Glomerular Diseases Flashcards
two things that can be treated w/ plasmaphoresis?
TTP and Good Pasture Sx
non pitting vs pitting edema
- Non-pitting edema: swollen cells due to increased ICF volume – does NOT respond to diuretics
- Pitting edema: increased ISF volume – nephrotic syndrome, CHF, pregnancy, cirrhosis
what are major transport mechanisms along the nephron?
- PCT: glucose, AA’s, phosphate, Cl-, Na+ all taken into cell - driven by Na/K ATPase pump
- DCT: Sodium brings Cl- in as well as Ca2+
- Principal cells: sodium comes in K+ moves out (driven by sodium ATPase pump)
- under ADH stimulation aquaporins are inserted here - Alpha intercalated cells: potassium in, H+ out
Beta intercalated cells: Cl- in, HCO3- out
diuresis
“well hydrated”
- CD impermeable to water
- dilute urine
- Low ADH
antidiuresis
“dehyrdration”
- CD highly water-permeable
- low volume concentrated urine
- high ADH
ADH increases H20 permeability of late distal tubule/collecting duct
anion gap acidosis
: E. Elm Park: Ethanol, Ethylene glycol, Lactic acid, Methanol, Paraldehyde, Aspirin, Renal failure, Ketone bodies
azotemia
elevation of blood urea nitrogen (BUN) and Creatine levels, largely related to decreased glomerular filtration rate (GFR)
• Pre-renal azotemia: due to hypoperfusion of kidneys (i.e. hemorrhage, shock, volume depletion, CHF), impairs renal fn. in the absence of parenchymal damage (BUN:Cr >20:1)
• Postrenal azotemia: urine flow obstructed beyond the level of kidney
Uremia
when azotemia is associated with other sx and clinical signs: failure of renal excretory function but also host metabolic and endocrine alterations resulting from renal damage.
AKI
dominated by oliguria or anuria, and recent onset of azotemia (elevated BUN). Can result from glomerular, interstitial, or vascular injury or acute tubular injury
• rapid decline in GFR
• frequently reversible, though can progress to CKD
• severe forms have oliguria and anuria
CKD
Chronic Kidney disease (CKD): prolonged signs of uremia, ending in chronic renal parenchymal diseases
• GFR is less than 20-25% of normal.
• (<60 ml/min for 3 mos) or persisitent albuminuria
• milder, often clinically silent
• kidneys can’t regulate volume and solute composition → edema, metabolic acidosis, hyperkalemia
• CKD is generally irreversible
ESRD
End-Stage renal disease:
• GFR is less than 5% of normal – terminal stage of uremia
Renal tubular defects characterized by what?
Renal tubular defects: dominated by polyuria, nocturia, electrolyte disorders. Result from diseases that directly affect tubular structure (medullary cystic disease) or cuase defects in specific tubular functions
UTI’s dominated by what?
Urinary tract infections: see bacteriuria and pyuria (bacteria and leukocytes in urine) – may effect the kidney “pyelonephritis” or the bladder “cystitis”
Nephrolithiasis - see what?
Nephrolithiasis: renal stones – see severe spasms of pain (renal colic) and hematuria
nephritic syndrome
due to glomerular disease and glomerular inflammatory response. Decreased GFR • hematuria • hypertension • azotemia • oliguria • edema • mild/moderate proteinuria
ex. APSGN
RPGN
RPGN - basics
Rapidly progressive glomerulonephritis: “Crescentic Glomerulonephritis”
• nephritic syndrome with rapid decline in GFR (hours to days)
• acute nephritis, proteinuria, acute renal failure
Nephrotic syndrome
due to glomerular disease, not inflammatory reaction, minimal changes in GFR
• severe proteinuria (>3.5 g/day)
• hypoalbuminemia (<3.0 gm/dL)
• hyperlipidemia/lipiduria (due to increased lipoprotein synth in liver)
• generalized edema, periorbital edema
ex: MG, MCD, FSGS
chronic renal failure
azotemia –> uremia
mixed glomerulopathies?
MPGN, IgA nephropathy, Alport Syndrome, Thin BM disease
Hereditary glomerulopathies?
