My Clinical Notes

Acute nephritic syndrome

• Haematuria, azotaemia, variable proteinuria, oliguria, oedema and hypertension
• Causes;
  • Primary;
    • Poststreptococcal glomerulonephritis
    • Rapidly progressive glomerulonephritis
  • Secondary
    • Henoch-Schonlein purpura
    • SLE
    • PAN
    • Bacterial endocarditis

 

Nephrotic syndrome

• Greater than 3.5g of proteinuria, hypoalbuminaemia, hyperlipidaemia, lipiduria

 

Glomerulonephritis

The various types of glomerulonephritis are characterised by one of more of four basic tissue reactions;

• Hypercellularity
  • Increased number of cells in the tufts
  • Can be associated with;
  • Cellular proliferation of mesangial or endothelial cells
• Leukocyte infiltration
  • Formation of crescents – accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes
  • This epithelial cell proliferation occurs following an immune/inflammatory injury. Fibrin seems to play a role in eliciting the crescent response
• Basement membrane thickening
  • Best seem as thickening of the capillary walls, seen with PAS staining
  • Can be due to;
    • Deposition of amorphous material such as immune complexes or amyloid
    • Proper thickening of the basement membrane as occurs in diabetic glomerulosclerosis
• Hyalinisation and sclerosis
  • Hyalinisation denotes accumulation of eosinophilic material composed of plasma proteins which have been extruded from the circulating plasma into the glomerular structures
  • This change contributes to the obliteration of the capillary lumen of the glomerular tuft
  • Hyalinisation results as a consequence of endothelial or capillary wall damage

 

Pathogenesis

• Immune mechanisms underlie most forms of primary glomerulonephritis and many of the secondary glomerular disorders
• There are two forms of antibody-associated injury
  • Antibodies reacting in situ within the glomerulus either with intrinsic glomerular antigens or molecules planted in the glomerulus
  • Deposition of circulating immune complexes in the glomerulus

 

In situ Immune complex deposition

• In this form of injury antibodies react directly with intrinsic tissue antigen or ‘antigens’ planted in the glomerulus from the circulation

 

Anti-GBM Antibody-induced nephritis

• Induced in rats by immunising with rabbit- anti- rat kidney antibody
• Antibodies are directed against normal components of the GBM
• Results in diffuse linear pattern or antibody binding
• This occurs in Goodpasteur’s disease where there is nephritis and lung disease due to antibodies which recognise the non-collagenous domain of the a3-chain of collagen type IV
• This type of injury accounts for 5% of glomerular nephritis cases

 

Heymann Nephritis

• Induced in rats by immunising with an antigen contained within preparations of proximal tubule brush border
• The rats develop antibodies to this antigen and a membranous glomerulopathy resembling that of human disease
• Characterised by the presence of numerous electro-dense deposits alone the subepithelial aspect of the basement membrane
• The pattern of immunofluoresence is granular rather than linear
• Disease results from the binding of antibody to antigen located on the basal surface of visceral epithelial cells and cross reacting with the brush border antigen used in the initial experiments
• Antibody binding to glomerular epithelial cell membrane is followed by complement activation and then shedding of the immune aggregates from the cell surface to form the characteristic subepithelial deposits

 

Antibodies against planted antigens

• Planted antigens include cationic molecules that bind to glomerular amionic sites, DNA, nucleosomes and other nuclear proteins, bacterial products, aggregated proteins such as aggregated immunoglobulin and immune complexes
• Causes a granular immunofluorscent staining

 

Circulating Immune complex nephritis

• Caused by trapping of circulating antigen-antibody complexes within the glomerulus
• Antibodies are not specific for components of the glomerulus
• May be against endogenous antigens such as in SLE or against infectious components
• Such as;
  • Streptococci
  • Surface antigen of Hep B virus
  • Hep C virus antigen
  • Treponema pallidum
  • Plasmodium falciparum
  • Tumours may also cause immune complex mediated nephritis
• Glomerular lesions consist of leukocytic infiltrate and proliferation of mesangial and endothelial cells
• Results in granular deposits in the along the basement membrane or in the mesangium
• Once deposited they may be degraded by neutrophils and macrophages and the inflammatory reaction subsides. This can occur in post-streptococcal glomerulonephritis
• Highly cationic immunogens tend to cross the basement membrane and achieve a subepithelial location. Highly anionic molecules are excluded from the GBM and are trapped subendothelially. Molecules that are more neutral tend to accumulate in the mesangium

 

Antibodies to glomerular cells

• Direct binding of antibody to components of the glomerulus can be cytotoxic
• Antibodies to mesangial cells may cause mesangiolysis folled by proliferation whereas antibodies to endothelial cells may cause injury and intravascular thrombosis and antibodies to epithelial components may cause proteinuria

