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GLOMERULONEPHRITIS

Lecturer prof. Yu.R. Kovalev

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DEFINITION AND CLASSIFICATION

Glomerulonephritis is diffuse bilateral immune-mediated glomerular injury

1. Acute

2. Subacute (rapidly progressive)

3. Chronic

Primary – pathologic process is confirmed into the kidneys (poststreptococcal glomerulonephritis or Ig A nephropathy)

Secondary glomerulonephritis is associated with systemic diseases

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COMMON CAUSES1. poststreptococcal acute glomerulonephritis;

2. other postinfective acute nephritic syndroms — following staphylococcal, pneumococcal and viral infections;

3. collagen disorders — systemic lupus erythematosus and periarteritis nodosa;

4. miscellaneous groups — Henoch-Schonlein syndrome, infective endocarditis, hypersensitivity angiitis, and early stages of Goodpasture's syndrome.

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Etiology Histopathology Patho-genesis

Acute (postinfectious) glomerulonephritis –Streptococci, other bacteria

Light: Diffuse proliferative glomerulonephritis Immunofluorescence: IgG; C3, granular pattern

Immune complexes

IgA nephropathy –

In association with viral upper respiratory tract infections; gastrointestinal infection or flu-like syndrome

Light: Mesangioproliferative glomerulonephritis Immunofluorescence: IgA (with or without IgG, C3)

Unknown

Rapidly progressive glomerulonephritis –

Postinfection, lupus erythematosus, Goodposture’s syndrome (if lung hemorrhage), subacute infective endocarditis, shunt infections; idiopathic.

Light: Crescentic glomerulonephritis Immunofluorescence: IgG, IgA; C3 granular pattern

Immune complexes, anti-GBM autoanti-bodies

TYPES OF NEPRITIS

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PATHOGNESIS AND PATHOLOGY OF

POSTSTREPTOCOCCAL GN The streptococcal antigens of nephritogenic strain of -hemolytic strepococcus of group A stimulate the production of antibodies. (M types are 1,2,4,12 a.o.) The antigens and antibodies combine to form immune complexes. These get deposited in the kidney and initiate acute inflammatory reaction in the glomerulus. The kidneys are enlarged. The glomeruli are swollen and show proliferation of the endothelial cells. Capillares of glomeruli and mesangium or infiltrated by polymorphonuclear cells.

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PATHOGENESIS AND PATHOLOGY OF POSTSTREPTOCOCCAL GN

In addition to the proliferation, electron dense deposits are seen under electron microscopy. These are the immune complex deposits. Immunofluorescence microscopy shows a granular pattern of distribution of immune complexes in the glomeruli.

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CLINICAL FEATURES Acute nephritic syndrome is characterised by hematuria with or without dysmorphic red cells, red blood cell casts, proteinuria, oliguria, hypertension, fluid retention and edema. Acute renal failure sometimes may occur.

The illness starts about 10 days after streptococcal pharyngitis; less often after skin lesions (impetigo). In this case latent period is more prolonged and consists 2 weeks.

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CLINICAL FEATURES It is more common in children but can occur in any age. Both sexes are affected. The onset is often abrupt with puffiness of the face, oliguria, reddish smoky urine, hypertension, and edema. Severity of the disease is variable. Mild cases may go unnoticed (subclinical type). Severe cases present with life-threatening complications like hypertensive encephalopathy, acute left ventricular failure or acute renal failure.

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URINE EXAMINATIONUrine volume is reduced, it is reddish-brown and contains protein. At this stage the specific gravity is normal or raised. Numerous red cells are seen. The presence of red cell casts indicates active glomerulonephritis.

After a variable period, the activity of the disease ceases and the urine output and renal functions improve. Urinary abnormalities also clear up. Though erythrocytes and casts disappear promptly, microhematuria and proteinuria may persist for up to 6 months.

The blood pressure promptly returns to normal in most cases with recovery.

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BLOOD EXAMINATIONThe blood chemistry is altered depending on the severity of the disease. The antistreptolysin O (ASO) titre is significantly elevated and this suggests recent streptococcal infection. The serum complement levels are reduced during the active stage of the disease.

During the oliguric phase elevation of creatinine level may be evident but it usually rapidly falls to normal values.

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DIAGNOSISAny patient presenting with puffiness of face, oliguria, hematuria hypertension and edema should be investigated to exclude acute nephritic syndrome.

Diagnosis should be confirmed by urinary findings and biochemical examination of blood. Etiological diagnosis is made by estimating serum complement levels, isolation of the infection agent, estimation of ASO titre and if necessary renal histology.

Reduction in serum complement levels and demonstration of immune complexes in histological specimens by immunofluorescence microscopy are diagnostic of immune complex nephritis.

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DIAGNOSISRenal biopsy is indicated under the following conditions: •failure rises promptly (rapidly progressive glomerulonephritis); •presence of hypertension, azotemia and hematuria for a long time (1 month and more); •possibility of systemic diseases like vasculitis and collagen diseases.

