INDEX PATIENT - kznhealth.gov.za · – Azotemia – → uremia -azotemia associated with a...
Transcript of INDEX PATIENT - kznhealth.gov.za · – Azotemia – → uremia -azotemia associated with a...
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INDEX PATIENT
• Mr S.S• 24 yr old• Referred from EDH – May 2003• Problem – Nephrosis
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INDEX PATIENT
• Admitted – 27/06/2006• M/C – generalized body swelling
– SOB– OLIGURIA
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INDEX PATIENT
• HMC– Treated at EDH - from 1996– Nephrosis– HT– Hypercholesterolaemia– Normal renal function– R/F – Grey’s – 05/2003
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INDEX PATIENT
• Was put on– Lipitor– Renitec– Lasix– aldactone
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INDEX PATIENT
• Renal Bx – 08/2003– ? Mesangial proliferation– ? FSGS– Put on prednisone – 60mg/d x6/12– Lipitor/renitec/diuretics - continued
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INDEX PATIENT
• 02/2004 – responded to Rx (at 6/12)– No oedema– No proteinuria– BP controlled– Lost 6kg wt– Steroids tappered– Maintained on Zocor / enalapril / lasix
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INDEX PATIENT
• 05/2004 (3/12 after remission)– High BP– Proteinuric 2+– Oedema 2+– Restarted on Prednisone x6/12
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INDEX PATIENT
• At 6/12 – did not respond– Proteinuric 3+– Blood 2+– High BP– 02/2005 – started on Imuran 150mg/d– Did not respond after 6/12– Ur prot 5.2g/d– U&E – normal, CMP - normal
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INDEX PATIENT
• 11/2005 – repeat renal Bx– FSGS– Put on predn, imuran, INH 200mg/d,
pyridoxine. Lasix, aldactone, enalapril, zocor,– Still HT, proteinuric, haematuric 1+– Alb 7, Ur 7.8, Cre 180– Cr Cl – 50ml/min
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INDEX PATIENT
• 12/2005 – Ur – 23.2, Cre 396– Secondary hyperparathyroidism– Tetralac added to Rx
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INDEX PATIENT
• PMH – as above– Not diabetic, no RVD, no hepatitis– Rest of history – non contributory
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INDEX PATIENT
• On exam– Grossly oedematous– BP 136/81mmHg, Pulse 71, regular– Wt 79.6 kg, 3+ proteinuria, 1+ haematuria– Pale, not jaundiced– Not in CCF– LFT’s – normal– Chest – no pl effusion
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INDEX PATIENT
• Abd – no ascites• CXR – no organomegally• Echo – normal• Complement & Ig – not demonstrated• U/S – kidney – bilateral dense
parenchyma– R -12.1 cm, Lt – 11.2cm, no hydronephrosis– Spleen, liver – normal; no ascites
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INDEX PATIENT
• WCC 13.8,• Hb 6.7,• Plt 751• U&E 142/4.08/126/10.1/23.3/464• Ca 2.19 (Corrected), P 2.59• Chol – 6.58• Ur MCS, B/C - Negative
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INDEX PATIENT
• ASSESSMENT– 24 yr old male patient with
• Nephrotic syndrome - FSGS• CRF• Steroid responsive/relapsing• Thrombocytosis
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PRIMARY GLOMERULOPATHIES
DR SD MTHIYANEGREY’S HOSPITAL
26 JULY 2006
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INTRODUCTION
• Glomerulopathy (GN) group of disorders in which:
• there is primarily an immunologicallymediated injury to glomeruli, although
• renal interstitial damage is a regular accompaniment
• kidneys are involved symmetrically
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INTRODUCTION• Followed by secondary mechanisms of
glomerular injury: – fibrin deposition– platelet aggregation– neutrophil infiltration and – free radical-induced damage.
• renal lesion may be part of a generalized disease (e.g. systemic lupus erythematosus, SLE).
