IUHS Student-2-Student USMLE Step 1 Recall
Kidney
Glomerular Disease
Nephritic Syndrome
hematuria (RBC casts)...
Hypertension...
azotemia...(abnormal increase in concentration of urea and other nitrogenous substances in the blood plasma)...
oliguria...(scanty urine production)...
proteinuria (<3.5g/day)...albumin lost...moderate loss...
type III hypersensitivity reaction...
Acute
Gomerulonephritis
characterized anatomically by inflammatory alterations in the glomeruli and clinically by the syndrome of acute nephritis...
Nephritic Syndrome - the nephritis patient usually presents with hematuria, red cell casts in the urine, azotemia, oliguria, and mild to moderate hypertension...
pulmonary congestion due to fluid overload is a common finding in acute glomerulonephritis...
the patient also commonly has proteinuria and edema, but these are not as severe as those encountered in the neprhotic syndrome...
the acute nephritis syndrome may occur in such multisystem diseases as SLE and polyarteritis nodosa...
typically, however, it is characteristic of acute proliferative glomerulonephritis and is an important component of crescentic glomerulonephritis...
anemia and hypocalcemia can be present...
Acute Proliferative (Poststreptococcal, postinfectious) Glomerulonephritis
as the
name implies, this cluster of diseases is characterized histologically by
diffuse proliferation of glomerular cells, associated with
influx of leukocytes...
these lesions are typically caused by immune complexes...the prototype exogenous pattern is postinfectious glomerulonephritis, whereas that produced by an endogenous antigen is lupus erythmatosus....
most common are streptococcal, but the disorder has also been associated with other infections...
most cases of postinfectious GN are subclinical and found among contacts of the index case...
anti-streptolysin Ab (ASLO) are present serologically...
"lumpy bumpy pattern"...
Poststreptococcal Glomerulonephritis
usually appears 1 to 4 weeks after a streptococcal infection...its an immunologically mediated disease...
the latent period between infection and onset of nephritis is compatible with the time required for the building up of antibodies...
serum complement levels are low, compatible with involvement of the complement system...
the presence of granular immune deposits in the glomeruli suggests an immune complex-mediated mechanism, and so does the finding of electron dense deposits...
a cytoplasmic antigen called endostreptosin and several cationic antigens, including a proteinase related to the streptococcal erythrogenic toxin, are present in affected glomeruli...
"lumpy bumpy pattern"...
immune complex deposition occurs sub-epithelial...subepithelial (humps) immune complexe deposits...
enlarge, hypercellular glomeruli...the hypercelllularity is caused by (1) infiltation by leukocytes, both neutrophils and monocytes, (2) proliferation of endothelial and mesangial cells and, in many cases, epithelial cells...
the
proliferation and leukocyte infiltration are diffuse, that is, involving all
lobules of all glomeruli...
there is also swelling of endothelial cells, and the combination of proliferation, swelling, and leukocyte infiltration obliterates the capillary lumens...
small deposits of fibrin within capillary lumens and mesangium can be demonstrated in most cases...there may be interstitial edema and inflammation, and the tubules often contain red cell casts...
there are granular deposits of IgG, IgM, and C3 in the mesangium and along the basement membrane...
a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cocoa-colored urine) 1 to 2 weeks after recovery from a sore throat...
the patient exhibits red cell casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension...
in adults the onset is more likely to be atypical, with the sudden appearance of hypertension or edema, frequently with elevation of BUN....
elevations of antistreptococcal antibody titers (anticationic proteinase and ant-DNase B), a decline in the serum concentration of C3, and the presence of cryoglobulins in the serum...
