Atlas of Histopathology Ivan Damjanov
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The Cardiovascular System7

Da Zhang,
Ivan Damjanov
 
Normal Histology
The kidney is a complex organ composed functional units called nephrons (Figs 7.1A and B). Each nephron consists of a glomerulus, proximal and distal tubules, a loop of Henle and collecting ducts. Nephrons are surrounded by an interstitium that contains capillaries, veins and arteries. Nephrons form the urine which flows through the collecting ducts into the renal calices and renal pelvis, from which it enters into the ureters, bladder and urethra.
The ureters, urinary bladder and the urethra are simple organs which contain a prominent smooth muscle layer, allowing them to contract or expand, and thus propel, store or extrude urine. Except for the terminal part of the urethra, which is lined by squamous epithelium, the remaining parts of the lower urinary system are lined by urothelial (transitional) epithelium.
 
Overview of Pathology
The most important diseases of the urinary system are as follows:
  • Developmental disorders
  • Glomerular diseases
  • Vascular kidney diseases
  • Infectious diseases
  • Neoplasms.
 
Developmental Disorders
The most important developmental disorders of the kidney that produce typical histopathologic changes are: (a) polycystic kidney disease and (b) multicystic renal dysplasia.
Polycystic kidney disease is an autosomal dominant developmental disorder accounting for approximately 10% of all cases of end stage kidney disease in nephrology or renal dialysis and renal transplantation departments. The kidneys are enlarged, contain numerous cysts filled with clear fluid. Microscopically the cysts are lined by nondescript cuboidal or simple flat epithelium derived from dilated renal tubules and ducts (Figs 7.2A and B).
Multicystic renal dysplasia is a developmental disorder that usually affects only one kidney, but may be bilateral as well. It presents a multicystic enlargement of the kidney, with numerous cysts replacing 178the normal parenchyma of the kidney. The solid tissue between the cysts consists of dysplastic tubules that cannot be properly classified, and stromal tissue that may contain heterologous elements such as bone, skeletal muscle or cartilage (Fig. 7.3).
 
Glomerular Diseases
Glomerular diseases may result from: (a) proven or presumed immunological injury (e.g. poststreptococcal glomerulonephritis or membranous nephropathy); (b) metabolic disorders (e.g. diabetic nephropathy); (c) circulatory disorders (e.g. hypertension). Immunologic diseases of the kidney may occur in an isolated form (e.g. acute poststreptococcal glomerulonephritis), as part of a pulmonary renal syndrome (e.g. Goodpasture syndrome or Wegener granulomatosis) or as part of a systemic disease (e.g. lupus nephritis, which occurs in systemic lupus erythematosus).
Acute poststreptococcal glomerulonephritis is an immunologically mediated disease that occurs typically 10–14 days after an upper respiratory tract streptococcal infection. Immune complexes composed of streptococcal antigens and antibodies desposit or form in the glomeruli and are seen along the glomerular basement membranes. The glomeruli are enlarged, hypercellular and their capillary lumina are obliterated by inflammatory cells or proliferating endothelial and mesangial cells (Figs 7.4A to C). Immunofluorescence microscopy studies show widespread deposits of immune complexes in the glomerular basement membrane and mesangial areas. By electron microscopy there are typical deposits of immune complexes in the form of subepithelial ‘humps’; the smaller immune complexes seen by immunofluorescence microscopy are presumably not evident by electron microscopy. The disease occurs mostly in children and heals spontaneously in over 90% of cases. The remaining 9% patients may have protracted disease, and in 1% of all patients the disease may progress to chronic glomerulonephritis and end stage kidney disease. Acute poststreptococcal glomerulonephritis of adults has a less favorable outcome than the same disease in children and one-third of patients have chronic consequences.