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INTRODUCTION
• Glomerular injury– by a variety of factors and – in the course of a number of systemic
diseases – primary or secondary – both the clinical manifestations and
glomerular histologic changes in primary and secondary forms can be similar
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Primary Glomerulopathies
• Acute diffuse proliferativeglomerulonephritis– Poststreptococcal– Non-poststreptococcal
• Rapidly progressive (crescentic) glomerulonephritis
• Membranous glomerulopathy
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Primary Glomerulopathies
• Minimal change disease• Focal segmental glomerulosclerosis• Membranoproliferative
glomerulonephritis• IgA nephropathy• Chronic glomerulonephritis
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Systemic Diseases with Glomerular Involvement
• Systemic lupus erythematosus• Diabetes mellitus• Amyloidosis• Goodpasture syndrome• Microscopic polyarteritis/polyangiitis• Wegener granulomatosis• Henoch-Schönlein purpura• Bacterial endocarditis
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Hereditary Disorders
• Alport syndrome• Thin basement membrane disease• Fabry disease
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PATHOGENESIS OF GLOMERULAR INJURY
• Little - known of etiologic agents and triggering events
• Immune mechanisms underlie most forms of GN
• Glomerular deposits of immunoglobulins and complement - found in the majority of patients with glomerulonephritis
• Cell-mediated immune reactions - play a role• In concert with antibody-mediated events
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Immune Mechanisms of Glomerular Injury
• Antibody-Mediated Injury – In Situ Immune Complex Deposition – Circulating Immune Complex Deposition
Endogenous antigens (e.g., DNA, tumor antigens)Exogenous antigens (e.g., infectious products)
• Cytotoxic Antibodies• Cell-Mediated Immune Injury• Activation of Alternative Complement
Pathway
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Antibody-associated injury
• Two forms of antibody-associated injury – (1) injury by antibodies reacting in situ within
the glomerulus (insoluble fixed or planted Ags)
• insoluble fixed (intrinsic) glomerular antigens– NC1 domain of collagen type IV antigen (anti-GBM
nephritis)– Heymann antigen (membranous glomerulopathy)– Mesangial antigens
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Antibody-associated injury• with molecules planted within the glomerulus
– Exogenous (infectious agents, drugs)– Endogenous (DNA, nuclear proteins, immunoglobulins,
immune complexes, IgA) , and
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Antibody-associated injury– (2) injury resulting from deposition of
circulating antigen- antibody complexes in the glomerulus
• Endogenous antigens (e.g., DNA, tumour antigens)
• Exogenous antigens (e.g., infectious products)
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CLINICAL MANIFESTATIONS
• Five major glomerular syndromes– Acute nephritic syndrome– Rapidly progressive glomerulonephritis– Nephrotic Syndrome – Chronic Renal Failure – Asymptomatic haematuria or proteinuria
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CLINICAL MANIFESTATIONS
• Due to both the primary glomerulonephritides and the systemic diseases
• Common systemic disorders– diabetes mellitus– SLE– vasculitis and – amyloidosis
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The Glomerular Syndromes
• Acute nephritic Syndrome– Hematuria– azotemia - elevation of the blood urea
nitrogen (BUN) and creatinine levels – variable proteinuria– oliguria– edema and– hypertension
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The Glomerular Syndromes• Rapidly progressive glomerulonephritis
– Acute nephritis– proteinuria and– acute renal failure
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The Glomerular Syndromes• Nephrotic syndrome
– >3.5 gm proteinuria– hypoalbuminemia– hyperlipidemia– lipiduria
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The Glomerular Syndromes• Chronic renal failure
– Azotemia– → uremia -azotemia associated with a
constellation of clinical signs and symptoms and biochemical abnormalities - progressing for years
– end result of all chronic renal parenchymaldiseases.
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The Glomerular Syndromes• Asymptomatic hematuria or proteinuria
- Glomerular hematuria;- subnephrotic proteinuria
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Investigation of glomerulardiseases
• Urine microscopy – Red cells, red-cell casts
• Urinary protein– Nephrotic or sub-nephrotic range proteinuria
• Serum urea– May be elevated
• Serum creatinine– May be elevated
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Investigation of glomerulardiseases
• Culture (throat swab, discharge from ear, swab from inflamed skin)– Nephritogenic organism (not always)
• Antistreptolysin-O titre– Elevated in post-streptococcal nephritis
• C3 and C4 levels– May be reduced
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Investigation of glomerulardiseases
• Antinuclear antibody– Present in significant titre in systemic lupus
erythematosus• ANCA
– Positive in vasculitis
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Investigation of glomerulardiseases
• Anti-GBM– Positive in Goodpasture's syndrome
• Cryoglobulins– Increased in cryoglobulinaemia
• Creatinine clearance– Normal or reduced
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Investigation of glomerulardiseases
• Chest X-ray– Cardiomegaly, pulmonary oedema (not
always)• Renal imaging
– Usually normal• Renal biopsy
– Any glomerulopathy
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HISTOLOGIC ALTERATIONS• Four basic tissue reactions.
