proteinuria &
TRANSCRIPT
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PROTEINURIA &
NEPHROTIC SYNDROME
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Glomerular anatomy & filtration barrier
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Proteinuria
• Normal urine < 150 mg/day in adults
– Small MW proteins filtered across GCW
– Tamm-Horsfall proteins secreted by tubular
cells• Abnormal proteinuria
– Failure of the GCW filtration barrier – glomerular proteinuria
– Decreased reabsorption into, or increasedrelease from, tubular cells – tubular proteinuria
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• Tubular proteinuria – Low MW proteins, (generally < 40,000 D)
– Amounts < 1 g/day
• Glomerular proteinuria – Proteins of greater molecular size
– May be up to many grams per day
• Selective proteinuria – Proteins much larger then albumin are excluded, e.g.
MCD where the injury is of limited nature
• Non-selective proteinuria
– More extensive damage – Immunoglobulins & larger proteins
• Glomerular disease – Primary
– Secondary to systemic diseases
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Case
• 6 y/o girl with progressive swelling on her
face, ankles, BP 95/60, otherwise normal.
PMHx (-). UA: protein++++
• Cr=0.5 mg/dl, Alb 1.3 g/dl,
urine microscopy: many hyaline casts,
24h U protein =6g, cholesterol elevated
• Patient was referred to a nephrologist for a
possible renal biopsy
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• Percutaneous renal biopsy can be performed toestablish the correct diagnosis & prognosis in patients
with suspected parenchymal renal disease.• It is usually a safe procedure, but bleeding complications
can occur.
• It may not be used
– when the diagnosis is In little doubt, – when it is unlikely to lead to a change in therapy,
– when the chance for complication is greater than usual
• Abnormalities may be – Segmental, involving part of a glomerulus only
– Global, the whole glomerulus
– Focal, involving a few glomeruli only
– Diffuse, involving most glomeruli
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Treatment
• In general, the primary forms of GN causing NSare treated with corticosteroids; which have anti-inflammatory action
• In some cases immunosuppressive drugs are
used – Cyclophosphamide
– Azathioprine / Imuran
– Mycophenolic acid / MMF
– Cyclosporin• With secondary GN, treatment is directed
towards the primary disease
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GLOMERULONEPHRITIS
&
ACUTE NEPHRITICSYNDROME
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Acute glomerulonephritis
• Inflammatory renal disease involving theglomeruli of all or some of the millionnephrons of each kidney
• Classification based on pathologicalappearance of glomeruli, and other components of the nephron; blood
vessels, interstitium• Primary or idiopathic
• Secondary to a another (systemic) disease
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• To confirm the presence of renal inflammation, urine
sediment examination should be performed on acentrifuged sample of fresh urine (casts may breakdownwithin 1-2h)
• When cells or cellular debris aggregate in the tubular lumen, they may form casts of the tuble
• Granular or cellular casts (epithelial, red, or white cells)indicate the presence of renal parenchymal disease
• Hyaline – proteinaceous – casts are found withproteinuria
• An active sediment contains elements consistent withrenal inflammation and/or cell necrosis
• A benign sediment may contain a few cells and onlyhyaline casts.
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Nephritic Syndrome
• Hematuria, Hypertension, reduced GFR
• Active urinary sediment and Hematuria areindicative of renal inflammation
• Oliguria & renal impairment are aconsequence of glomerular infiltration withinflammatory cells & release of vasoactive
hormones & cytokines• Hypertension is the result of salt & water
retention & vasoactive hormone release
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Consequences of glomerular disease
• Proteinuria; due to impaired filtration barrier of GCW
• Hematuria; due to leak into Bouwman’s space acrossGCW or into tubular lumen
• Renal impairment; multifactorial – Acute inflammatory process
• Proliferation intrinsic glomerular cells
• Glomerular infiltration with leukocytes• Haemodynamic changes induced by vasoactive hormones &
cytokines
– Chronic renal scarring• Caused by continuing inflammation,hypertension, proteinuria &
other factors
– Structural and/or functional damage of glomeruli andtubulointerstitium
• Hypertension – Salt and water retention
– Glomerular capillary & arteriolar scarring
– Neurohumoral changes, in particular activation of Renin- Angiotensin system
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Diagnosis of glomerular disease /
nephritic syndrome• Combination of clinical features, serologic tests, and
renal biopsy
• A positive test result suggest the primary diagnosis, butdoes not prove that it is the cause of the renal disease
• Renal biopsy usually establishes the diagnosisdefinitively
• GN may occur in isolation or as part of a multisystemdisease
• Acute nephritic syndrome can occur either restricted tothe kidney or involve multiple organ (systemic disease)
• Without rapid treatment, irreversible renal failure maydevelop over a short period
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Respiratory & skin, other postinfectios GN
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• IgA nephropathy: – Acute nephritis
– Macroscopic hematuria occurring at the time or within a few days of (a viral) soar throat
– Shorter prodrome & recurrent distinguishes it from poststreptococcal GN
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Pathologenesis of acute glomerulonephritis
• GN may be initiated by an immune response to – An exogenous antigen, e.g. streptococcal
– An endogenous antigen, e.g. DNA in SLE
– Autoimmune response to a renal antigen, e.g. GBM in Goodpasteur’ssyndrome
• The antibodies involved in these responses form the basis for diagnostic serological tests
• Ag is part of a circulating IC , or is deposited in the kidney to form anIC in situ – the IF pattern is discontinues or granular
– Corresponding electron-dense deposits are seen wit EM
– E.g. membranous GN, post-streptococcal GN, and SLE
• If the AB is directed against an intrinsic renal Ag – IF pattern is continuous / linear
– No electron-dense deposits on EM
– E.g. Goodpasteur’s syndrome
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Pathology of acute GN
• The glomerulus may be altered in a # of ways in GN – Intrinsic cells – endothelial, mesangial, epithelial – may
proliferate
– Circulating leukocytes may infiltrate
– Platelets may accumulate mesangial matrix may expand
– The GBM may change
– Scarring may develop
• Hallmark of severe disease is development of aglomerular crescent
– A cellular, fibrinous, and later, fibrous lesion in Bouwman’sspace
– The greater the size, and the number of crescents, the moresevere the disease
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• Fig 3. The thickened capillary wall shows numerous "holes" in tangential sections,indicating deposits. (Deposits do not take up the silver stain.) Well-developed spikesaround the deposits are not present in this early stage II membranousglomerulonephritis, but segmental, small nubs of silver-stained basement membrane
material protruding from the basement membrane contour on the epithelial side canbe seen (Jones' silver stain, original magnification x400).
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• Diffuse coarsely granular capillary wall IgG deposits in stage II-III membranous
glomerulonephritis (immunofluorescence with anti-IgG, original magnification x100).
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• Diffuse proliferative acute postinfectious glomerulonephritis with numerous
PMNs with PAS-positive cytoplasm and endocapillary proliferation (periodicacid-Schiff; original magnification x400).