Rapidly progressive glomerulonephritis (RPGN), also known as subacute glomerulonephritis, is a severe form of glomerular injury characterized by focal fibrinoid necrosis of glomerular loops and formation of crescents in the urinary space between the capillary loops and the Bowman capsule (Figs 7.5A and B). The prototypical disease presenting as crescentic glomerulonephritis is Goodpasture syndrome, a pulmonary-renal syndrome mediated by cytotoxic antibodies against the globular part of collagen type IV in the glomerular and pulmonary basement membranes. Crescentic glomerulonephritis may also be a feature of Wegener granulomatosis and in many cases its pathogenesis remains unknown. In all these patients immunofluorescence microscopy will reveal no immune deposits in the glomeruli and it is thus customary to call such cases ‘pauci-immune crescentic glomerulonephritis’. Timely treatment may prevent the progression of the disease, which without treatment has a tendency to destroy glomeruli and cause progressive renal failure within a matter of several weeks.
IgA nephropathy is a milder form of chronic glomerulonephritis in which the changes are limited to mesangial areas. Microscopically, it presents with widening of mesangial areas, which contain deposits of IgA and proliferating mesangial cells (Figs 7.6A and B). The tissues present with microscopic hematuria and proteinuria and few other clinical symptoms. Although it has presumptively an immunologic pathogenesis, it usually does not respond to corticosteroids and immunotherapy. Overall IgA nephropathy has a good prognosis, although in a minority of cases it may progress to end-stage kidney disease.
Lupus nephritis is a common feature of systemic lupus erythematosus. Although all parts of the kidney may be involved, glomerular changes predominate. Glomerulonephritis may present in several forms, and it is customary to classify them in six categories, reflecting the severity of the disease. For example, in class III lupus nephritis there is focal and segmental mesangial proliferation, whereas in class IV most glomeruli are involved and show proliferative and exudative glomerulonephritis (Figs 7.7A and B). The deposits of immune complexes on the subepithelial and subendothelial side 179of the glomerular basement membranes and in the mesangial areas may be demonstrated by immunofluorescence microscopy and electron microscopy. There is also proliferation of mesangial and endothelial cells, and in severe cases even formation of epithelial cell crescents. Inflammatory cells are also seen in the glomeruli and include neutrophils or macrophages. Lupus nephritis usually responds favorably to corticosteroids and immunomodulatory therapy, but if untreated it will cause kidney failure.
Membranous nephropathy is an immunologically mediated disease characterized by diffuse ‘membranous’ thickening of the glomerular basement membranes without cellular proliferation or exudation of inflammatory cells in the glomeruli (Figs 7.8A to D). This thickening results from the widespread deposition and/or formation of the immune complexes along the subepithelial side of the glomerular basement membranes. By immunofluorescence microscopy immune deposits appear granular (lumpy-bumpy). By electron microscopy one may see that these dense deposits are separated one from another by uninvolved basement membrane. Membranous nephropathy presents with nephrotic syndrome which does not respond to steroid therapy. It is a slowly progressive disease and, over a period of approximately 10 years, it will usually cause renal failure.
Minimal change disease (nil disease) is a disease of unknown etiology, thought to be immunologically mediated by cytokines secreted by T lymphocytes and macrophages. By light microscopy the glomeruli appear normal (Figs 7.9A and B). There are no immune deposits visible by immunofluorescence microscopy or electron microscopy. The only change is seen by electron microscopy and it involves fusion of the foot processes of glomerular epithelial cells (podocytes). Minimal change disease presents clinically with nephrotic syndrome, which typically responds well to steroid treatment.
Focal glomerulosclerosis (FGS) is a name for a heterogeneous group of renal diseases that presents with sclerosis and hyalinization of some capillary loops in some glomeruli (Figs 7.10A and B). Clinically FGS presents with nephrotic syndrome that does not respond to steroid treatment. Currently FGS is the most common cause of nephrotic syndrome in adults, most likely because it is one of the renal features of AIDS and, among others, it is a well known may be a complication of intravenous drug abuse. The FGS is resistant to therapy and has a tendency to progress to end stage kidney disease.
