I. MEDICAL RENAL BIOPSY HANDLING AND PROCESSING. This chapter covers medical renal biopsies; biopsy for diagnosis of renal masses is covered in Chapter 20. Renal allograft biopsy pathology is added at the end of this chapter. Renal biopsies are usually received in transport media, allowing distribution of tissue for light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM).
A. Light microscopy. A minimum of three hematoxylin and eosin (H&E), one trichrome, two periodic acid-Schiff (PAS) stains, and one Jones silver-stained section is required. A minimum of seven glomeruli and one artery is required for adequate LM evaluation.
B. Immunofluorescence. A minimum of two glomeruli is required. A direct IF method is routinely used employing a panel of antibodies, including anti-IgG, IgA, IgM, C3, C1q, fibrinogen, albumin, and kappa and lambda light chains. It is important to document the staining pattern (linear vs. granular) and distribution (mesangial, loop, or combined).
C. Electron microscopy. Ultrastructural evaluation of two glomeruli is recommended. EM allows for evaluation of cellular and extracellular abnormalities in the glomeruli, tubules, interstitium, and vessels. EM is very useful in confirming the presence and distribution of electron-dense deposits, which can be located in the mesangium or the glomerular capillary basement membrane. In the basement membrane, electron-dense deposits can be subepithelial, subendothelial, or intramembranous (surrounded by basement membrane).
II. GLOMERULAR DISEASES. Glomerular diseases may be primary or secondary (associated with systemic diseases). Patients can be grouped into those that present with nephrotic syndrome (>3 g urine protein/day), nephritic syndrome (proteinuria + hematuria), or isolated hematuria. It is important for the pathologist to have access to patient’s clinical and laboratory data. For example, minimal change disease (MCD), focal segmental glomerulosclerosis, and membranous glomerulonephritis (GN) usually present with nephrotic syndrome. In contrast, postinfectious GN usually presents with nephritic syndrome.
A. MCD/focal segmental glomerulosclerosis (FSGS). MCD and FSGS are the most common causes of nephrotic syndrome in children and are also common in adults, affecting about 10% to 20% of patients with kidney disease. Primary
FSGS may be idiopathic, secondary, or familial (Am J Nephrol. 2003;23:353). Less than nephrotic range proteinuria may be present in advanced cases. Some patients have concurrent hematuria and hypertension (HTN).
The classic findings in MCD (Table 19.1) are as follows:
LM: Normal-appearing glomeruli
EM: Extensive foot process effacement (e-Fig. 19.1).*
The diagnostic features of FSGS are as follows:
LM: Segmental sclerosis in some but not all glomeruli. Accurate diagnosis of FSGS depends on the extent of the disease and the number of glomeruli present in the biopsy. Diagnosis may be missed because of sampling error, particularly with the smaller needles currently used. It has been estimated that in a biopsy containing 10 glomeruli, there is a 35% chance of missing FSGS. Notably, even one glomerulus with FSGS is sufficient for diagnosis. The corticomedullary glomeruli are the first to be sclerosed; therefore, needle biopsies should opt to sample this region.
IF: Is either entirely negative or has focal and weak mesangial C3 or IgM immunoglobulin deposits.
EM: Shows focal foot process effacement (e-Fig. 19.2), the degree of which may depend on the degree of proteinuria. Other EM findings in MCD/FSGS include microvillus transformation of foot processes, endothelial cell edema, podocyte detachment, and glomerular basement membrane (GBM) wrinkling (see e-Fig. 19.2F).
Beyond this classic presentation, light and electron microscopic findings may be similar in MCD and FSGS. For example, glomeruli may appear normal in FSGS and focal foot process effacement may be present in MCD.
