Pathology Education

General Pathology 601 for Dental Students

Pathology of Kidney and Collecting System 1
Section 1 & Section 2

Davis Massey, MD, PhD, DDS
Hematology/Coagulation Fluids & Renal Pathology
Gateway Bldg, 6th floor
Office: 804-828-9739 x406
FAX: 804-828-9749
damassey@mail2.vcu.edu

Objectives
Upon completion of this lecture you will be able to:

Describe the five syndromes clinically present in glomerular diseases.
List three areas of immune complex localization seen in most patients.
Recognize the etiology and pathogenesis, and clinical manifestations of primary glomerular diseases.
Recognize the etiology and pathogenesis, and clinical manifestations of renal manifestations in systemic disease.

Important Terms--definitions
Diffuse
Focal
Segmental
Global
Proliferative
Exudative
Membranous
Mesangial
Crescent
Glomerulosclerosis
End stage renal disease

Pathology of Glomerular Disorders

About 80,000 patients in the U.S. require hemodialysis for end stage renal failure (ESRD). In two-thirds of these patients ESRD resulted from a glomerular disease. The major clinical manifestations of glomerular injury include proteinuria, hypoalbuminemia, edema, hyperlipidemia, and lipiduria. Glomerular injury is usually acquired but in rare cases may have a congenital (hereditary) etiology. Acquired glomerular disease may develop in the kidney (primary renal disease) or as a secondary manifestation of a systemic disease such as lupus erythematosus (secondary renal disease).

Clinical Manifestations of Glomerular Injury

The body has a limited ability to respond to glomerular injury. Therefore, all glomerular diseases clinically present as one of the following syndromes:

1) Nephrotic Syndrome - The nephrotic syndrome is not a disease; it is a group of signs and symptoms commonly seen in patients with glomerular diseases that are characterized by a marked increase in capillary wall permeability to serum proteins rather than (or sometimes in addition to) glomerular inflammatory changes. The primary abnormality in nephrotic syndrome is the excretion of large amounts (> 3.5 gm per day) of protein in the urine. Other manifestations secondary to proteinuria include hypoalbuminemia, edema, hyperlipidemia, and lipiduria. In two-thirds of adults and most children, the nephrotic syndrome is idiopathic and a manifestation of one of three types of primary glomerular disease: minimal change nephrotic syndrome (MCNS) or its variants, membranous glomerulonephritis, or membranoproliferative glomerulonephritis (MPGN).

2) Acute Glomerulonephritis - Abrupt onset of hematuria (> 5 RBC's/high-powered microscope field) and proteinuria, usually associated with some impairment in renal function. Retention of salt and water with hypertension and edema is common. The etiology is usually an acute glomerular inflammatory process.

3) Rapidly Progressive Nephritic Syndrome - Abrupt onset of hematuria, proteinuria, anemia, and rapidly progressing renal failure. Death may rapidly ensue without proper diagnosis and treatment. Goodpasture’s syndrome and diffuse crescentic glomerulonephritis are the most common causes, although this pattern of presentation may be seen with lupus nephritis and other diseases.

4) Chronic Nephritic Syndrome - Slowly developing renal failure accompanied by proteinuria, hematuria, and hypertension. Many renal diseases present in this manner, including lupus nephritis, focal segmental glomerulonephritis, IgA nephropathy, renal amyloidosis, diabetic glomerulosclerosis, etc.

5) Recurrent or Persistent Hematuria - Insidious or abrupt onset of gross or microscopic hematuria with little or no proteinuria and no evidence of other features of the nephritic syndrome. IgA nephropathy commonly presents in this manner, and it may be seen in patients with focal segmental glomerulosclerosis and other diseases.

General Features of Glomerular Pathology

An understanding of glomerular disease requires an understanding of the unique terminology of this area of pathology. The most important terms are defined below.

Pathophysiology of Glomerular Injury
Most glomerular diseases are mediated by the immune system. In most cases of immune injury, complexes of antigen and antibody (i.e., immune complexes) appear in the glomerulus as discontinuous, or granular, deposits of immunoglobulin, and/or complement. In the laboratory, immune deposits are identified by immunofluorescence microscopy and electron microscopy. With these techniques the location of the immune complexes within the glomerulus is an important clue to the diagnosis of the disease process. Three areas of immune complex localization are seen in most patients.