Diabetic glomerulopathy may present in two forms: (a) diffuse glomerular basement membrane and (b) nodular mesangial glomerulosclerosis (Kimmelstiel-Wilson disease) (Fig. 7.11). In all forms of diabetic renal disease there is also hyalinization of arterioles and fibrosis of the intima and media of renal arteries. Glomerular and vascular changes are in part caused by hypertension which is almost invariably present in OST patients. Diabetic glomerulopathy presents with proteinuria which may progress to nephrotic syndrome. In later stages of the disease there is also tubular atrophy and loss which combined with glomerular and vascular lesions leads to renal failure.
Renal amyloidosis may develop due to the deposition of amyloid fibrils in the glomeruli, in the glomerular basement membranes and in the mesangial matrix (Figs 7.12A and B). The deposits of amyloid cause thickening of the glomerular basement membranes and expansion of mesangial areas leading to complete hyalinization of glomeruli and ultimately to renal failure. In addition to glomeruli amyloid deposits may be found in arterioles, arteries and tubular basement membranes and interstitial spaces. Amyloid may be of the AA type (derived from the serum amyloid associated (SAA) protein, or of the AL type (derived from light chain of immunoglobulins). Amyloidosis is an incurable disease.
Chronic glomerulonephritis is the outcome of many glomerular diseases. Microscopically it presents with hyalinization of glomeruli (Fig. 7.13). Loss of glomeruli is accompanied by an atrophy and a loss of tubules, interstitial fibrosis and secondary obliterative (endarteritic) changes in the arteries and arterioles. Clinically chronic glomerulonephritis is equivalent to end stage renal disease manifesting itself as renal failure and uremia. The disease requires renal dialysis or renal transplantation.180
 
Vascular Kidney Diseases
Hypertension represents the most common causes of renal injury and renal failure in the elderly. The renal changes are included under the term of nephroangiosclerosis which includes fibrosis of arteries, hyalinization of arterioles, hyalinization of glomeruli, atrophy and a loss of tubules, accompanied by interstitial fibrosis (Fig. 7.14). Vascular changes of hypertension may be superimposed on many other renal diseases. Hypertension is most often combined with diabetes mellitus.
Acute tubular necrosis is common complication of renal hypoperfusion typically found in shock. Inadequate blood supply may lead to hypoxic necrosis, which most prominently affects the proximal tubules (Fig. 7.15). If the patients survive and the blood supply is reestablished the tubules may regenerate. It is worth mentioning that similar tubular necrosis may be caused by numerous nephrotoxins, heavy metals or cytotoxic drugs.
 
Infectious Diseases
Pyelonephritis is a generic term used for renal infections, most often caused by bacteria. Bacteria may reach the kidney hematogenously (descending infection) or through the ureters (ascending infection).
Acute pyelonephritis presents with bacterial spread to the kidneys and a subsequent suppurative inflammation which involves the tubules and spreads to the renal interstitium (Figs 7.16A and B).
Chronic pyelonephritis is a complication of acute infection that has not been cured. It presents with chronic tubulointerstitial inflammation and destruction of tubules. The remaining tubules undergo atrophy and contain eosinophilic casts, which give them the appearance of the thyroid (thyroidization of the renal parenchyma), whereas the blood vessels show secondary narrowing and thickening of their walls, similar to the changes of nephroangiosclerosis (Fig. 7.17).
Cystitis, i.e. the inflammation of the urinary bladder, is a very common bacterial infection.
Acute cystitis presents microscopically with mucosal infiltrates neutrophils (Figs 7.18A and B). Infection may be accompanied by ulceration of the urothelium and hemorrhage.
Chronic cystitis is usually associated with infiltrates of lymphocytes, plasma cells and macrophages in the lamina propria. Longstanding inflammation may be associated with deposition of fibrous tissue in the lamina propria and muscularis.
 
Neoplasms
Benign neoplasms of the kidney and the urinary system in general are much less common than the malignant tumors.