Rapidly
Progressive (Crescentic) Gomerulonephritis (RPGN)
RPGN is a syndrome associated with severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis...
it is characterized clinically by rapid and progressive loss of renal function associated with severe oliguria and (if untreated) death from renal failure within weeks to months...
regardless of the cause, the histologic picture is charaterized by the presence of crescents in most of the glomeruli (crescentic glomerulonephritis)...
these are produced in part by proliferation of the parietal epithelial cells and Bowman capsule and in part by infiltration of moncytes and macrophages...
complement levels are normal b/c it is not consumed in anti-GBM disease...
the renal manifestations of all forms include hematuria with red cell casts in the urine, moderate proteinuria occasionally reaching the nephrotic range, and variable hypertension and edema...
in goodpasture syndrome, the course may be dominated by recurrent hemoptysis or even life-threatening pulmonary hemorrhage...
serum
analyses for anti-GBM, antinuclear antibodies, and ANCA are helpful in the
diagnosis of specific subtypes...
rising urea nitrogen and creatinine ...
RBC casts in urine...
although milder forms of glomerular injury may subside, the renal involvement is usually progressive during a matter of weeks, culminating in severe oliguria...
within 3 months you will die from renal failure...
Type I RPGN
best remembered as anti-GBM disease and hence is characterized by linear deposits of IgG and, in many cases, C3 in the GBM, as previously described...
anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhages associated with renal failure (goodpastures syndrome)...
the goodpasture antigen resides in the noncollagenous portion of the alpha-3 chain of collagen type IV...
Type II RPGN
an immune complex-mediated disese....it can be a complicaiton of any of the immune complex nephritides, including postinfectious glomerulonephritides, SLE, IgA nephropathy, and Henoch-Schonlein purpura...
in some cases, immune complexes can be demonstrated, but the underlying cause is undertermined....
in all of these cases, immunofluorescence studies reveal the characteristic 'lumpy bumpy' (IgA, Bergers Disease) granular pattern of staining...these patients cannot usually be helped by plasmapheresis, and they require treatment for the underlying disease...
Type III RPGN
also called pauci-immune type, is defined by the lack of anit-GBM antibodies or immune complexes by immunofluorescence and electron microscopy...
most of these patients have antineutrophil cytoplasmic antibody (ANCA) in the serum, which, as plays a role in vasculitides...
type III RPGN is a component of a systemic vasculitis such as Wegener granulomatosis or microscopic polyarteritis...
pauci-immune crescentic glomerulonephritis is isolated and hence idiopathic...more than 90% of such idiopathic cases have C-ANCA or P-ANCA in the sera...
Crescentic Glomerulonephritis
kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces...
glomeruli may show focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation...
histologic picture, however, is dominated by the formation of distinctive crescents...crescents are formed by proliferation of parietal cells and by migration of monocytes and macrophages into Bowman space...
neutrophils and lymphocytes may be present...the crescents eventually obliterate Bowman space and compress the glomerular tuft...
fibrin strands are prominet between the cellular layers in the crescents, and indeed the escape of fibrin into Bowman space is an important contributor to crescent formation...
Goodpastures Syndrome
Hallmark Patient - young, adult, 20-40 years old male smoker with hemoptysis and hematuria...
immunologic markers include HLA B27 and HLA-DRw2...
subendothelial deposition...fibrinoid necrosis...
Definitive Diagnosis - circulating anti-glomerular basement membrane antibodies..anti-type IV collagen, specific for lungs and kidneys...
linear pattern on immunofluorescent staining of renal biopsy...usually IgG...2/3 also have linear C3...IgG is against the collagen...
100% of Goodpastures have glomerulonephritis...but only 80% have lung involvement...
almost all with lung involvement smokers...or other pre-existing lung damage...
most useful pulmonary function test (PFT) in Goodpastures CO diffusion...increased carbon monoxide uptake > 30% due to blood in alveoli...
Glomerulonephritis Grim: 90% have crescentic, rapidly progressive glomerulonephritis...
outlook very grim: 50% die within 2 years...
Treatment: plasmapheresis initially, to clear anti-GBM antibodies...cytotoxic agents: cyclophosphomide, azathioprine...cortisone...
