Glomerular Renal Disease

Clinical Manifestation of Glomerular Disease

Hematuria – RBC casts (consists of coagulated RBC in the shape of a tubule; resulting from bleeding into the glomerulus or tubule)

Proteinuria

Oliguria

Azotemia

Edema

Hypertension

Five Clinical Syndromes of Glomerulonephritis

(1) Acute Glomerulonephritis

Hematuria
Proteinuria < 3 gms/24 hours
Hypertension

(2) Nephrotic Syndrome – all symptoms are related to Ý permeability of plasma proteins Þ proteinuria + hypoalbuminemia Þ ß oncontic pressure and edema; and Ý synthesis of proteins including lipoproteins Þ hyperlipidemia

Proteinuria > 3.0 - 3.5 gms/24 hours
Hypoalbuminemia
Edema
Hyperlipidemia

(3) Chronic Glomerulonephritis

Proteinuria
Azotemia
Hypertension
Hematuria

(4) Rapidly Progressive Glomerulonephritis (Despite name Þ subacute signs and symptoms) cresecents and progressive renal failure

Oliguria
Azotemia within 2-12 weeks
Hypertension
Hematuria

(5) Asymptomatic Urinary Abnormalities

Hematuria
Proteinuria

Types of Glomerulonephritis

(1) Acute Post-Streptococcal Glomerulonephritis (Acute Glomerulonephritis)

Clinical Features

Most common in children aged 3 to 8
Follows Streptococcal pharyngitis or pyoderma in 1 to 2 weeks
Hematuria, proteinuria, hypertension—common
Oliguria, edema—less frequent

Pathogenesis (unknown) – immunologically mediated; only certain streptococcal serotypes nephritogenic

Laboratory Features

Classic features of acute glomerulonephritis: hematuria (100%), proteinuria (90%), azotemia (40%)
Hypocomplementemia, antistreptolysin 0 or anti-DNAse B (90-95%)
Throat culture positive (30%); Urine cultures – sterile

Pathology

Light microscopy – diffuse proliferative glomerulonephritis; hypercellular and ß capillary lumen

Electron microscopy – large subepithelial deposits ("humps")

Immunofluorescence microscopy – C3 and IgG in mesangium and capillary wall

Course and Prognosis

Spontaneous resolution – healing without residual in over 95% 2. No specific treatment

(2) Minimal Change Disease (Foot Process Disease, Lipoid Nephrosis, Nil Disease) (Nephrotic Syndrome)

Clinical Features

Full blown nephrotic syndrome

Most common in children 2-4 years of age; 20% of adult idiopathic nephrotic syndrome
No hypertension, hematuria, azotemia

Pathogenesis – unknown

Not immune complex mediated

Proteinuria due to loss of normal anionic charge of glomerular basement membrane (GBM)

Laboratory Features

Complement levels – normal
Hypoalbuminemia, hyperlipidemia

Pathology

Light microscopy – normal
Electron microscopy – effacement or "fusion" of foot processes; GBM normal
Immunofluorescence microscopy – negative

Course and Prognosis

Prompt response to steroid treatment; children have better prognosis than adults; 25% no relapse, 20% infrequent relapse, 20% frequent relapse, 25% steroid dependent, 10% steroid resistant
Long-term prognosis - good

(3) Membranous Glomerulonephropathy (Chronic Glomerulonephritis)

Clinical Features

Most frequent cause of nephrotic syndrome in adults; rare in children.
Nephrotic syndrome – 80%
Hypertension, hematuria – common

Pathogenesis

Immunologically mediated
In situ immune complex formation; cationic antigens localize in subepithelial spaces of anionic GBM

Laboratory Features

Complement levels – normal
No serologic abnormalities in idiopathic variety

Pathology

Light microscopy – no inflammation, thick capillary walls, subepithelial spikes on silver stain; spikes are a proliferation of the GBM between immune complex deposits
Electron microscopy – subepithelial deposits
Immunofluorescence microscopy – IgG, C3, granular deposition along glomerular basement membrane, IgA and IgM less common

Course and Prognosis variable

Spontaneous remission (25%) Þ often younger, women and lack HTN

Persistent proteinuria (25%) Þ often older, men and HTN

Renal failure in 5 years (25%)

Slow decrease in renal function (25%)

Corticosteroids alone – questionable benefit
Corticosteroids combined with cytotoxic drugs may be optimum regimen

(4) Focal Segmental Glomerulosclerosis

Clinical Features

Most frequent cause of nephrotic syndrome in black adults, less common in children
Nephrotic syndrome (70%); Isolated non-nephrotic proteinuria (30%); hypertension; hematuria-frequent

Pathogenesis – unknown

Laboratory Features

Complement levels – normal
No serologic abnormalities

Pathology

Light microscopy – some glomeruli (focal) with sclerosis in portion (segmental) of glomerular tuft
Electron microscopy – some degree of foot process effacement
Immunofluorescence microscopy – focal segmental IgM and C3, nonspecific trapping

Course and Prognosis

Usually progressive proteinuria and loss of renal function

Children and adults similar course – most develop end stage renal disease after 5-20 years

Therapy – 40-50% respond to steroids with remission of proteinuria Þ requires 3-4 months of steriods

(5) Membranoproliferative Glomerulonephritis

Clinical Features – two major morphologic types:

Type I – Older children and adults, Nephrotic syndrome most common presentation
Type II – Younger age of onset, Acute glomerulonephritis or recurrent macroscopic hematuria