Oncocytoma is the most common benign renal tumor. It is composed of uniform cells which have small round nuclei and abundant eosinophilic cytoplasm (Fig. 7.19). The tumor has an excellent prognosis and rarely, if ever, undergoes malignant transformation.
Malignant neoplasms of the kidneys and the lower urinary system are common. The most important neoplasms are: (a) renal cell carcinoma; (b) Wilms' tumor and (c) urothelial carcinoma of the calices, renal pelvis, ureters, urinary bladder and urethra.
Renal cell carcinoma is a malignant tumor most often originating from the proximal renal tubules. Microscopically it presents most often as a clear cell carcinoma (Figs 7.20A and B). Papillary renal cell carcinomas are less common, but have a better prognosis than clear cell carcinoma.
Wilms' tumor (nephroblastoma) is malignant neoplasm of infancy and childhood. The tumor is composed of immature cells resembling those found in normal nephrogenesis. Three paterns, known as blastemal, stromal and epithelial, are most often recognized (Fig. 7.21).
Urothelial carcinomas most often occur in the urinary bladder but they may originate from any part of the urinary tract lined by urothelium of the kidney to the urethra. Most tumors present as papillary outgrowth, which can be microscopically subdivided into two groups: (a) low grade papillary carcinomas and (b) high grade papillary carcinomas (Figs 7.22A to C). These tumors are initially limited in growth but may become invasive; high grade tumors have a tendency to become invasive carcinomas more often than the low grade tumors.181
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Figs 7.1A and B: Normal urinary system
A. Kidney consists of glomeruli, tubules, stroma and blood vessels. B. Urothelial epithelium. Also known as transitional epithelium, it consists of several layers, including a surface layer of umbrella cells. The thickness of the epithelium varies: it is thick in contracted organs and thin in expanded organs.
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Figs 7.2A and B: Polycystic kidney disease
A. Normal renal parenchyma has been replaced by cysts lined by nondescript simple epithelium derived from dilated tubules and ducts. B. Higher power view shows nondescript cuboidal cells lining the cysts.
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Fig. 7.3: Multicystic renal dysplasia
The solid tissue taken out around the nondescript cysts contains atrophic tubules, fetal glomeruli, stromal connective tissue and cartilage (C).
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Figs 7.4A to C: Acute poststreptococcal glomerulonephritis
A. The glomerulus is hypercellular and contains numerous neutrophils as well as proliferating mesangial and endothelial cells. B. Immunofluorescence microscopy shows widespread immune complex deposits in the glomerulus. C. By electron microscopy the capillary lumen is obliterated by proliferated cells. On the subepithelial surface of the glomerular basement membrane there are deposits of immune complexes forming typical humps (arrows).
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Figs 7.5A and B: Crescentic glomerulonephritis
A. The urinary space between the collapsed capillary loops and the Bowman's capsules contains inflammatory cells admixed to proliferating epithelial cells and strands of fibrin. B. The disease leads to rapid destruction of glomeruli which become replaced by fibrous connective tissue (shown here as blue with the trichrome stain).
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Figs 7.6A and B: IgA nephropathy
A. The glomerulus shows widening of mesangial areas which contain an increased number of mesangial cells. B. Immunofluorescence microscopy shows deposits of IgA in the mesangial areas (arrows).
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Figs 7.7A and B: Lupus nephritis
A. The glomerulus is hypercellular and also segmentally shows thickening of the glomerular basement membranes in the form of so-called ‘wire loops’ (arrows). B. Immunofluorescence microscopy shows widespread deposits of immune complexes along the glomerular basement membranes and in the mesangial areas.
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Figs 7.8A to D: Membranous nephropathy
A. Light microscopy shows diffuse thickening of the glomerular basement membranes without increased cellularity of the glomerulus. B. Deposits of immune complexes along the glomerular basement membrane are accompanied by projections of the basement membrane which is best demonstrated by silver impregnation. C. Immunofluorescence microscopy shows granular (lumpy-bumpy) deposits along the glomerular basement membranes. D. Electron microscopy shows evenly spaced deposits of dense immune complexes on the epithelial side of the basement membrane.