IgA
Nephropathy (Berger Disease)
this form of glomerulonephritis is characterized by the presence of prominent IgA and C3 deposits in the mesangial regions, detected by immunofluorescence microscopy...
IgA nephropathy is a frequent cause of recurrent gross or microscopic hematuria and is probably the most common type of glomerulonephritis worldwide...
mild proteinuria is usually present, and the nephrotic syndrome may occasionally develop...a patient may rarely present with rapidly progressive crescentic glomerulonephritis...
secondary IgA nephropathy occurs in patients with liver and intestinal diseases...
associated with celiac sprue and Henoch-Schonlein purpura...
IgA, the main immunoglobulin in mucosal secretions...in patients with IgA nephropathy, serum polymeric IgA is increased, and circulating IgA immune complexes are present in some patients...
the prominent mesangial deposition of IgA suggest entrapment of IgA immune complexes in the mesangium, and the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway...
IgA
complexes are then entrapped in the mesangium,
where they activate the alternative complement pathway and initiate glomerular
injury...
in support of this scenario, IgA nephropathy occurs with increased frequency in patients with gluten enteropathy celiac disease), in whom intestinal mucosal defects are well defined, and in liver disease, in which there is defective hepatobiliary clearance of IgA complexes...
lumpy bumpy appearance...
disease affects young children and young adults...more than half the patients present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract...
30-40% have only microscopic hematuria, with or without proteinuria, and 5% to 10% develop a typical acute nephritic syndrome...
the hematuria typically lasts for several days and then subsides, only to return every few months...
many patients maintain normal renal function for decades...
slow progression to renal failure occurs in 25-50% of cases during a period of 20 years...
Focal
Proliferative Glomerulonephritis
focal glomerulonephritis represents a histologic entity in which glomerular proliferation is restricted to segments of individual glomeruli and commonly involves only a certain proportion of glomeruli...
focal glomerulonephritis occurs under three circumstances:
1) it may be an early manifestation of a systemic disease...SLE...
2) it may be a component of a known glomerular disease, such as IgA nephropathy...
3) it can occur unrelated to any systemic or other renal disease and constitutes a form of primary idiopathic focal glomerulonephritis...
"wire loop" appearance in glomerular capillaries...
Nephrotic Syndrome
the charge barrier of heparan sulfate is lost in nephrotic syndrome...
1) massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children)...
2) hypoalbuminemia, with plasma albumin levels less than 3 gm/dl...
3) generalized edema...pitting edema...caused by decreased capillary oncotic pressure...
4) hyperlipidemia and lipiduria...
oval fat bodies (fatty casts) present with nephrotic syndrome...
Diffuse mesangial deposition of acidophilic bodies which can be stained with iodine...
diabetes mellitus can cause nephrotic syndrome and an increase in ADH secretion...
Membranous Glomerulonephritis (Membranous Nephropathy)
membranous glomerulonephritis is the most common cause of the nephrotic syndrome in adults (85%)...it is characterized by diffuse thickening of the glomerular capillary wall and the accumulation of electron-dense, immunoglobulin containing deposits along the epithelial (subepithelial) side of the basement membrane...
membranous glomerulonephritis occurring in association with other systemic diseases and a variety of identifiable etiolgoic agents is referred to as secondary membranous glomerulonephritis...
subepithelial deposits along the basement membranes...
drugs (pencillamine), captopril, underlying malignant tumors, SLE, infections, and metabolic disorders are often associated with Membranous Glomerulonephritis...hepatitis B...
like Pencillamine...
"finely granular"..."spike and dome"
the spike and dome of the kidney world...
membranous
glomerulonephritis in humans is linked to the HLA
locus, which influences the ability to elaborate antibodies to the
nephritogenic antigen...
how does the glomerular capillary wall become leaky in membranous glomerulonephritis?...with the paucity of neutrophils, monocytes, or platelets in glomeruli and the virtually uniform presence of complement, experimental work suggests a direct action of C5b-C9, the membrane attack complex of complement...
