Glomerular injury results in multiple signs and symptoms, including proteinuria caused by altered permeability of capillary walls, hematuria caused by rupture of capillary walls, azotemia caused by impaired filtration of nitrogenous wastes, oliguria or anuria caused by reduced urine production, edema caused by salt and water retention, and hypertension caused by fluid retention and other factors. The nature and severity of disease in a given patient are dictated by the nature and severity of glomerular injury.

Glomerular syndromes include asymptomatic hematuria or proteinuria, nephrotic syndrome, nephritic (glomerulonephritic) syndrome, rapidly progressive glomerulonephritis, and syndromes with concurrent glomerular and extrarenal features, such as pulmonary-renal syndrome and dermal-renal syndrome. Specific glomerular diseases tend to produce characteristic syndromes of kidney dysfunction ( Table 16.1 ). The diagnosis of a glomerular disease requires recognition of one of these syndromes followed by collection of data to determine which specific glomerular disease is present. Alternatively, if reaching a specific diagnosis is not possible or not necessary, the physician should at least narrow the differential diagnosis to a likely candidate glomerular disease.

Evaluation for pathogenic processes, often by serology, as well as identification of patterns of injury in a kidney biopsy specimen, is required for a definitive diagnosis. Table 16.2 illustrates parameters that are used to categorize glomerulonephritis. Fig. 16.1 shows the relative frequencies that major categories of glomerular disease are identified in kidney biopsy specimens. These frequencies are different from the overall prevalence of these diseases in patients with these syndromes, because some categories of disease have presentations that are more likely to prompt biopsy (e.g., rapidly progressive glomerulonephritis) than other diseases (e.g., steroid-responsive childhood nephrotic syndrome). Fig. 16.2 depicts some of the clinical and pathologic features used to resolve the differential diagnosis in patients with antibody-mediated glomerulonephritis, Figs. 16.3 through 16.6 illustrate the distinctive ultrastructural features of some of the major categories of glomerular disease, Fig. 16.7 illustrates some of the major patterns of immune deposition identified by immunofluorescence microscopy, and Fig. 16.8 illustrates common patterns of injury of focal segmental glomerulosclerosis (FSGS).

Frequencies of kidney biopsy diagnoses versus age from 1986 to 2015 in the University of North Carolina (UNC) Nephropathology Laboratory.

The diagnoses are separated into those that usually cause a glomerulonephritic presentation and those that usually cause the nephrotic syndrome. Approximately one-third of the patients in this kidney biopsy population from UNC were blacks, which influences the high frequency of lupus glomerulonephritis and FSGS. (A) Causes of glomerulonephritis. (B) Causes of nephrotic syndrome. ANCA , Antineutrophil cytoplasmic antibody; DDD , dense deposit disease; DKD , diabetic kidney disease; FSGS , focal segmental glomerulosclerosis; GBM , glomerular basement membrane; GN , glomerulonephritis; IgA , immunoglobulin A; MN , membranous nephropathy; MIDD , monoclonal immunoglobulin deposition disease; MCD , minimal change disease; MPGN , membranoproliferative glomerulonephritis; Lupus , systemic lupus erythematosus.

(From O’Shaughnessy MM, Hogan SL, Poulton CJ, et al. Temporal and demographic trends in glomerular disease epidemiology in the Southeastern United States, 1986–2015. Clin J Am Soc Nephrol . 2017;12:614–623.)

Features that distinguish among different immunopathologic categories of immune-mediated glomerulonephritis.

ANCA , Antineutrophil cytoplasmic antibody; DDD , dense deposit disease (which is a C3 glomerulopathy and not an immune complex disease); EGPA , eosinophilic granulomatosis with polyangiitis; GBM , glomerular basement membrane; GN , glomerulonephritis; IF , immunofluorescence microscopy; IgA , immunoglobulin A; Imm Cx , immune complex; MPGN , membranoproliferative glomerulonephritis; SLE , systemic lupus erythematosus.

Ultrastructural changes in glomerular capillaries caused by glomerular diseases that typically result in the nephrotic syndrome.