– Hypercellularity - increase in the number of cells in the glomerular tufts.
– Due to: • Cellular proliferation of mesangial or endothelial cells • Leukocytic infiltration - neutrophils, monocytes,, lymphocytes • Formation of crescents - proliferating parietal epithelial cells
and infiltrating leukocytes– Also precoagulants - tissue factor and cytokines (interleukin-1,
tumor necrosis factor, and interferon-γ.)
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HISTOLOGIC ALTERATIONS
• Basement Membrane Thickening– deposition of immune complexes
• on the endothelial or epithelial side of the basement membrane or
• within the GBM itself. • Fibrin, amyloid, cryoglobulins, and abnormal
fibrillary proteins may also deposit in the GBM; or – thickening of the basement membrane proper,
as occurs in diabetic glomerulosclerosis.
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HISTOLOGIC ALTERATIONS– Hyalinization
• the hyalin is extracellular• consists of amorphous substance• made up of plasma proteins that have exuded from
circulating plasma into glomerular structures.
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HISTOLOGIC ALTERATIONS• Sclerosis• - obliteration of capillary lumina of the glomerular
tuft
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MECHANISMS OF PROGRESSION IN
GLOMERULAR DISEASES• Immunologic mechanisms and mediators
that initiate glomerular injury• Outcome of such injury depends on
several factors– initial severity of renal damage– the nature and persistence of the antigens– and the immune status– age and genetic predisposition of the host
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MECHANISMS OF PROGRESSION IN
GLOMERULAR DISEASES– progression to ESRD proceeds
• at a relatively constant rate• independent of the original stimulus or activity of
the underlying disease • once there destruction of functioning nephrons and
reduction the GFR to about 30% to 50% of normal
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MECHANISMS OF PROGRESSION IN
GLOMERULAR DISEASESThe two major histologic characteristics of such
progressive renal damage are– focal segmental glomerulosclerosis and– tubulointerstitial fibrosis; we discuss these
separately
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Focal Segmental Glomerulosclerosis (FSGS).
• Patients develop proteinuria• Even if the primary disease was nonglomerular. • The glomerulosclerosis - initiated by the
adaptive change - in the relatively unaffected glomeruli of diseased kidneys
• Compensatory hypertrophy - maintains renal function
• Proteinuria and glomerulosclerosis soon develop• eventually to total glomerular sclerosis and
uremia.
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Focal Segmental Glomerulosclerosis (FSGS).
• The glomerular hypertrophy is associated with hemodynamic changes
• Include increases in glomerular blood flow, filtration, and transcapillary pressure (capillary hypertension)
• often with systemic hypertension.
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Focal Segmental Glomerulosclerosis (FSGS).
• The sequence of events entails– endothelial and epithelial cell injury– increased glomerular permeability to
proteins– and accumulation of proteins in the
mesangial matrix.
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Focal Segmental Glomerulosclerosis (FSGS).
• Followed by proliferation of mesangial cells• Infiltration by macrophages• Increased accumulation of extracellular matrix• And segmental and eventually global sclerosis
of glomeruli (renal ablation FSGS). • This results in further reductions in nephron
mass• Hence a vicious circle of continuing
glomerulosclerosis
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Focal Segmental Glomerulosclerosis (FSGS).
• Mediators of chronic inflammation and fibrosis, particularly TGF-β, play a role in the induction of sclerosis.
• interrupt these mechanisms of progressive glomerulosclerosis involve treatment with inhibitors of the renin-angiotensin system
• reduce intraglomerular hypertension• also have direct effects on each of the
mechanisms identified • shown to ameliorate progression of FSGS in
both animal and human studies
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TREATMENT OF FSGS• Prednisolone 0.5-2 mg/kg/day• continued for 6 months before declaring the
patient resistant to therapy; this is common. • The use of ciclosporin at doses to maintain
serum trough levels at 150-300 ng/mL may be effective in reducing or stopping urinary protein excretion.