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Figs 7.9A and B: Minimal change disease
A. By light microscopy the glomeruli appear essentially normal, and the glomerular basement membranes are of normal thickness (PAS staining). B. By electron microscopy the only visible change is the fusion of the foot processes of the epithelial cells (arrows).
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Figs 7.10A and B: Focal segmental glomerulosclerosis
A. The middle of the three glomeruli shows sclerosis of the capillary loops at 6 o'clock, whereas the other two glomeruli are essentially normal (PAS stain). B. A portion of the glomerular capillaries is hyalinized (arrow).
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Fig. 7.11: Diabetic nodular glomerulosclerosis
Mesangial areas show nodular widening (arrows).
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Figs 7.12A and B: Amyloidosis
A. Eosinophilic deposits of amyloid have obliterated the normal capillary structure of the glomerulus. B. Electron microscopy shows that amyloid has a fibrillar beaded structure.
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Fig. 7.13: Chronic glomerulonephritis
Only one of the five glomeruli depicted here is still preserved whereas the other four are almost completely hyalinized (arrows). Fibrous tissue is replacing most of the tubules and the remaining tubules are atrophic.
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Fig. 7.14: Nephroangiosclerosis
Hypertension causes vascular changes such as thickening of the arterial walls and narrowing their lumina and atrophy of the tubules.
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Fig. 7.15: Acute tubular necrosis
Necrotic proximal tubules have lost their nuclei and have finely granular amorphous eosinophilic cytoplasm (asterisk). The remaining distal tubules and glomeruli have preserved nuclei.
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Figs 7.16A and B: Acute pyelonephritis
A. In early stages of the ascending infection the tubules contain neutrophils in their lumen. B. In advance stages of the infection the intratubular pus has caused dilatation of tubules and atrophy of the tubular cells. Inflammatory cells are also found in the interstitial spaces.
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Figs 7.17A and B: Chronic pyelonephritis
A. Chronic inflammation has caused destruction of the tubules in the midozone. In the upper part of the figure one may see atrophic tubules filled with proteinaceous casts (thyroidization of the kidney). In the lower part of the figure one may see the preserved glomerulus and tubules which have been spared of destruction. B. At higher magnification one may see that the inflammatory infiltrate consists predominantly of lymphocytes and plasma cells. On the left side one may see the epithelium lining the pyelon.
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Figs 7.18A and B: Cystitis
A. Acute cystitis is evidence by the infiltrates of neutrophils transmigrating through the urothelium. B. Chronic cystitis is characterized by infiltrates of lymphocytes, plasma cells and macrophages in the lamina propria of the urinary bladder.
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Fig. 7.19: Renal oncocytoma
The tumor is composed of oncocytes, i.e. cells that have abundant eosinophilic cytoplasm, and relatively uniform nuclei.
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Figs 7.20A and B: Renal cell carcinoma
A. Clear cell carcinoma is composed of sheets of clear cells that have hyperchromatic nuclei. B. Papillary renal cell carcinoma is composed papillae lined by cuboidal cells which have eosinophilic cytoplasm.
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Fig. 7.21: Wilms' tumor
The tumor is composed of immature cells forming tubules and called epithelial cell (E), forming dense aggregates of hyperchromatic cells, called blastema cell (B), and loosely arranged cells called stromal cells (S).
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Figs 7.22A to C: Urothelial carcinoma of the bladder
A. Papillary carcinoma of low grade malignancy forms papillae by relatively uniform cells. B. Papillary carcinoma of high grade malignancy forms papillae lined by cells that show much more pleomorphism and mitotic activity. C. Invasive urothelial carcinoma is formed of cells that invade the muscle layer of the bladder.