C5b-C9 causes activation of glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage...
this disorder usually begins with the insidious onset of the nephrotic syndrome or, in 15% of patients, with non-nephrotic proteinuria...
hematuria and mild hypertension are present in 15% to 35% of cases...
the course is irregular but generally indolent...progression is associated with increasing sclerosis of glomeruli, rising BUN, relative reduction in the severity of proteinuria, and development of hypertension...
proteinuria persists in more than 60% of patients, only about 10% die or progress to renal failure within 10 years, and no more than 40% eventually develop renal insufficiency...
often associated with Lung and Colon Cancer...
Minimal
Change Disease (Lipoid Nephrosis)
this relatively benign disorder is the most frequent cause of nephrotic syndrome in children...
it is characterized by diffuse loss of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy...effacement of epithelial (podocyte) foot processes...
the peak incidence is between 2 and 6 years of age...peak age is 2 years old...
the disease sometimes follows a respiratory infection or routine prophylactic immunization...
its most characteristic feature is its usually dramatic response to corticosteroid therapy...
pathogenesis is possibly lymphokine production by T cells...
1) the clinical association with respiratory infections and prophylactic immunization...
2) the response to corticosteroid and immunosuppressive therapy....
3) the association with other atopic disorders (eczema, rhinitis)...
4) the increased prevalence of certain HLA haplotypes in patients with minimal change disease associated with atopy...
5) the increased incidence of minimal change disease in patients with Hodgkin disease, in whom defects in T cell mediated immunity are well recognized...
6) the recurrence of proteinuria after transplantation in patients with the related disorder focal segmental glomerulosclerosis...
7) reports of proteinuria-inducing factors in the plasma or lymphocyte supernatants of patients with lipoid nephrosis and focal glomerulosclerosis...
there
is elaboration of cytokine-like substances that affect visceral epithelial cells
and causes proteinuria...there is primary visceral epithelial cell injury,
defects in the charge barrier that contribute to
proteinuria...detachment of epithelial cells, a consequence of
diminshed adhesion to GBM, may also lead to protein loss....
mutation of renal glomerular protein, nephrin, this protein resembles immunoglobulin-like cell adhesion receptors that participate in cell-cell and cell-matrix interactions, thus supporting the role for epithelial adhesion defects in this disease...
despite massive proteinuria, renal function remains good, and there is commonly no hypertension or hematuria...
the proteinuria is highly selective, most of the protein consisting of albumin...
most children (more than 90%) with minimal change disease respond rapidly to corticosteroid therapy...
long term prognosis for patients is excellent, and even steroid dependent disease resolves when children reach puberty...
minimal change disease in adults can be associated with Hodgkin disease and, less frequently, other lymphomas and leukemias...
minimal change disease may follow NSAID therapy, usually in association with acute interstitial nephritis...
Periorbital edema is likely to be present...
Focal
Segmental Gomerulosclerosis
as the name implies, this lesion is characterized by sclerosis of some, but not all, glomeruli (thus it is focal); and in the affected glomeruli, only a portion of the capillary tuft is involved (thus, it is segmental)....
often occurs in children...
focal segmental glomerulosclerosis is frequently accompanied clinically by the nephrotic syndrome or heavy proteinuria...
"holly leaf" mesangial deposits...
1) in associaition with other known conditions, such as
HIV infection and heroin addiction...
2) as a secondary event, reflecting glomerular scarring, in other forms of focal glomerulonephritis (IgA nephropathy)...
3) as a component of the adaptive response in glomerular ablation nephropathy in advanced stages of other renal disorders such as reflux nephropathy, or with unilateral renal agenesis...
4) in certian inherited, congenital forms of nephrotic syndrome, where the disease, in certain pedigrees, has been linked to chromosome 19q13, close to the locus of nephrin...
