Extracapillary proliferation (i.e., crescents) may be present ( Fig. 7-14 , A ). Type II and III patterns of injury are generally less proliferative forms than type I MPGN. In particular, type II (dense deposit disease) is characterized by thickening of the capillary walls, which stain strongly with PAS and trichrome but are negative on silver stain ( Fig. 7-15 , A ).

Ancillary Studies

Differential Diagnosis

MPGN can mimic a variety of diseases, and clinical information needs to be integrated with IF and EM. The most difficult discrimination is between idiopathic MPGN and postinfectious GN (PIGN). A positive antistreptolysin O (ASO) titer and the presence of typical humps (in PIGN) should help to discriminate between the two. Lupus nephritis can also present with MPGN pattern, but in this case, the clinical history or positive laboratory tests of lupus, positive IF for all Ig and complements, and the presence of tubuloreticular inclusions (TRIs) in endothelial cells guide the diagnosis. In cryoglobulinemia, the presence of monoclonal (type I) organized deposits should help in the diagnosis. IgA NP with MPGN pattern shows IgA and C3 positive staining rather than IgG and C3. Other possible diseases that resemble MPGN are light chain deposition disease (LCDD), diabetes, and transplant glomerulopathy. Neither immunoglobulin nor complements are detected with IF in these latter cases.

Prognosis and Treatment

MPGN is a progressive disease with high recurrence in transplant.

Epidemiology

The acute form of postinfectious (poststreptococcal) GN is less frequent in the United States but still common in underdeveloped countries. Poststreptococcal GN is more common in children, whereas other forms of postinfectious GN, secondary to endocarditis, deep visceral abscesses, or infected atrioventricular shunts, are more frequently seen in adults.

Clinical Features

The classic presentation is nephritic syndrome. Children have development of renal symptoms 2 to 3 weeks after an upper respiratory infection, generally caused by β-hemolytic streptococcus. Hypocomplementemia and positive serology for ASO are also common findings.

Pathologic Features

Ancillary Studies

Electron Microscopy

The most characteristic finding is the presence of large, usually sparse subepithelial deposits (humps); smaller subendothelial and mesangial electron dense deposits are also common ( Fig. 7-16 ).

Differential Diagnosis

For information on the differential diagnosis, see the section on MPGN and Table 7-6 .

Prognosis and Treatment

Prognosis in children is good, whereas the prognosis in adults is more variable.

Epidemiology

Lupus is mainly a disease of the young female (female:male ratio, 13:1) and is more common in black and Asian women, although systemic lupus erythematosus complicated with nephritis is more frequent in men and male patients have a worse renal outcome.

Clinical Features

Patients present with a variety of clinical symptoms. In mesangial proliferative forms, hematuria is the classic presentation, whereas in forms with endocapillary proliferation, nephritic syndrome is more common, sometimes accompanied by severe proteinuria. Class V lupus nephritis (membranous) generally presents with nephrotic syndrome.

Pathologic Features

Ancillary Studies

Differential Diagnosis

Lupus nephritis can mimic a variety of diseases. Class II can mimic IgA nephropathy; classes III and IV may mimic any form of proliferative glomerular disease, idiopathic or secondary. Class V is obviously very similar to idiopathic or other secondary forms of membranous glomerulopathy. Clinical information together with a positive IF for all Ig and complement fraction should guide the diagnosis. The presence of ultrastructural tubuloreticular inclusions and positive immunofluorescence staining for C1q are strongly suggestive of lupus nephritis.

Prognosis and Treatment

The prognosis varies according to the class. Class II lupus nephritis generally progresses very slowly, whereas classes III and IV have a more aggressive course. In approximately one fourth of the cases, transformation from one class to another can occur. Despite some controversy, lesions with high activity, including fibrinoid necrosis of glomeruli and vessels and crescents, need aggressive treatment. Lesions with high chronicity index also have a poor prognosis. Consolidated assessment of the biopsy activity or chronicity may provide better correlations with clinical and outcome parameters in the future.

Epidemiology

Among the patients with primary amyloidosis, approximately 10% to 20% have myeloma, and the remaining ones have monoclonal spikes in urine or serum only. Patients with secondary amyloidosis have a history of chronic inflammatory disease such as osteomyelitis, rheumatoid arthritis, tuberculosis, or cancer. This form is the result of increased serum amyloid A (SAA) levels from protracted tissue destruction and inflammation and reduced capacity of liver enzymes to degrade it.

Clinical Features

The most common clinical presentation is nephrotic range proteinuria or NS with or without renal failure.

Pathologic Features

Microscopic Findings

Glomeruli, tubules, interstitium, and vessels may be involved by amyloidosis. Amyloid appears as a smudgy accumulation of acellular material that may involve mesangial areas or capillary walls. It is pale on H&E and PAS and is silver negative ( Fig. 7-18 , A ). Occasionally, projections of epimembranous spicules may be seen protruding from the capillary walls into the urinary space. Congo red is positive with classic birefringence; this is the most specific stain for amyloidosis ( Fig 7-18 , B ). Immunofluorescence for thioflavin T is a very sensitive technique. It is possible to discriminate between AL and AA with pretreatment of the sections with potassium permanganate before staining with Congo red. AA is Congo red negative, whereas AL maintains the classic birefringence. Immunostaining for κ, λ, AA, or other components in familial forms of amyloidosis confirms the diagnosis and further characterizes the disease ( Fig. 7-18 , C and D ).

Ancillary Studies

Differential Diagnosis

Any lesion with hypocellular expansion of the mesangium may be in the differential diagnosis with amyloidosis (see Table 7-6 ). Nodular sclerosis or hyalinosis can also resemble amyloidosis. Congo red positive staining is the first step toward the diagnosis of amyloidosis versus all the other diseases with organized deposits. Amyloid fibrils are randomly arranged and measure 9 to 11 nm versus 12 to 30 nm (generally around 20 nm) in fibrillary glomerulopathy; moreover, whereas AL amyloid contains only one of the light chains, fibrillary glomerulopathy is always positive for IgG and both light chains. In immunotactoid glomerulopathy, deposits are composed of bundles of microtubules (and not fibrils) with a parallel arrangement that measure 10 to 90 nm (generally >30 nm) and are composed of Ig (IgG), C3, or both or most frequently only one of the light chains. Cryoglobulinemia is characterized in most of the cases by curved microtubules that measure 25 to 35 nm. In diabetic glomerular sclerosis, collagen fibers (diabetic fibrillosis) are negative on IF and argyrophilic on silver staining and measure 5 to 20 nm.

Prognosis and Treatment

Prognosis is generally poor. End-stage renal disease is the major cause of morbidity and mortality in primary forms. Patients with primary amyloidosis have a worse prognosis compared with those with AA amyloidosis. AL forms are treated with chemotherapy.