Glomerular hypercellularity and enlargement (glomerulomegaly) is thought to represent an early lesion of FSGS. A recent FSGS classification scheme describes various histologic patterns with significantly different prognosis (Kidney Int. 1990;38:115). Glomerulomegaly is rare (seen in only about 3% of FSGS), but the following variants are more frequent: perihilar FSGS (26%), tip lesion (17%), usual type not otherwise specified (NOS) (42%), and collapsing FSGS (11%) (see e-Fig. 19.2A-E) (Am J Kidney Dis. 2004;43:368). The tip and cellular lesions have the best prognosis and collapsing FSGS the worst (Kidney Int. 2006;69:920). Tubulointerstitial damage and vascular thickening indicate chronic disease. Pathologic similarities between MCD and FSGS initially suggested that they were one disease with a spectrum of findings, but recent clinical and molecular studies have demonstrated that FSGS has worse prognosis and different pathogenesis.
B. Collapsing FSGS is a distinct FSGS variant considered by some to be an entirely different disease.
LM: Characterized by segmental glomerular capillary collapse and podocyte hypertrophy, often accompanied by microcystic tubular dilatation and interstitial inflammation (see e-Fig. 19.2E). The main difference from usual FSGS is the collapse of the loops versus sclerosis, and podocyte proliferation versus podocyte loss.
EM: Shows proliferating podocytes and wrinkled/collapsed capillary loops. Clinically, it is characterized by black racial predominance, a high incidence of nephrotic syndrome, and rapidly progressive renal failure. First identified in HIV patients, collapsing FSGS was later recognized in association with viruses such as Parvovirus 19 and hepatitis B and C, and with pamidronate chemotherapy (Semin Diagn Pathol. 2002;19:106). It is an aggressive and difficult to treat disease (Semin Nephrol. 2003;23:209), and may also involve the allograft kidney. Pathogenesis involves podocyte cell cycle dysregulation resulting in proliferation.
TABLE 19.1 Major Glomerular Patterns and Differential Diagnosis on Light Microscopy
Minimal change disease
Thin membrane disease
>50% = crescentic
<50% = other GN
FSGS, focal segmental glomerulonephritis; GN, glomerulonephritis; NOS, not otherwise specified, IG, immunoglobulin; HSP, Henoch-Schönlein purpura; MCD, minimal change disease; MPGN, membranoproliferative glomerulonephritis; MIDD, monoclonal immunoglobulin deposition disease.
C. Mesangial proliferative glomerulonephritis (IGA, IgM, IgG and C3). Mesangial hypercellularity is defined as more than three mesangial cells per glomerular segment; many glomerular diseases may have increased mesangial cells (Table 19.1) including variants of MCD and FSGS. Mesangial hypercellularity indicates mesangial immune deposits and/or reactive proliferation. The most common disease is IgA nephropathy, clinically characterized by micro or macrohematuria and varying proteinuria (rarely nephrotic syndrome or crescentic GN) (Nephrol Dial Transplant. 2001;16 Suppl 6:77).
LM: Mesangial hypercellularity varies from focal to diffuse.
IF: Diagnosis is made by the presence of predominant or co-dominant IgA mesangial deposits (e-Fig. 19.3). Mild IgG and IgM deposits may also be present, particularly in Henoch-Schönlein purpura (HSP), which is thought of as the systemic form of IgA.
EM: Shows mesangial/paramesangial deposits and occasionally capillary loop, subendothelial deposits that may extend to the GBM and cause splitting (more common in HSP), or “humps.”
Histological parameters which negatively affect prognosis in IgA disease include glomerular sclerosis, capillary wall IgA deposits, and vascular and tubulointerstitial fibrosis. Glomerular sclerosis is the best independent predictor of adverse outcome and renal failure. HSP mimics IgA pathologically, but clinically is a systemic disease that presents with skin rash, arthritis, and abdominal pain in addition to nephritis. IgA is the most common glomerular disease worldwide with variable prognosis (˜30% develop end-stage renal disease [ESRD]). HSP tends to be self-limiting with only about 18% of patients progressing to ESRD. Both may recur in transplant kidneys, but clinical symptoms are mild despite IgA deposition.