5) as a primary disease (idiopathic focal segmental glomerulosclerosis)...
is associated with or accompanies other vasculitic syndromes...
accounts
for 10-15% of cases of nephrotic syndrome in children and adults...
patients differ from the usual patients with minimal change disease in the following respects (1) they have a higher incidence of hematuria, reduced GFR, and hypertension; (2) their proteinuria is more often nonselective; (3) they respond poorly to corticosteroid therapy; (4) many progress to chronic glomerulonephritis, and at least 50% develop end-stage renal disease within 10 years; and (5) immunofluorescence microscopy shows deposition of IgM and C3 in the sclerotic segment... epithelial damage is the hallmark of focal segmental glomerulosclerosis...
the hyalinosis and sclerosis represent entrapment of plasma proteins in extremely hyperpermeable foci with increased ECM deposition...
the recurrence of protienuria, sometimes within 24 hours after transplantation, suggest a circulating factor, perhaps a cytokine, as the cause of epithelial damage...
renal ablation focal segmental glomerulosclerosis occurs as a complication of glomerular and nonglomerular diseases causing reduction in functioning renal tissue, particularly reflux nephropathy and unilateral agenesis...
most often idiopathic but can be associated with HIV or heroin use...
most patients will need transplant within 10 years...
Diabetic Gomerulosclerosis (Nodular Glomerulosclerosis)
diabetes mellitus is a major cause of renal morbidity and mortality, and diabetic nephropathy is one of the leading causes of chronic kidney failure in the US...
the morphologic changes in the glomeruli include
(1) capillary basement membrane thickening,
(2) diffuse diabetic glomerulosclerosis, and
(3) nodular glomerulosclerosis...
1) diabetic glomerulosclerosis is caused by the metabolic defect, that is, the insulin deficiency, or the resultant hyperglycemia, or some other aspects of glucose intolerance...
2) biochemical alterations in diabetic GBM are significant and include increased amount and synthesis of collagen type IV and fibronectin and decreased synthesis of proteoglycan heparan sulfate...
3) nonenzymatic glycosylation of proteins, known to occur in diabetics and giving rise to advanced glycosylation end products, may contribute to glomerulopathy...
4) hemodynamic changes initiate the progression of diabetic glomerulosclerosis...there is an increased GFR, increased glomerular filtation area, increased glomerular capillary pressure, and glomerular hypertrophy...
to sum up, two process seem to play a role in the fully developed diabetic glomerular lesions: a metabolic defect, possibly linked to advanced glycosylation end products, that accounts for the thickened GBM and increased mesangial matrix that occur in all patients; and hemodynamic effects, associated with glomerular hypertrophy, which leads to glomerulosclerosis in about 40% of patients...
compensatory
release of aldosterone...
the increased GFR typical of early-onset type 1 diabetics is associated with microalbuminuria, defined as urinary albumin excretion of 30 to 300 mg/day of albumin...
microalbuminuria and increased GFR are important predictors of future overt diabetic nephropathy in these patients...
overt proteinuria then develops, which may be mild and asymptomatic initially but gradually increases to nephrotic levels in some patients...
this is followed by progressive loss of GFR, leading to end stage renal failure within a period of 5 years...
PAS+ nodules resulting from increased mesangial matrix deposition are evident...they are called
Kimmelstiel-Wilson nodules...
ovoid hylaine masses on the periphery of the glomerulus...
Membranoproliferative Glomerulonephritis (MPGN)
characterized histologically by alterations in the basement membrane, proliferation of glomerular cells, and leukocyte infiltration...
b/c the proliferation is predominantly in the mesangium, a frequently used synonym is mesangicapillary glomerulonephritis...
MPGN accounts for 5-10% of cases of idiopathic nephrotic syndrome in children and young adults...