- Alport syndrome
- Thin basement membrane disease
- Fabry disease
what are parts of glomerulus?
mesangial cells in center, endothelium (in inside surrounding RBCs), BM in middle, viscerial epithelium (urinary space), parietal epithelium
- glomerular basement membrane: made of collagen Type IV, laminin, enactin
- visceral epithelial cells (podocytes): filtration slits: nephrin molecules and podocin
- mesangial cells lie b/w the capillaries and are for contractile, phagocytic and proliferative purposes
Glomerulus characteristics:
- high permeability to water, small solutes, cationic ions
- larger and more anionic, the less permeable – exclusion of albumin
what are crescents?
accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes.
i. occurs following immune/inflamm. injury
ii. fibrin leaks into urinary space often through ruptured membranes
Hyalinosis and Sclerosis?
a. Hyalinosis = accumulation of material that is homogenous and eosinophilic by light microscopy. results in endothelial or capillary wall injury and glomerular damage
b. Sclerosis = accumulations of extracellular collagenous matrix
Diffuse, global, focal, segmental
Diffuse = involving all glomeruli Global = involving the entire glomerulus Focal= involving only a portion of the glomeruli Segmental = affecting a part of each glomerulus
Subepithelial humps?
APGN (nephritic)
IF: see granular IgG and C3 in GBM and mesangium
LM: diffuse proliferation of leukocytes
GBM dirsuption of fibrin, crescents?
Anti-GBM Ab (Goodpastures syndrome) = nephritic
IF: see linear IgG and C3;
LM: fibrin in crescents
subepithelial deposits?
membranous glomerulopathy (nephrotic)
IF: see diffuse granular IgG and C3
LM: diffuse capillary wall thickening
just fusion of foot processes?
MCD (nephrotic)
no unusual IF or LM
fusion of foot processes and sclerosis?
FSGS (nephrotic)
IF: focal; IgM and C3
LM: focal segmental sclerosis
see subendothelial deposits?
MPGN Type I - Hematuria and proteinuria
IF: IgG, C3, C1q +C4
LM: mesangial proliferation
dense deposits?
MPGN Type II: Dense deposit disease - hematuria and renal failure
IF: C3, IgG, no C1q or C4
LM: mesangial prooliferation , GBM splitting
mesangial and paramesangial deposits?
IgA nephropathy; causes recurrent hematuria
IF: IgA, IgG, IgM, C3 in mesangium
LM: focal mesangial proliferation widening
APGN pathogenesis?
• Immune complex injury triggered by exogenous bacterial, viral or fungal antigen
• Poststreptococcal Glomerulonephritis:
o Group A, Beta-hemolytic Streptococcus
o appears 1 to 4 weeks after strep infection of pharynx or skin
o usually in children ages 6-10
o granular immune deposits in glomeruli
• Nonstreptococcal Acute Glomerulonephritis:
o Staph endocarditis, pneumonococcal pneumonia, Hep B, Hep C, varicella, HIV, malaria, toxoplasmosis
o Staph known to have IgA deposition – normally seen in IC people/drug users
APGN histology?
• Diffuse proliferative glomerulonephritis:
• enlarged, hypercellular glomeruli:
o infiltration by leukocytes, neutrophils and monocytes
o proliferation of endothelial and mesangial cells
o Crescent formation
• IF: shows granular deposits of IgG, IgM, C3 along the GBM and mesangium
• EM: shows electron dense deposits on epithelial cell surface “humps” = Ag-Ab complexes at epithelial cell surface
APGN clinical course?
- young child develops malaise, fever, nausea, oliguria, hematuria 1-2 weeks after recovery from sore throat
- red cell casts in urine, mild proteinuria
- periorbital edema
- mild/moderate hypertension
- elevation of antistrep Ab (ASO) titers and decline in C3 concentration
- treatment is good with conservative fluid management and most children will recover
- Adults recover in 60% of cases, 40% of adults devlope RPGN or chronic renal disease
RPGN
– Crescentic Glomerulonephritis
• rapid and progressive loss of renal fn. associated w/ severe oliguria and nephritic syndrome
• severe glomerular injury: collapsed compacted glomerular tufts
• death from renal failure occurs w/in weeks to months
• histologically see presence of crescents in glomeruli – due to proliferation of parietal and visceral epithelial cells lining Bownman capsule and infiltration of monocytes and macrophages
• rapid obliteration of urinary space
• In most cases, glomerular injury is immunologically mediated:
RPGN Type I
Type I: Anti-GBM antibody induced disease:
• IF: linear deposits of IgG and often C3 in GBM
ex. Goodpasture syndrome: pulmonary hemorrhage associated w/ renal failure
o production of anti-GBM Abs to the Type IV collagen
o ages 20-40, females more common
o presents w/ pulmonary hemorrhage, recurrent hemoptysis and later dev. of RPGN
tx: plasmapheresis to remove Abs, IMsuppressive therapy, even w/ tx prognosis is poor
RPGN Type III
Pauci-Immune type: 50% prevalence
• defined by lack of anti-GBM aabs or immune complexes via IF
• pt. have circulating antineutrophil cytoplasmic Abs (ANCAs) that produce cytoplasmic or perinuclear staining patterns
RPGN Type II
: Immune Complex Deposition:
o ex: Idiopathic, Post-infectious GN, Lupus nephritis, Henoch-Schonlein purpura (IgA nephropathy), acute proliferative GN
o RPGN frequently shows cellular proliferation w/in the glomerular tuft in addition to crescent formation
o pt. can not normally be helped by plasmapheresis
histology of RPGN?