Within the glomerular mesangium, as in IgA nephropathy, and early lupus nephritis (Class II or III).
Along the subendothelial surface of the capillary wall as seen in Type I membranoproliferative glomerulonephritis and some forms of lupus nephritis.
Along the subepithelial surface of the capillary wall, as in membranous nephropathy and the so-called subepithelial humps in post-streptococcal glomerulonephritis.

Rare patients develop glomerulonephritis due to the development of antibody against glomerular basement membrane antigens, which results in a continuous, linear, ribbon-like pattern of staining along all glomerular capillary walls by immunofluorescent microscopy.

Several glomerular diseases (minimal change nephrotic syndrome and idiopathic, rapidly progressive glomerulonephritis) are believed to be immunologically mediated but do not have visible immune deposit formation in glomeruli. A few glomerular diseases develop through non-immune mechanisms of injury. Common terms used to describe glomerular pathologic diseases include:

Diffuse - Disease process affecting the vast majority (>75%) of glomeruli.
Focal - Disease process affecting less than the majority (<75%) of glomeruli.
Segmental - Process affecting only part of a glomerulus.
Global - Process affecting the entire glomerulus.
Proliferative - More cells than normal in glomerulus. Implies multiplication of in situ glomerular cells. Endothelial and mesangial cells, principally the latter.
Exudative - More cells than normal in glomerulus implying inflammatory cells -- neutrophils and monocytes.
Membranous - A process affecting principally the glomerular basement membrane, hence, membranoproliferative means membranous thickening and cellular proliferation.
Mesangial - Pertaining to the mesangium.
Crescent - A lesion composed of cellular and/or fibrous tissue proliferation which fills all of part of Bowman's space.
Glomerulosclerosis - "Scarring" of a glomerulus due to any chronic process, including vascular disease.
End stage renal disease (chronic glomerulosclerosis) – Chronic renal failure resulting from a renal disease. Nearly all of the glomeruli show glomerulosclerosis and there is scarring of the interstitium (interstitial fibrosis) with tubular atrophy. Proteinuria and variable hematuria occur. Death results from uremia unless dialysis or renal transplantation is undertaken.

Primary Glomerular Diseases

Glomerular Diseases with Nephrotic Syndrome

Minimal Change Disease (Lipoid nephrosis, foot process disease)

Age, Incidence and Epidemiology – Children 1-8 years and adults in 2^nd-3^rd decade. Represents 80% of childhood nephrotic syndrome and 20% of adult nephritic syndrome.
Etiology and pathogenesis - Idiopathic etiology in majority of cases. Pathogenesis is loss of net negative charge on capillary basement membrane.
Clinical Manifestations - Nephrotic syndrome, may be severe. History of recent URI in 30%. Association with Hodgkin’s lymphoma in some patients.
Clinical Laboratory Findings - Heavy proteinuria with minimal or only modest urinary sediment (cells and casts).
Anatomic Pathology – Normal light microscopy. Foot process fusion on electron microscopy.
Course & Prognosis – Most children show complete remission with steroid treatment. Adults are more resistant to steroid therapy and have a higher incidence of complications.

Focal Segmental Glomerulosclerosis (FSGS)

Age, Incidence and epidemiology - 80% occur before 35 years. Constitutes about 10-15% of cases of nephrotic syndrome in childhood.
Etiology and Pathogenesis - Idiopathic in majority of cases. Chronic ureteral reflux or heroin abuse in some patients. Clinical Manifestations - Nephrotic syndrome with many patients showing hematuria, hypertension, and/or renal insufficiency. Clinical Laboratory Findings - Proteinuria with or without hematuria. Anatomic Pathology – Focal and segmental sclerosis initially, progressing to global sclerosis of the glomerulus.
Course & Prognosis - Slowly progressive with approximately 25% of patients developing renal insufficiency in 5 years, and 50%-80% within 10 years. Usually steroid resistant. Recurrence after renal transplantation is very common.