Pathogenesis – Immune complex mediated (Circulating immune complexes in 50%)

Laboratory Features

Type I – C3 low; C1q, C4 borderline Þ classic complement pathway

Type II – C3 low; C1q, C4 normal; C3 nephritic factor Þ alternative complement pathway

Pathology

Type I

Light microscopy – mesangial cell proliferation and matrix expansion
Electron microscopy – subendothelial and mesangial deposits
Immunofluorescence microscopy – C3 and immunoglobulins

Type II

Light microscopy – mesangial cell proliferation and matrix expansion

Electron microscopy – diagnostic; homogeneous fusiform electron dense deposits in lamina densa

Immunofluorescence microscopy – C3 in discontinuous linear pattern in GBM; circulating Ab termed nephritic factor (C3 NeF) Þ Ab which binds C3 convertase

Course and Prognosis

Type I – slowly progressive; median survival free of renal failure 9-12 years
Type II – median survival free of renal failure 5-10 years
Therapy – controversial; long-term alternate-day steroids may be beneficial

(6) Goodpasture's Syndrome (Rapidly Progressing Disease)

Clinical Features

Clinical complex of glomerulonephritis and pulmonary hemorrhage due to anti-GBM antibody that cross-reacts with alveolar tissue
More common in males; second to third decade
Hemoptysis initial feature in 70%
Progression to renal failure in weeks to months if untreated

Pathogenesis

Due to binding of IgG to a ₃chain of Type IV collagen

Deposition of anti-GBM antibody with complement activation, neutrophil infiltration, glomerular necrosis

Type IV collagen major component of glomerular and alveolar extracellular matrix

Pulmonary toxins (e.g. smoking, infection) may expose previously sequestered antigens

Laboratory Features – 90-95% have detectable circulating anti-GBM Ab

Iron deficiency anemia common
Complement levels – normal

Pathology

Light microscopy – focal, segmental glomerulonephritis with diffuse crescent formation
Electron microscopy – no electron dense deposits
Immunofluorescence microscopy – diffuse linear deposition of IgG along GBM

Course and Prognosis

Untreated – death or renal failure in 90% at 1 year

Treatment

Plasma exchange, steroids, cytotoxic drugs
Stabilization or improvement in renal function - over 50%

(7) IgA Nephropathy (Bergers Disease)

Clinical Features

Most common form of primary glomerulonephritis worldwide; most common in children, young adults
Two major presentations

(a) Macroscopic hematuria (episodes may recur; often coincident with upper respiratory infection)
(b) Asymptomatic microscopic hematuria and mild proteinuria

Pathogenesis – Immune complex disease; IgA and unknown antigen localized in glomerular mesangium

Laboratory Features

Serum IgA increased in 50% – nonspecific
Complement levels – normal

Pathology

Light microscopy – mesangial enlargement due to increase in cells and matrix
Electron microscopy – electron dense deposits in mesangium
Immunofluorescence microscopy – IgA in mesangium of all glomeruli; C3 and IgG in majority of cases

Course and Prognosis – 20-25% progress to end stage renal disease after 20 years; No proven treatment

(8) Diabetic Glomerulosclerosis

Clinical Features

Most common cause of end stage renal disease in U.S.

Occurs in only 30% of diabetics
Predictors of nephropathy:

Genetic predisposition to hypertension
Poor glycemic control
Glomerular hyperfiltration

Onset after 10-20 years of diabetes
Proteinuria initial manifestation
Nephrotic syndrome and hypertension frequent

Pathogenesis

Hyperglycemia - nonenzymatic glycation of extracellular matrix proteins with consequent accumulation
Glomerular hyperfiltration

Increased glomerular capillary pressure
Hydraulically mediated glomerular injury

Laboratory Features

Complement levels – normal
Bland proteinuria – microscopic hematuria unusual

Pathology

Light microscopy

Thickened GBM, increased mesangial matrix; normal cellularity
Nodules – 20% Intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease – hyaline masses situated in the periphery of the glomerulus

Electron microscopy – no deposits
Immunofluorescence microscopy – generally negative

Course and Prognosis – microalbuminuria progresses to overt proteinuria leading to a decline in GFR

Generally inexorable progression–end-stage renal disease 6-8 years after detection of overt proteinuria
Excellent glycemic control (glycohemoglobin<7.5%) and excellent BP control (ACE inhib.) slow progression

(9) Lupus Nephritis

Clinical Features – clinical manifestations are a function of the organs involved Þ highly variable

SLE – systemic illness, 90% female
Clinically evident renal disease in 70% at initial diagnosis
Depend on nature and extent of renal involvement
Presentations: Acute glomerulonephritis > proteinuria alone > nephrotic syndrome

Pathogenesis

Immunologically mediated
antibody-antigen immune complexes (DNA-antiDNA complexes) – circulating or in situ formation

Laboratory Features

Hypocomplementemia – frequent (remember Þ also seen in acute post streptococcal nephritis)

Circulating immune complexes

Hematuria, proteinuria, azotemia

Pathology

Light microscopy

Mesangial expansion (15%); b.Focal proliferative (25%); c.Diffuse proliferative (50%); d.Membranous (10%)

Electron microscopy – mesangial, subendothelial or subepithelial deposits
Immunofluorescence microscopy – IgG, IgM, IgA, and C3

Course and Prognosis

Variable – asymptomatic urinary abnormalities Þ renal failure

Histologic transitions – 20% Þ from one form to another

Steroids or steroids plus cytotoxic drug beneficial