It is contraindicated in cases of bleeding disorders, thrombocytopenia, uncontrolled hypertension.

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COURSE AND PROGNOSISIn 90 per cent of children the recovery is uneventful and complete. The proteinuria and microscopic hematuria may persist for a few weeks or months. Some children develop nephrotic syndrome or chronic glomemlohephritis. Chronic renal failure may develop in 2-5 per cent of cases the acute phase. During recovery any intercurrent infection may precipitate transient exacerbation of the clinical and urinary abnormalities.

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COURSE AND PROGNOSISIn adults uneventful recovery occurs only in 50 per cent of subjects. Many develop renal failure, hypertension, nephrotic syndrome or chronic glomerulonephritis slowly progressing to renal failure.

Less than 5% of adults will develop a rapidly progressive glomerulonephritis, and a smaller percentage will progress to end-stage renal disease.

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MANAGMENT

Bed rest during 3-4 weeks or more (persistent hematuria and/or proteinuria)Restriction of fluid consists 500 ml + volume of diuresis of previous dayRestriction of NaCl – 0,5 – 2,0 g a dayProtein restriction - 0,5 g a day for 3-4 weeksAdequate nutrition (more carbohydrate and fat calories)

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MANAGMENT

Moderate or severe arterial hypertension requires ACE inhibitors or angiotensin II receptor blocking agents

Hard edema – diuretics (lasix, etacrinic acid)

Acute renal failure – hemodialysis or peritoneal dialysis

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IgA NEPHROPATHY

IgA nephropathy (Berger's disease) is a primary renal disease of IgA deposition in the glomerular mesangium. IgA nephropathy may also be associated with hepatic cirrhosis, celiac disease, and infections such as with CMV; gastrointestinal adenocarcinoma as well

IgA nephropathy is the most common form of acute glomerulonephritis in the United States and is even more prevalent worldwide, particularly in Asia. It is most commonly seen in children and young adults, with males affected two to three times more commonly than females.

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CLINICAL FEATURES •nephritic syndrome - gross hematuria often developing in 24 – 48 h after pharyngeal or gastrointestinal infection, vaccination or strenuous exercises

•gastrointestinal symptoms (10%),

•flu-like illness (15%)

•no significant latent period

•nephrotic syndrome is rare

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The urine becomes red or cola-colored 1-2 days after onset. In contrast to postinfectious glomerulonephritis, this feature has been called "synpharyngitic hematuria" since there is no significant latent period. Other findings include asymptomatic microscopic hematuria as an incidental finding and the nephroric syndrome. Approximately one-third of patients will experience a clinical remission.

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DIAGNOSIS

The serum IgA level is increased in up to 50% of patients, and for that reason a normal serum IgA does not rule out the disease. Serum complement levels are usually normal, and renal biopsy is the standard for diagnosis. Glomeruli show a focal glomerulonephritis with diffuse mesangial IgA deposits and proliferation of mesangial cells.

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COURSE AND PROGNOSISForty to 50 percent of patients will have progressive renal insufficiency. The remainder will show chronic microscopic hematuria and a stable serum creatinine. The most unfavorable prognostic indicator is proteinuria > 1 g/d. Others include hypertension, persistent microscopic hematuria and proteinuria, glomerulosclerosis, and abnormal renal function.

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MANAGEMENTTreating of acute nephritic syndrome is the same as an acute poststreptococcal glomerulonephritis. In a case of severe form, or nephrotic syndrome, or rapidly progressive variant high doses of glucocorticoids sometimes with cytotoxic agents have to be prescribedIn patients with recurrent tonsillitis a tonsillectomy may reduce proteinuria and hematuria

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Rapidly progressive glomerylonephritis (RPGN)

Extracapillary (crescentic) GNHematuriaNephritic urinary sedimentSubnephrotic proteinuriaRapidly progressive renal failure over weeks (with or without pulmonary hemorrage)Hipertension is unusual (20% on cases)Serologic marcers – circulation anti-GBM antibodiesPrognosis for renal function is poor (without immunosuppressive therapy greates then 80% developed ESRD within 1 year.

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Treatment of RPGN

Plasmapheresis

Pulses Prednisolone 1-2 g/d for 3 day then1mg/kg/d

Ciclophosphamide 2-3 mg/kg/d

Dialysis

Renal transplantation

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CHRONIC NEPHRITISChronic glomerulonephritis is characterized chiefly by persistent urinary abnormalities (proteinuria, hematuria) and by slowly progressive impairment of renal function, eventuating by hypertension, contracted granular kidneys and end-stage renal failure.

Evolution of chronic glomerulonephritis varies considerably (10 – 20 years or more) depending upon the nature of the disease and the presence or absence the complications, especially hypertension.