• Relapse after reducing or stopping ciclosporin is very common. Long-term use may be required to maintain remission.
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TREATMENT• Cyclophosphamide, chlorambucil or azathioprine
is used for second-line therapy in adults• In FSGS patients with mesangial hypercellularity
and tip lesion, use of cyclophosphamide 1-1.5 mg/kg/day with 60 mg of prednisolone for 3-6 months
• followed by prednisolone and azathioprine as maintenance therapy has found some success.
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TREATMENT
• About 50% of patients progress to end-stage renal failure within 10 years of diagnosis
• particularly those who are resistant to therapy
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Tubulointerstitial Fibrosis• Manifested by tubular damage and interstitial
inflammation• Contributes to progression in both immune and
nonimmune glomerular diseases, for example, diabetic nephropathy
• Due to:– ischemia of tubule segments downstream from
sclerotic glomeruli– acute and chronic inflammation in the adjacent
interstitium– damage or loss of the peritubular capillary blood
supply.
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Membranous glomerulopathy
• mainly in adults• predominantly in males• present with
– asymptomatic proteinuria or– frank nephrotic syndrome.– Microscopic haematuria, hypertension and/or
renal impairment may accompany the nephrotic syndrome
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Membranous glomerulopathy– hypertension and the degree of renal
impairment are poor prognostic signs. – half of patients undergo spontaneous or
therapy-related remission. – 40% develop chronic renal failure, with
persistent nephrotic range proteinuria.
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Membranous glomerulopathy• Aetiopathogenesis
– An identical glomerular histological picture –primary or secondary
– drugs (e.g. penicillamine, gold, NSAIDs, probenecid, mercury, captopril),
– autoimmune disease (e.g. SLE, thyroiditis),– infectious disease (e.g. hepatitis B, hepatitis
C, schistosomiasis, Plasmodium malariae),
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– neoplasia (e.g. carcinoma of lung, colon, stomach, breast and lymphoma) and
– other causes (e.g. sarcoidosis, kidney transplantation, sickle cell disease).
– deposits in the subepithelial aspects of the capillary walls
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TREATMENT• Oral high-dose corticosteroids - ineffective • The use of azathioprine is not associated with
any significant benefits• The alkylating agents
– cyclophosphamide and chlorambucil, are both effective in the management of membranous GN.
– Due to long-term toxicity - reserved for patients who exhibit clinical features
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TREATMENT– such as severe or prolonged nephrosis (i.e.
proteinuria > 6 g/day for > 6 months)– renal insufficiency and hypertension– that predict a high likelihood of progression to
end-stage renal failure.
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TREATMENT• Chlorambucil (0.2 mg/kg/day in months 2, 4• and 6 alternating with oral prednisolone 0.4
mg/kg/day in months 1, 3 and 5) • and cyclophosphamide (1.5-2.5 mg/kg/day for 6-
12 months• with 1 mg/kg/day of oral prednisolone on
alternate days for the first 2 months) are equally effective
• Ciclosporin and mycophenolate with oral steroids may become the agents of choice for membranous GN
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TREATMENT
• As membranous GN is caused by circulating autoantibodies– anti-B lymphocyte therapy would seem more
logical than – broad-spectrum immunosuppressive agents,
which are more effective against T lymphocytes
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TREATMENT
• Anti-CD20 antibodies (rituximab, which ablates B lymphocytes), – improve renal function, – reduce proteinuria and – increase the serum albumin; – no significant adverse affects have been
shown in the short term.
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IgA nephropathy• This disease has replaced post-streptococcal
glomerulonephritis as the commonest form of glomerulonephritis world-wide
• There is a focal and segmental proliferativeglomerulonephritis with mesangial deposits of polymeric IgA1
• In some cases IgG, IgM and C3 may also be seen in the glomerular mesangium.
• The disease may be a result of an exaggerated bone marrow and tonsillar IgA1 immune response to viral or other antigens
• associated with an abnormality in O-linked galactosylation in the hinge region of the IgA1 molecule.