 

Cell-mediated immunity in glomerulonephritis

• Suggested by the presence of activated macrophages and T cells and their products in the glomerulus in some forms of human and experimental glomerulonephritis, in vitro and in vivo evidence of lymphocyte activation on exposure to antigen in human and experimental glomerulonephritis, abrogation of glomerular injury by the deletion of T cells and successful attempts to transfer disease by T cells in experimental models

 

Epithelial cell injury

• Can be achieved by antibodies, toxins or cytokines
• Results in changes such as effacement of foot processes, vacuolisation, retraction and detachment of cells form the GBM and functionally by proteinuria

 

Mediators of glomerular damage

Cells

• Neutrophils and monocytes infiltrate due to activation of complement and by Fc mediated adherence and activation. Release proteases, oxygen-derived free radicals and arachidonic acid metabolites which contribute to reductions in GFR
• Macrophages, T cells and NK-T cells release biologically active mediators
• Platelets aggregate in the glomerulus
• Resident glomerular cells particularly mesangial cells can be stimulated to produce, reactive oxygen species, cytokines, chemokines, growth factors, eicosanoids, nitric oxide and endothelin

Soluble mediators

• Complement
• Eicosanoids, nitric oxide, angiotensin and endothelin are involved in haemodynamic changes
• Cytokines such as IL-1, TNFalpha
• Chemokines such as MCP-1 and RANTES
• Growth factors such as PDGF are involved in mesangial cell proliferation. TGF-b and FGF are critical for ECM deposition and hyalinisation
• The coagulation system – fibrin may be involved in crescent formation

 

Mechanisms of progressive in glomerular disease

• Once any disease, glomerular or otherwise, destroys sufficient nephrons to reduce the GFR to 30-50% of  normal, progression to end-stage renal failure occurs at a fairly constant rate
• The two main histological characteristics of progressive renal damage are focal segmental glomerulosclerosis and tubulointerstitial necrosis

 

Focal segmental glomerulosclerosis

• Is due to an adaptive change that occurs in the unaffected glomeruli of diseased kidneys
• In rats subjected to a subtotal nephrectomy there is compensatory hypertrophy of the remaining glomeruli to maintain renal function but proteinuria and glomerulosclerosis soon develop
• The glomerular hypertrophy is associated with haemodynamic changes, including increases in glomerular blood flow, filtration and transcapillary pressure often with systemic hypertension
• Sequence of events is due to endothelial and epithelial injury, increased glomerular permeability to proteins, accumulation of protein in the mesangial matrix and eventually segmental and then global sclerosis of the glomeruli
• TGF-b plays a particular role in sclerosis
• Treatment involves inhibition of the renin-angiotensin system
• Contributing to progressive injury is the inability of mature podocytes to proliferate after injury. This leads to abnormal protein filtration and loss of structural support for the glomerular capillary walls. This may lead to a segmental loop dilation incompletely opposed intracapillary pressures and eventual sclerosis of this segment.

 

Tubulointerstitial fibrosis

• Contributes to immune and non-immune glomerular diseases such as diabetic nephropathy
• There is a better correlation in decline in renal function with tubulointerstitial damage compared with glomerular injury
• Tubulointerstitial fibrosis may be due to ischaemia of tubule segments downstream of sclerotic glomeruli, acute and chronic inflammation of the interstitium, damage or loss of the peritubular capillary blood supply
• Proteinuria may also cause direct injury to and activation of tubular cells. Activated tubular cells express adhesion molecules and produce pro-inflammatory cytokines which contribute to interstitial fibrosis

 

Nephrotic Syndrome

 

Manifestations of nephrotic syndrome are;

• Massive proteinuria with the daily loss of greater than 3.5g of protein per day (less in children)
• Hypoalbuminaemia with plasma levels less than 30g/L
• Generalised oedema
• Hyperlipidaemia and lipiduria

 

Pathology

• The initial event in a derangement in the glomerular capillary walls resulting in increased permeability to plasma proteins. Massive proteinuria results
• This leads to albumin depletion and oedema is a result of loss of colloid osmotic pressure
• There is also sodium and water retention aggrevating the oedema. This is due to compensatory secretion of aldosterone mediated by hypovolaemic enhanced ADH secretion, stimulation of the sympathetic system and the reduction in secretion of naturitic peptides
• The process of hyperlipidaemia is complex and results in increased cholesterol levels, triglyceride, VLDL, LDL, Lp(a) lipoprotein and apoprotein and there is a decrease in HDLP in some patients
• This seems to be due to increased synthesis by the liver, abnormal transport of circulating lipids and decreased catabolism
• Lipiduria follows again due to leakiness of the glomerular capillary wall. The fat appears in the urine either as free fat or as oval fat bodies representing lipoprotein resorbed by tubular epithelial cells and then shed into the urine
• These patients are particularly susceptible to infection particulary staphylococci and pneumococci possibly due to loss of immunoglobulin and complement components in the urine
• Thrombotic and thromboembolic complications are common due to loss of anticoagulant factors e.g. antithrombin III and antiplasmin activity through the leaky glomerulus. This can cause renal vein thrombosis