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CLINICAL FORMS OF CHRONIC NEPHRITIS

•Hypertensive

•Nephrotic syndrome

•Miscellaneous

•Latent

•Terminal (end stage)

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NEPHROTIC SYNDROME

Chronic glomerulonephritis is often assotiated with nephrotic syndrome

Nephrotic syndrome - massive proteinuria (more than 3.5 g in 24 h. in adults). It is often associated with edema, hypoalbuminemia (less than 30 g/l), hyperlipidemia and lipiduria.

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COMMON CAUSES OF NEPHROTIC SYNDROME

•Primary glomerulonephritis or associated with allergy, Hodgkin's disease, NSAIDs, systemic lupus erythematosus, Henoch-Schonlein syndrome a.o.•Congenital nephrotic syndrome, •Amyloidosis•Diabetic nephropathy

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PATHOGENESIS AND PATHOLOGY

Minimal-change glomerular lesions or membranous nephropathy or focal segmental glomerular sclerosis usually associated with isolated nephrotic syndrome with bland urine sedimentsMesangiocapillary and mesangioproliferative changes as a rule accompanied by mixed nephrotic/nephritic syndrome with active urine sediments

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PATHOGNESIS AND PATHOLOGY The profound proteinuria due to increase in the glomeruler capillary permeability is responsible for most of the clinical manifestations of nephrotic syndrome. If the glomerular damage is severe, albumin and immunoglobulins appear in the urine, whereas with mild damage, only albumin escapes in urine. The former is called nonselective proteinuria and the latter, selective proteinuria. Thus, assessing the selectivity of proteinuria helps in assessing the degree of damage to the glomerular filtering mechanism.

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PATHOGNESIS AND PATHOLOGY

The loss of protein in the urine results in hypoalbuminemia. However, poor intake, defective synthesis, and abnormal catabolism can exaggerate this phenomenon. Reduction in serum albumin results in the shift of fluid from the intravascular to the extravascular compartment to produce edema and arterial hypotension. In addition to the levels of serum cholesterol and lipids increase on account of associated defects in lipid metabolism.

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CLINICAL FEATURES OF NEPHROTIC SYNDROME

Initially edema presents in the dependent areas of the body such as the lower extremities; however, it can become generalized. Patients can experience dyspenea due to pulmonary edema, pleural effusions, and diaphragmatic compromise with ascites. Complaints of abdominal fullness may also be present in patients with ascites.

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CLINICAL FEATURES OF NEPHROTIC SYNDROME

Patients may show signs and symptoms of infection more frequently than the general population owing to loss of immunoglobulins and certain complement moieties in the urine

Patients with serum albumin less than 2 g/dL can become hypercoagulable. Nephrotic patients have urinary losses of antithrombin III, protein C, and protein S and increased platelet activation. Patients are prone to renal vein thrombosis and other venous thromboemboli, like pulmonary embolism.

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DIAGNOSIS OF NEPHROTIC SYNDROME

•Persistent proteinuria and/or hematuria

•Unexplained anemia and/or elevated blood uric nitrogen and creatinine

•Bilateral small kidneys

•Proves of secondary hypertension

•Clinical exacerbations of GN triggered by pharyngitis (synpharyngitic) or other infections

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DIAGNOSIS OF CHRONIC NEPHRITIS

•Persistent proteinuria and/or hematuria

•Unexplained anemia and/or elevated blood uric nitrogen and creatinine

•Bilateral small kidneys

•Proves of secondary hypertension

•Clinical exacerbations of GN triggered by pharyngitis (synpharyngitic) or other infections

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DIAGNOSIS OF CHRONIC NEPHRITIS

Renal biopsy reveals

• variable combinations of proliferative, membranous and sclerotic changes

• arteriolosclerosis induced by secondary hypertension

• additional findings: tubulointersticial inflammation and scarring

Glomerular hypertension and hyperfiltration through remnant functioning nephrons stimulate progression to ESRD

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MANAGEMENT OF CHRONIC NEPHRITIS

The daily total dietary protein intake should replace the daily urinary protein losses so as to avoid negative nitrogen balance. Protein malnutrition often occurs with urinary protein losses greater than 10 g/d.

Protein restriction to 0.6 g/kg/d in patients with a GFR < 25 mL/min prior to starting dialysis is recommended.

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MANAGEMENT OF CHRONIC NEPHRITIS

Dietary salt restriction is essential for managing edema; however, most patients also require diuretic therapy. Commonly used diuretics include thiazide and loop diuretics. Both are highly protein-bound. With hypoalbuminemia, diuretic delivery to the kidney is reduced, and patients often require large doses. The combination of loop and thiazide diuretics can potentiate the diuretic effect. This may be needed for patients with refractory fluid retention associated with pleural effusions and ascites.

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MANAGEMENT OF CHRONIC NEPHRITIS

Dietary management of hypercholesterolemia and hypertriglyceridemia in patients with nephrotic syndrome is of little value; however, dietary modification and exercise should be advocated. Aggressive pharmacologic treatment should be pursued.

Patients with renal vein thrombosis and recurrent thromboemboli require indefinite anticoagulation.