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IgA nephropathy• Quantitative and structural changes of IgA1 play a key
role • CD89 expressed on blood myeloid cells and the
transferring receptor (CD71) on mesangial cells• Abnormal IgA1 induces the release of soluble CD89• responsible for the formation of circulating IgA
complexes• These complexes may then be trapped by CD71• which is overexpressed on mesangial cells in IgA
nephropathy patients, • allows IgA complex formation in the mesangium• .
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IgA nephropathy• Up to 50% of patients exhibit elevated
serum IgA (polyclonal) concentration• Superimposed crescent formation is
frequent• particularly following macroscopic
haematuria due to upper respiratory tract infection
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IgA nephropathy• Several diseases - associated with IgA
deposits• including Henoch-Schönlein purpura• chronic liver disease• malignancies (especially carcinoma of
bronchus)
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IgA nephropathy• seronegative spondyloarthrides• coeliac disease• mycosis fungoides and • psoriasis
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IgA nephropathy• Clinical presentation:
– IgA nephropathy - children and young males– They present with asymptomatic microscopic
haematuria or– recurrent macroscopic haematuria– sometimes following an upper respiratory– or gastrointestinal viral infection.
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IgA nephropathy– Proteinuria occurs– and 5% can be nephrotic. – The prognosis is usually good
• especially in those with normal blood pressure• normal renal function and• absence of proteinuria at presentation..
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IgA nephropathy• recurrent macroscopic haematuria - good
prognostic sign• may be due to 'lead-time bias' • The risk of end-stage renal failure
– is about 25% in those with proteinuria of more than 1 g per day
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IgA nephropathy– elevated serum creatinine– hypertension– ACE gene polymorphism (DD isoform)– and tubulointerstitial fibrosis on renal biopsy
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Management
• Steroids– Patients with proteinuria over 1-3 g/day, – mild glomerular changes only and– preserved renal function – Steroids reduce proteinuria and stabilize renal
function.
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Management– The combination of:– Cyclophosphamide– dipyridamole and– warfarin should not be used, – nor should ciclosporin.
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Management– In patients with progressive disease
(creatinine clearance less than 70 mL/min), use:
– fish oil or prednisolone with cyclophosphamide for 3 months
– followed by maintenance with prednisoloneand azathioprine
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Management– A tonsillectomy :– can reduce proteinuria and haematuria in
those patients with recurrent tonsillitis.
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Management– All patients, – with or without hypertension and proteinuria,
should receive a combination of ACE inhibitor and angiotensin II receptor antagonist rather than each agent alone
– because reduction of proteinuria and preservation of renal function are better with combination therapy despite similar blood pressure control.
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RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN
• RPGN is a syndrome with• glomerular haematuria (RBC casts or
dysmorphic RBCs),• rapidly developing acute renal failure over
weeks to months and• focal glomerular necrosis• with or without glomerular crescent
development on renal biopsy.
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RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN
• The 'crescent' is an aggregate of macrophages and epithelial cells in Bowman's space
• RPGN can develop with immune deposits (anti-GBM or immune complex type) or
• without immune deposits (pauci-immune).
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RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN
• It can also develop as an idiopathic primary glomerular disease or
• can be superimposed on other glomerulardiseases, primary or secondary
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MANAGEMENT• This is based on counteracting the factors
involved in the pathogenesis. • plasma exchange is used to remove circulating
antibodies• steroids to suppress inflammation from antibody
already deposited in the tissue and • cyclophosphamide to suppress further antibody
synthesis. • The prognosis is directly related to the extent of
glomerular damage
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MANAGEMENT
• if left untreated, autoantibodies diminish spontaneously within 3 year
• autoreactive T cells cannot be detected in the convalescent patients.
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INDEX PATIENT• The patient was put on
– Zocor 20mg od– Predn 60mg/d– INH 200mg/d– Pyridoxine 25mg/d– Losec 20mg/d– Disprin 150mg/d– Furosemide 80mg PO TDS– Aldactone 100mg/d
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INDEX PATIENT
• Responded - on D/C– BP low, 1+ proteinuria, no oedema– Passing >1l urine/day– For follow up at renal clinic
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REFERENCES
• KUMAR & CLARK• ROBBINS PATHOLOGY• NEJM