- kidneys enlarged and pale
- crescents formed by proliferation of parietal (and visceral) epithelial cells and migration of monocytes and macrophages into urinary space
- Fibrin strands are frequently prominent b/w the cellular layers of the crescents
- EM may show ruptures in the GBM
clinical course of RPGN?
- hematuria w/ RBC casts in urine
- moderate proteinuria occasionally reaching the nephrotic range
- variable HTN and edema
- in Goodpasture syndrome may see hemoptysis and life-threatening pulmonary hemorrhage
- renal involvement is progressive and may cause severe oliguria in a few weeks
most common nephrotic syndromes in adults?
most common in children?
- FSGS
- MG
children: MCD
membranous glomerulopathy Pathogenesis/histology?
second most common cause of nephrotic syndrome in adults
• diffuse thickening of glomerular capillary wall due to accumulation of electron dense, Ig-containing deposits along the subepithelial side of BM
o “spikes” project from BM toward urinary space
o effaced foot processes (worn away)
o Thick BM: 5-20 fold increase in thickeness
o Subepithelial Deposits: dense aggregates of IgG → give “lumpy bumpy” spike appearance
- Autoimmune disease linked w/ HLA-DQA1 and Abs to renal autoantigen PLA2 receptor and IgG’s
- 85% idiopathic, no associated condition – responds poorly to steroid tx
Can be Secondary, associated with: (responds better to tx)
o Drugs: penicillamine, NSAID’s
o Malignant tumors: carcinomas of lung and colon and melanoma
o SLE
o Infections: chronic hep B, hep C, syphilis, schistosomiasis, malaria
o AI disorders (Hashimoto’s thyroiditis)
clinical features of MG?
- onset of nephrotic syndrome: nonselective proteinuria seen in 60%
- hematuria and and mild hypertension in 15-35%
- 40% develop renal insufficiency
- 10% progress to ESRF
- corticosteroids and IS tx generally no efficacious, in contrast with tx of patients with minimal change disease
MCD path/histo?
most common cause of nephrotic disease in children !!!
- peaks incidence: ages 2 to 6
- disease sometimes follows resp. infection / prophylactic immunization
dramatic response to corticosteroid therapy – completely reversible!
Morphology:
• glomeruli are normal by light microscopy
• principle lesion is in visceral epithelial cells which show uniform and diffuse effacement of foot processes = “fusion” of foot processes
MCD clinically?
- massive proteinuria: usually selective, only albumin
- renal fn. remains good, no HTN or hematuria
- MCD in adults linked with Hodgkin lymphoma and lymphomas/leukemias
- The 5 - 10% of putative minimal change disease (MCD) in children that does not respond to corticosteroid therapy generally have FSGS upon biopsy
what treat w/ corticosteroids?
MCD
FSGS path/histo?
focal = only some glomeruli are affected, segmental= only a portion of glomerular tuft exhibits sclerosis
most common cause of NS in adults in US!!!
- nephrotic syndrome w/ heavy proteinuria
- often associated with: HIV, heroin addiction, SS disease, morbid obesity
• Idiopathic FSGS is the most common cause of nephrotic syndrome in adults in US: esp. Hispanic and African-America patients
• Uncommmon inherited forms of genes that encode proteins localized in the podocyte slit diaphragms and adjacent cytoskeletal structures:
o NPHS1: nephrin, key component of slit diaphragm
o NPHS2: podocin, (accounts for 30% of steroid-resistant nephrotic syndromes in children)
o alpha-actinin 4 protein
o TRPC6 and APOL1 proteins
Pathogenesis:
• degeneration and focal disruption of visceral epithelial cells
• lesions tend to involve the juxtamedullary glomeruli
• see collapse of capillary loops
• sclerotic/nonsclerotic areas show diffuse effacement of foot processes
• in time this leads to global sclerosis of glomeruli
• collapsing glomerulopathy – subtype of FSGS
FSGS clinically?
heavy, nonselective proteinuria
- can also have hematuria, reduced GFR and HTN
• generally a diagnosis that implies a poor prognosis as progressive renal disease tends to occur
• 20% of patients follow an unusually rapid course with massive proteinuria and renal failure within 2 years
• little tendency for spontaneous remission, though children have better prognosis
how does MCD differ from FSGS?