In the normal glomerular capillary, note the visceral epithelial cell with intact foot processes (green) , endothelial cell with fenestrations (tan) , mesangial cell (brown) with adjacent mesangial matrix (light gray) , and basement membrane with lamina densa (light blue) that does not completely surround the capillary lumen but splays out as the paramesangial basement membrane. In minimal change disease, note the effacement of foot processes and microvillus transformation. In diabetic glomerulosclerosis, note the thickening of the lamina densa and expansion of mesangial matrix. In idiopathic membranous glomerulopathy, note the subepithelial dense deposits with adjacent projections of basement membrane (see also Fig. 16.6 ). In secondary membranous glomerulopathy, note the mesangial and small subendothelial deposits in addition to the requisite subepithelial deposits. In amyloidosis, note the fibrils within the mesangium and capillary wall.

(Courtesy J. Charles Jennette, MD.)

Ultrastructural changes in glomerular capillaries caused by glomerular diseases that typically result in hematuria and the nephritic syndrome.

In thin basement membrane nephropathy, note the thin lamina densa of the basement membrane (compare to the normal glomerular capillary in Fig. 16.3 ). In mesangioproliferative glomerulonephritis (e.g., mild lupus nephritis, immunoglobulin A nephropathy), note the mesangial dense deposits and mesangial hypercellularity. In acute diffuse proliferative glomerulonephritis (e.g., poststreptococcal glomerulonephritis), note the endocapillary hypercellularity contributed to by leukocytes, endothelial cells, and mesangial cells and the dense deposits, which include not only conspicuous subepithelial “humps” but also inconspicuous subendothelial and mesangial deposits. In proliferative lupus glomerulonephritis, note the extensive subendothelial and mesangial dense deposits. In membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), note the subendothelial deposits with associated subendothelial interposition of mesangial cytoplasm and deposition of new matrix material resulting in basement membrane replication. In dense deposit disease, note the intramembranous and mesangial dense deposits.

(Courtesy J. Charles Jennette, MD.)

Ultrastructural features of the major classes of lupus nephritis.

The sequestration of immune deposits within the mesangium in class II (mesangioproliferative) lupus glomerulonephritis causes only mesangial hyperplasia and mild renal dysfunction. Substantial amounts of subendothelial immune deposits, which are adjacent to the inflammatory mediator systems of the blood, cause focal (class III) or diffuse (class IV) proliferative lupus glomerulonephritis with overt nephritic signs and symptoms. Localization of immune deposits predominantly in the subepithelial zone causes membranous (class V) lupus glomerulonephritis, which usually manifests predominantly as the nephrotic syndrome.

(Courtesy J. Charles Jennette, MD.)

Ultrastructural stages in the progression of membranous glomerulopathy.

Stage I has subepithelial electron-dense immune complex deposits without adjacent projections of basement membrane material. Stage II has adjacent glomerular basement membrane (GBM) projections that eventually surround the electron-dense immune deposits in stage III. Stage IV has a markedly thickened GBM with electron-lucent zones replacing the electron-dense deposits.

(Courtesy J. Charles Jennette, MD.)

Immunofluorescence microscopy staining patterns for membranous glomerulopathy.

In membranous glomerulopathy, note the global granular capillary wall staining for IgG. In AL amyloidosis, note the irregular fluffy staining for lambda light chains. In MPGN, note the peripheral granular to bandlike staining for C3. In DDD, note the bandlike capillary wall and coarsely granular mesangial staining for C3. In acute postinfectious GN, note the coarsely granular capillary wall staining for C3. In IgA nephropathy, note the mesangial staining for IgA. In class IV lupus GN, note the segmentally variable capillary wall and mesangial staining for IgG. In anti-GBM GN, note the linear GBM staining for IgG. anti-GBM , Antiglomerular basement membrane; DDD , dense deposit disease; GN , glomerulonephritis; IgG , immunoglobulin G; LC , light chain; MPGN , membranoproliferative glomerulonephritis.

Pathologic variants of focal segmental glomerulosclerosis.

Podocytes showing parietal epithelial cells and tubular epithelial cells (green) , endothelial cells (pale yellow) , mesangial and arteriolar smooth muscle cells (red) , macrophages (light tan) , and collagenous matrix (black) . The photomicrographs of perihilar and cellular focal segmental glomerulosclerosis (FSGS) include periodic acid–Schiff staining, and the images of tip lesion and collapsing FSGS include Jones silver staining. Perihilar FSGS has perihilar sclerosis and adhesion. Tip lesion FSGS has consolidation of the tuft contiguous with the origin of the proximal tubule. Collapsing FSGS has collapse of capillaries with hypertrophy and hyperplasia of overlying epithelial cells. Cellular FSGS has endocapillary hypercellularity with foam cells.

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