Membranous Glomerulonephritis (MGN)

Age , Incidence and Epidemiology – Most common in 4th-6th decade, approximately 50% of adult nephrotic cases (most common cause of nephrotic syndrome in adults). Occasionally seen in children.
Etiology and Pathogenesis – Majority of cases idiopathic. Associated conditions: Carcinoma, chronic infections, heavy metal exposure, drugs. Clinical Laboratory Findings - Nonselective proteinuria ± hematuria. Clinical Manifestations - Nephrotic syndrome in most patients + microscopic hematuria. Systemic disease may be present, especially colon and lung carcinoma. Renal vein thrombosis is a common complication (50%). Anatomic Pathology – Thickened basement membranes with subepithelial deposits of IgG and C3 complement. Four pathologic stages.
Course & Prognosis – Good prognosis in children, 20-30% of adults progress to ESRD in a few years in spite of steroids.

Membranoproliferative Glomerulonephritis (MPGN), Type I

Synonyms - Mesangiocapillary glomerulonephritis
Age, Incidence and Epidemiology - Children and young adults (5-30 years), Slight predominance of female patients. Etiology and Pathogenesis – Immune complex disease of uncertain pathogenesis. Associated conditions: Chronic infections (especially hepatitis C), cancer, heroin abuse, SLE, etc. Clinical Manifestations – Usually nephrotic syndrome, less often acute nephritic syndrome. Recent history of URI in many patients. Hypertension and/or renal insufficiency may occur. Clinical Laboratory Findings – Decreased serum complement levels. Hepatitis C serology should be obtained. Anatomic Pathology - Glomerular hypercellularity with capillary basement membrane thickening and splitting. Subendothelial deposits of C3 complement and sometimes IgG.
Prognosis – Progressive deterioration of renal function; short remissions may occur early in course. Many patients develop end-stage renal insufficiency within 10 years.

Glomerular Diseases with Acute Nephritis

Acute Proliferative Glomerulonephritis

Synonyms - Acute post-streptococcal (post-infectious) GN.
Age, Incidence and Epidemiology - Peak incidence in children ages 3-14, declines with age. Usually occurs post-group A streptococcal infection (streptococcal pyoderma or impetigo in Southern states, pharyngitis in North), usually with type 12. Also reported with other infections.
Etiology and Pathogenesis - Immune complexes and planted bacterial antigens with activation of alternative complement pathway. Clinical Manifestations – Abrupt onset with oliguria, hematuria or tea-colored urine, edema, hypertension, and eventually renal failure 1-4 weeks post-infection. Edema, malaise, hypertension, headache, and gastrointestinal symptoms are common. Clinical Laboratory Findings – Urinalysis usually reveals signs of glomerular inflammation with proteinuria, RBC’s, WBC’s and casts. RBC casts are frequent. Positive streptococcal serology and decreased C3 complement. Beta-hemolytic streptococci are detected by culture in 25% of untreated patients. Anatomic Pathology – Enlarged, hypercellular glomeruli with cell proliferation and acute inflammatory cells. Subepithelial deposits of IgG and C3 complement in coarsely granular ("lumpy-bumpy" or "hump-like") pattern along capillary loops.
Prognosis – Generally good prognosis although rare patients die of renal failure and some have persistent disease.

Anti-Glomerular Basement Membrane Disease (Goodpasture’s Syndrome)

Age, Incidence and Epidemiology - 2nd-4th decades, usually males.
Etiology and Pathogenesis - The GBM and alveolar basement membrane becomes antigenic. Deposited antibodies activate complement system and damage membranes. Clinical Manifestations – Hemoptysis with coincident or subsequent acute renal failure. Clinical Laboratory Findings – Anti-GBM antibodies in 90% cases. Anatomic Pathology – Crescents in >50% of glomeruli. Diffuse, linear IgG outlining capillary loops.
Prognosis – 90% progress to end-stage renal insufficiency in 1-2 years. Prognosis may depend on pulmonary complications. Frequently recurs after renal transplantation.