Mesangial hypercellularity not infrequently accompanies various types of GN. For example, MCD and/or FSGS with mesangial hypercellularity are generally thought to have a worse prognosis. Focal IgM deposits are seen in some such cases. Rarely, diffuse IgM deposits are detected (which have raised considerable debate whether they represent a separate entity named IgM nephropathy).
An entity known as C1q nephropathy is characterized by predominant C1q deposits and is considered a variant of MCD/FSGS (Am J Clin Pathol. 1985:83:415). C1q nephropathy is primarily a disease of children and young adults. Other glomerulopathies characterized by isolated C3 or IgG mesangial deposits in patients without lupus stigmata were described recently and named accordingly. IgG glomerulopathy is a pediatric disease that may be an aberrant manifestation of lupus nephritis (LN), and it has been proposed that it should be treated as such (JASN 2002;13:379).
Recent studies have clarified the entity known as C3 glomerulopathy, which may present with mesangial hypercellularity or minimal changes. Immunofluorescene demonstrates isolated, granular, mesangial C3 deposits without IgG or C1q staining (e-Fig. 19.4). Interestingly, the disease is associated with dysregulation of the alternative complement pathway secondary to defects in complement factor H (Nat Rev Nephrol. 2010;6:494; Kidney Int. 2009;75:1230).
D. Membranous GN is the most common cause of nephrotic syndrome in adults (30% to 50% of cases). It may occur at any age, but accounts for <5% of childhood nephrotic syndrome. Most cases are idiopathic, but ˜10% are associated with identifiable causes such as malignancy, autoimmune diseases (e.g., systematic lupus erythematosus), drugs, and infections (hepatitis B, syphilis). Glomerular lesions resemble those seen in Heymann nephritis, an animal model in which antibodies react with the Heymann antigen, a complex of megalin and
the receptor-associated protein, expressed in the tubular brush border and the basal surface of the visceral epithelial cells.
LM: Membranous GN is a diffuse process in which the glomeruli are not hypercellular but usually exhibit thickening of the capillary basement membrane while maintaining luminal patency. In Jones silver-stained sections, the basement membrane can show “spikes” projecting from the epithelial side of the basement membrane. Spikes result from the presence of subepithelial electrondense deposits (silver stain negative) and deposition of basement membrane-like material on the sides of the deposits (e-Fig. 19.5). Glomeruli appear essentially normal in early cases.
IF: Diffuse, granular staining for IgG and C3 is present along the glomerular capillary loops by IF. Other immunoglobulins can be present but have lower intensity staining.
EM: At early stages, the electron-dense deposits are subepithelial. As the disease progresses, deposition of basement membrane-like material at the sides of the electron- dense deposits occurs so that with time, the electron-dense deposits are surrounded by basement membrane and thus becomes intramembranous. The deposits eventually become electron-lucent, suggesting resolution (e-Fig. 19.5).
E. Postinfectious glomerulonephritis (PIGN). PIGN is a classic complication of streptococcal pharyngitis and presents acutely with nephritic syndrome. However, classic PIGN is currently infrequent; most cases follow staphylococcal skin infections and other bacterial, viral, fungal, or parasitic infections, and are more frequently chronic or atypical (Hum Pathol. 2003;34:3).
LM: The pathology is unique, characterized by white cells in the glomeruli (predominantly neutrophils in the acute phase), and lymphocytes or macrophages in chronic cases.
IF: There are large granular IgG and C3 deposits along capillary loops (e-Fig. 19.6). Occasionally, deposits are located predominantly in the mesangium (instead of in the loops) and are C3 or IgA/IgM instead of IgG (Semin Diagn Pathol. 2002;19:146).
EM: Shows characteristic bell-shaped deposits (humps). Erythrogenic toxin type B is thought to be the target antigen for immune complexes that are implanted in the GBM.