- FSGS has higher incidence of hematuria, reduced GFR and HTN
- in FSGS proteineuria is nonselective
- FSGS has poor response to corticosteroid therapy
- FSGS has progression to CKD with at least 50% developing ESRD w/in 10 years
HIV-associated nephropathy
• most commonly a severe form of collapsing variant of FSGS
o collapsing variant occurs in 5-10% of HIV-infected individuals and occurs more frequently in African-Americans than in Caucasians
o collapsing variant tends is NOT JUST CONFINED TO GLOMERULUS!!!
• see striking focal cystic dilation of tubule segments, filled with proteinaceous material, inflammation and fibrosis
• Pathogenesis is related to infection of glomerular and tubular cells by HIV due to podocyte expression of HIV gene products
• Human Immunodeficiency Virus (HIV) infection can directly or indirectly cause renal disease including acute renal failure and/or acute interstitial nephritis
Membranoproliferative Glomerulonephritis (MPGN) path/histo?
- mixed nephritic/nephrotic
“mesangiocapillary glomerulonephritis”
• Marked by alterations in glomerular BM, proliferation of glomerular cells and leukocyte infiltration
o glomerular proliferation is predominantly mesangial cells but may occasionally involve capillary loops
Histology:
• Mesangial cell proliferation
• Increased mesangial matrix (looks black)
• BM thickening and splitting
• Accentuation of lobular architecture
• Influx of acute inflammatory cell – neutrophils
clinical features of MPGN?
- present in adolescence/adulthood w/ nephrotic syndrome and nephritic component marked by hematuria or mild proteinemia
- nephritic features: microscopic hematuria, HTN, oliguria, edema, renal insufficiency
- nephrotic features: varying degrees of proteinuria
- few spontaneous remissions
- 50% develop CRD over 10 year span
- high recurrence in transplant
- no tx known
Type I MPGN?
- Subendothelial deposits
* evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways
Type II MPGN?
“Dense deposit disease”
• intramembranous deposits (in GBM)
• children and young adults
• hematuria w/ nephritic factor and/or NS or subnephrotic proteinuria
• considered a type of C3 glomerulopathy:
profound hypoclomementemia
o C3NEF or “nephritic factor” IgG autoantibody binds C3 convertase leading to continuous activation of alternative pathway
recurrence of MPGN II following renal transplant supports role of circulating factor
secondary MPGN?
• occurs more in adults
• assoc.. w/ chronic antigenemia – resulting from immune complex disorders
o Hep B/C, SLE, alpha1 antitrypsin deficiency, HIV, Schistomosiasis, Malignancy, lymphorecticular lymphomas, melanoma
• poor prognosis as primary, with relentless progression to chronic renal failure (50% in 10 years)
IgA nephropathy path/hist?
“Berger Disease”
• focal proliferative nephritis , most often involving mesangium and not capillary loops
• most common cause of GN worldwide
• cause of recurrent gross or microscopic hematuria
Histology
• Renal biopsy shows glomeruli/mesangial proliferation
• IF: mesangial deposits of IgA and C3
• see mesangial cell proliferation and matrix increase
IgA nephropathy clinical features?
- recurrent gross hematuria (predominantly nephritic presentation)
- onset may follow resp. infection
- mostly affects older children/young adults
- more common in Caucasians/Asians
- male predominance
- gross hematuria after infection of respiratory, GI or urinary tract
- hematuria typically lasts for several days and subsides, but reteurns every few months
- slow progression to chronic renal failure in 15-40% of people within 20 years
- onset in old age results in increased progression
two eponymic disease assoc w/ IgA nephropathy?
• Berger Disease: Renal IgA nephropathy - no systemic disease
• Henoch-Schonlein purpura (HSP) - IgA nephropathy associated with systemic disease with skin (purpuric) manifestations and involvement of abdominal viscera other than kidney
o HSP is IgA mediated systemic vasculitis syndrome
o systemic childhood diseases
o onset often follows URI
o IgA nephropathy
o Ab pain, GI bleeding, arthralgia and palpable purpura on legs and buttocks
o deposition of IgA and sometimes IgG/C3 in mesangial region
2 diseases from family hx of hematuria?