 

Causes of nephrotic syndrome

• Primary glomerular disease
  • Membranous glomerulopathy
  • Minimal change disease
  • Focal segmental glomerulosclerosis
  • Membranoproliferative glomerulonephritidies
  • Other proliferative glomerulonephritis such as IgA nephropathy
• Systemic diseases
  • Diabetes
  • Amyloidosis
  • SLE
  • Drugs – NSAIDs, penecillamine
  • Infections – malaria, syphilis, hep B, C, AIDS
  • Malignant disease – carcinoma, lymphoma

 

Membrane glomerulopathy

• Is a primary disease in 85% of cases and secondary in the remaining due to drugs, malignant conditions, SLE, infections and other autoimmune diseases such as thyroiditis
• It is a form of immune complex mediated disease resembling Heymann nephritis
• Complement plays a role in the inducing the leakiness particularly the C5b-C9 attack complex. This causes activation of the glomerular epithelial and mesangial cells causing the release of proteases and oxidants which cause capillary wall damage
• Immunofluorescence demonstrates granular deposits. There is also uniform diffuse thickening of the glomerular capillary wall
• Proteinuria is nonselective and doesn’t respond to steroid treatment
• Prognosis is variable and roughly 25% undergo remission, 25% develop stable persisting proteinuria and 50% develop chronic renal failure over a period of 10 years

 

Minimal change disease (Lipoid disease)

• Most frequent cause of nephrotic disease in children, 2-6 years
• It is characterised by diffuse effacement of foot processes of epithelial cells in the glomeruli that appear virtually normal under light microscopy
• Sometimes follows a respiratory tact infection or vaccination
• Dramatic response to corticosteroids
• Not due to classical immune complex mechanism, the exact mechanism is unclear
• Although there is a massive proteinuria (selective for albumin) renal function generally remains good

 

Focal segmental Glomerulosclerosis

• Sclerosis of some but not all of the glomeruli and in the affected glomeruli on a portion of the capillary tuft is involved
• Occurs in the flowing settings;
  • Associated with other conditions such as HIV, heroin addiction, sickle cell disease and massive obesity
  • As a secondary event reflecting glomerular scarring eg IgA nephropathy
  • As a component of the adaptive response to loss of renal tissue
  • In inherited forms due to mutations in nephrin, podocin or a-actin 4
  • As a primary disease
• Differs from minimal change disease as;
  • There is a higher incidence of haematuria, reduced GFR and hypertension
  • Proteinuria is nonselective
  • There is poor response to corticosteroid therapy
  • There is progression to chronic glomerulosclerosis with around 50% developing end stage disease within 10 years
  • Immunofluoresence shows non-specific deposition of IgM and C3 in the sclerotic component
• Focal glomerulosclerosis initially affects the juxtamedullary glomeruli causing an increase in mesangial matrix which gradually expands to destroy the surrounding lobule until global sclerosis occurs

 

Membranoproliferative glomerulonephritis

• This is a diffuse global pattern of glomerulonephritis with features of both proliferation and membrane thickening that predominantly affects the mesangium
• May be due to secondary disease such as SLE, infective endocarditis, malaria, a1-antitryspin deficiency or infected ventricular CSF shunts or it may be idiopathic
• Primary membranoproliferative glomerulonephritis can be classified into type I and type II
• Type I is characterised by the presence of sub-endothelial electron dense deposits. C3 is deposited in a granular pattern and IgG and C1q and C4 are also present suggesting an immune complex pathogenesis. Type I may be due to antigens derived from infections such as hepatitis C and B becoming planted in the glomerular structures
• Type II is also called dense-deposit disease. The GBM is transformed into an irregular, ribbon-like extremely dense structure because of deposition of some unknown dense material. C3 is present but not IgG or the early complement components. Activation seems to be via the alternative complement pathway

 

IgA Nephropathy (Berger Disease)

• Due to IgA deposits in the mesangial areas
• Patients have increased levels of serum polymeric IgA and IgA containing immune complexes
• Of the two classes of IgA only IgA1 is involved in deposits
• May be due to increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental antigens
• Trapped IgA activates the alternative pathway of the complement pathway

 

 

This entry was posted on Friday, December 21st, 2007 at 4:58 pm and is filed under Kidney. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.