Glomerular Diseases with Primary Hematuria

IgA Nephropathy (Berger’s Disease)

Etiology and Pathogenesis - Mesangial deposits of immune complexes composed predominantly of IgA. Activation of complement system. Most common primary glomerular disease. Age, Incidence and Epidemiology – Mostly adolescents and young adults with a male bias. Clinical Manifestations - The classic presentation is gross hematuria occurring coincidentally with or immediately following (24-48 hours), a viral upper respiratory infection, flu-like illness, gastrointestinal syndrome, or other infectious prodromes. Many patients have subsequent intermittent episodes of gross hematuria, while others have only microscopic hematuria. Pathology – Focal and segmental glomerular mesangial proliferation, with IgA deposits. Clinical Laboratory Findings – Increased serum IgA. Normal C3 complement.
Prognosis – Generally benign but about 20% progress to renal insufficiency in 10 years. Frequently recurs after renal transplantation.

Renal Manifestations of Systemic Disease

Renal Manifestations of SLE (Lupus Nephritis)

Age, Incidence and Epidemiology - Relatively common, multisystem disease. Strong female bias (10:1, F:M), particularly among young black individuals. Pathogenesis - Precipitating cause is unknown, but considered to be an autoimmune disorder in which denatured DNA functions as the antigen. Clinical Manifestations - May present either as nephritis or nephrotic syndrome. Clinical Laboratory Findings – Variable proteinuria. Hematuria in severe cases with red and white blood cells, hyaline, granular, and broad casts ("telescoped" urinary sediment). Decreased serum complement levels, false positive test for syphilis, antinuclear antibodies, other autoantibodies (DNA, RNA, nucleoprotein, rheumatoid factor, blood cells, etc.). Anatomic Pathology – 5 types by WHO Classification
Prognosis – Renal failure in about 40% of patients. Related to histologic sub-class. Crescent formation more ominous. Transformation from one class to another not uncommon.

Diabetic Glomerulosclerosis (Kimmelstiel-Wilson Syndrome)

Age, Incidence and Epidemiology – Young adults to elderly, develops about 20 years after onset of diabetes mellitus. Most common glomerular disease. Etiology and Pathogenesis - Pathophysiology is poorly understood but probably multifactorial. Found in >20%-40% of patients with type I, insulin-dependent diabetes mellitus in approximately 20 years, and in 20%-30% of patients with type II DM. Clinical Manifestations - Main symptom is proteinuria, sometimes with full-blown nephrotic syndrome. Microscopic hematuria and hypertension may develop. Hypertension and retinopathy may be present. Clinical Laboratory Findings – Microalbuminuria is an early sign of diabetic nephropathy, usually about 10 years after onset of disease. Gross Pathology – Small, contracted kidneys with granular surface. Renal biopsy – Diffuse glomerosclerosis with marked thickening of capillary basement membranes initially (diffuse diabetic glomerulosclerosis), later becomes nodular (nodular diabetic glomerulosclerosis, Kimmelstiel-Wilson kidney).
Prognosis – Gradual progression to ESRD. Commonly recurs after renal transplantation.

Renal Amyloidosis

Age, Incidence and Epidemiology – AL amyloidosis - Older individuals with a male predominance. AA amyloidosis – Adults. Etiology and Pathogenesis - A disorder of protein metabolism characterized by extracellular deposition of amyloid - a beta pleated structure of proteinaceous material. Types of amyloidosis:
- Primary amyloidosis – Amyloid is derived from light chain of immunoglobulin molecule (AL amyloidosis). Usually associated with multiple myeloma.
- Secondary amyloidosis – Amyloid is derived from serum amyloid protein (AA amyloidosis). Associated with chronic infectious diseases (i.e., TB, osteomyelitis, leprosy) and chronic inflammatory diseases (i.e., rheumatoid arthritis, ankylosing spondylitis).
Clinical Manifestations – Proteinuria, often with nephrotic syndrome. Hypertension is usual. Clinical Laboratory Findings – Proteinuria. Monoconal light chain may be present in AL amyloidosis. Gross Pathology – Large pale kidneys with smooth and even surface. Indistinct corticomedullary junction. Anatomic Pathology – Light Microscopy: Amyloid deposited first in mesangium, small vessels, and later in glomerular capillary wall. May be nodular in configuration. "Apple" green birefringence of vessels and glomeruli when stained with Congo Red and polarized.
Prognosis – Usually progresses to renal failure. If underlying cause is eradicated in secondary amyloidosis (e.g. cure of TB), improvement may occur. Renal failure is common cause of death in primary amyloidosis. Poor post-transplant survival.

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Updated March 22, 2007