- alport syndrome (hereditary nephritis)
- Thin BM disease
80% with family hx of hematuria during childhood have these
Alport Syndrome
Hereditary Nephritis
• Typically presents at ages 5 – 20
• Generally exhibits hematuria with progression to CRF, nerve deafness and a potential spectrum of certain eye disorders (lens dislocation, posterior cataracts, corneal dystrophy) and auditory defects
• X-linked form and gender distribution
• In X-linked forms large deletions of alpha5 chain (COL4A5) of type IV collagen imply the likelihood of ESRD at an earlier age
Histology: Irregular thickening of GBM, “moth-eaten”/ frayed
thin BM disease
benign familial hematuria”
• usually a benign disease marked by diffuse thinning of GBM
• asymptomatic hematuria, mild/moderate proteineuria may exist
• prognosis is excellent – most pt. are heterozygotes for defective gene and thus are carriers
• unlike Alport, hearing loss, ocular problems, and family hx of renal failure are absent
which glomerulonephridities most cause chronic GN?
- crescentic (RPGN)
- FSGS
- MPGN
4/5: membranous nephropathy, IgA nephritis
clinical course of chronic glomerulonephritis?
Morphology: • cortex is thinned and increase in peripelvic fat • obliteration of glomeruli • arterial/arteriolar sclerosis • marked atrophy of associated tubules
Dialysis changes:
• arterial intimal thickening
• deposits of calcium oxalate crystals
• acquired cystic disease
Uremic complications:
• uremic pericarditis
• secondary hyperparathyroidism
• left ventricle hypertrophy
Clinical Course:
• slowly progresses to renal insufficiency and death from uremia
• pt. presents w/ complaints of loss of appetite, anemia, vomiting, weakness, edema
• proteinuria, HTN and azotemia are discovered upon medical examination
• most patients are hypertensive and sometimes shows up cerebral and cardiovascular
systemic diseases causing nephrotic syndrome/proteinuria?
- Diabetic Neuropathy
- SLE – 15% of patients
- Hep C- Cryoglobulinemia: Membranoproliferative Type 1
- HIV Nephropathy: Focal Segmental Glomerulosclerosis
systemic diseases causing nephritic sx?
- SLE (60-70%)
- Bacterial Endocarditis: Acute proliferative Glomerulonephritis
- Goodpasture Syndrome: RPGN
- Henoch-Schonlein Purpura (HSP): IgA Nephropathy
SLE
- can cause damage to kidney and includes hematuria, nephritic syndrome, nephrotic syndrome, HTN and renal failure
- in SLE see subendothelial dense deposits
- Renal glomerular capillary BM with dense deposits are called “wire loops” – due to the deposits stiffly opening the capillary loops in the glomerulus
- Marked increase in cellularity, glomerulus size is greatly enlarged and appears to be “stuffed” into Bowman’s capsule = decrease in urinary space
- IF: anti-IgG Abs seen in mesangial and capillary wall (subendothelial IgG localization)
review: what is SLE?
• characterized by autoantibodies that recognize ANA’s: antinuclear antibodies: directed against nuclear ags and can be grouped into four categories:
o 1: antibodies to DNA
o 2. antibodies to histones
o 3. antibodies to nonhistone proteins bound to RNA
o 4. antibodies to nucleolar antigens
• SLE starts out acutely, and becomes chronic and is characterized by febrile illness, injury to skin, joints, kidney and serosal membranes
• SLE effects women more often than men and is more predominant in black and Hispanic populations
malar rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, seizures, hemalytic anemia,
Diabetic nephropathy?
leading cause of kidney failure in US!
• non-nephrotic proteinuria, nephrotic syndrome, or chronic renal failure
• Changes to glomeruli:
o capillary BM thickening
o diffuse mesangial sclerosis
o nodular glomerulosclerosis
- advanced renal hyaline arterosclerosis:
o see markedly thickened afferent arterioles
Pathogenesis:
o DM glomeruosclerosis is most likely a metabolic defect due to insulin deficiency causing hyperglycemia and glucose intolerance
• see increased amounts of collagen type IV and increased ROS → damage glomerular filter: results in increased mesangial matrix
bacterial endocarditis-associated glomerulonephritis?
- immune complex nephritis initiated by complexes of bacteria Ag/Ab
- hematuria and proteinuria
amyloidosis
- deposits of amyloid w/in the glomeruli due to renal amyloid light chain- AL
- presents w/in the mesangium and capillary walls – eventually obliterates glomerulus completely
- congo red – positive test
- first present w/ nephrotic syndrome and may later die of uremia