F. Membranoproliferative glomerulonephritis (MPGN). Patients with MPGN can present with features of nephrotic and/or nephritic syndrome, and most patients have a low serum C3 level. Although MPGN can affect patients of all ages, it is more common in children. Three types of MPGN have been described; because all types can have similar histologic findings, EM is used to differentiate them. Type I is the most common type, followed by types II and III. It is important to note that MPGN type I can be associated with other diseases such as viral hepatitis, so patients should be worked up for secondary causes of MPGN when the pathologic diagnosis is established.
LM: MPGN is a diffuse glomerulopathy with endocapillary proliferation that results in lobular accentuation (e-Fig. 19.7). The GBMs are thick, and the capillary lumens are not evident. The Jones silver stain reveals double GBM contours, also known as “tram-tracking.” These findings are more commonly seen in MPGN type I. MPGN type II tends to have a less consistent histologic pattern.
IF: A strong and diffuse granular staining for C3 is observed along the glomerular capillary walls and the mesangium. Approximately 60% of type I MPGN also exhibit IgG and/or C1q immunostain. Negative immunostains for immunoglobulins and C1q are usually observed in MPGN type II.
EM: This is the most useful tool for differentiating MPGN types. MPGN type I shows mesangial interposition (extension of mesangial cell cytoplasm into the capillary wall) and subendothelial electron-dense deposits. When the mesangial cell cytoplasm extends into the glomerular capillary wall, basement
membrane-like material is laid down by the mesangial and endothelial cells, creating a second “new” basement membrane. This process results in the “tramtracking” observed by LM. MPGN type II is also known as dense deposit disease because it has ribbon-like electron-dense deposits along the capillary walls, often replacing the lamina densa. These deposits are not necessarily present in all capillary loops and may only be present in some segments and the mesangium. The composition of these electron-dense deposits remains uncertain. The ultrastructural findings of MPGN type III are similar to those of MPGN type I, but with subendothelial and subepithelial electron-dense deposits (e-Fig. 19.7).
G. Crescentic glomerulonephritis (crescentic GN). The term “crescentic GN” refers to the presence of cellular crescents in >50% of glomeruli available in a renal biopsy. Its usual clinical presentation is that of rapidly progressive GN. Patients can have a renal limited or systemic disease.
LM: Cellular crescents are identified in >50% of glomeruli (e-Fig. 19.8). Necrotizing glomerular lesions are commonly seen. Additional morphologic findings are dependent on the type of renal limited or systemic disease. Immunofluorescence is used to further classify crescentic GN.
IF: In anti-GBM disease or Goodpasture’s disease, glomeruli exhibit smooth linear IgG staining along the capillary basement membrane. Immune-complex GN has a granular staining pattern for one or more immunoglobulins. Pauciimmune GN has negative immunostain for all immunoglobulins.
EM: The smooth linear IgG staining of anti-GMB or Goodpasture’s disease does not have a morphologic correlation that can be detected by EM. The glomerular changes noted by EM correspond to the necrosis, disruption of the GBM, and crescents that are seen in all crescentic GN. Similar findings are also identified in pauci-immune GN. Cases of immune-complex GN will show electron-dense deposits (e-Fig. 19.8).
H. Lupus nephritis (LN). Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder with a peak incidence in the second and third decades of life and a female predominance (male-to-female ratio of 1:9). It is more common in African-Americans. The clinical diagnosis of lupus is based on clinical and laboratory criteria established by the American Rheumatism Association. Renal involvement by the disease is relatively common; approximately half of lupus patients develop lupus nephritis during the first year of the disease. Although this chapter emphasizes the glomerular findings of (LN), interstitial, tubular, and vascular lesions can also accompany the glomerular changes. Use of the ISN/RPS classification of LN, which is a modification of the WHO classification (Kidney Int. 2004;65:521), is recommended.
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Medical Diseases of the Kidney
Medical Diseases of the Kidney
Joseph P. Gaut
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