Anti-Hep B and Anti-Hep C are serologically active...
also, cryoglobulins are present...
polyarteritis nodosa...Hep B associated...
the glomeruli are large and hypercellular...the hypercelluarity is produced by proliferation of cells in the mesangium, although infiltrating leukocytes and parietal epithelial crescents are present in many cases...
the glomeruli have a "lobular" appearance accentuated by the proliferating mesangial cells and increased mesangial matrix...
the GBM is clearly thickened, often focally, most evident in the peripheral capillary loops...
the
glomerular wall often shows a "double-contour" or
"tram-track" appearance, especially evident in silver or PAS
stains...
this is caused by duplication of the basement membrane and the inclusion within the lamina rara interna of processes of cells extending into the peripheral capillary loops, so called mesangial and monocyte interposition...
Type I - 2/3 of cases is characterized by the presence of subendothelial electrondense deposits...mesangial and occasional subepithelial deposits (double tract deposits) may also be present...C3 is deposited in a granular pattern, and IgG and early complement components C1q and C4 are often also present, suggesting an immune complex pathogenesis...
Type II - the lamina densa of the GBM is transformed into an irregular, ribbon like, extremely electron dense structure (dense deposits) b/c of the deposition of dense material of unknown composition in the GBM proper, giving rise to the term "dense-deposit disease"...granular and linear pattern of C3...
Type III - C3 is present in irreular granular-linear foci in the basement membranes on either side, but not within the dense deposits...C3 is also present in the mesangium in characterisitc circular aggregates (mesangial rings)...IgG is usually absent, as are the early acting complement components (C1q and C4)...
most cases of type I MPGN present evidence of immune complexes in the glomerulus and activation of both classic and alternative complement pathways...
conversely,
most patients with dense-deposit disease (type II) have
abnormalities that suggest activation of the alternative complement pathway...
these patients have a consistently decreased serum C3, but normal C1 and C4, the immune-complex activated early components of complement...
they also have diminished serum levels of factor B and properdin, components of the alternative complement pathway...
may be secondary to many systemic disorders (SLE, endocarditis), chronic infections (HBV, HCV, HIV), and malignancies (CLL)...
manifested by hematuria or, more insidiously, as mild proteinuria...
few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course...
some patients develop numerous crescents and a clinical picture of RPGN...
about 50% develop chronic renal failure within 10 years...treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not been proved to be materially effective...
Alport Syndrome
alport
syndrome is the name usually given to the disease in which
nephritis is accompanied by nerve deafness and various
eye disorders, including lens dislocation, posterior cataracts, and corneal
dystrophy...
males tend to be more affected more frequently and more severely than females and are more likely to progress to renal failure...
females, however, are not completely spared...
the mode of inheritance is heterogeneous...
most patients have an X-linked dominant pattern, but autosomal recessive and autosomal dominant pedigrees also exist...
glomeruli are always involved...the most common early lesion is segmental proliferation or sclerosis, or both...
there is an increase in mesangial matrix and, in some patients, the persistence of fetal-like glomeruli...
in some glomerular or tubular epithelial cells acquire a foamy appearance owing to accumulation of neutral fats and mucopolysaccharides (foam cells)...
as the disease
progresses, there is increasing glomerulosclerosis,
vascular narrowing,
tubular atrophy, and interstitial fibrosis...
the GBM shows irregular foci of thickening or attenuation (thinning), with pronounced splitting and lamination of the lamina densa...
similar alterations are found in the tubular basement membranes...
the most common presenting sign is gross or microscopic hematuria, frequently accompanied by erythrocyte casts...
proteinuria may occur and, rarely, the nephrotic syndrome develops...
symptoms appear at ages 5 to 20 years, and the onset of overt renal failure is between ages 20 and 50 years in men...
the auditory defects may be subtle, requireing sensitive testing...
Chronic Glomerulonephritis
best
considered an end-stage pool of glomerular disease fed by a number of streams of
specific types of glomerulonephritis...
most cases of chronic glomerulonephritis occurs as sequela of poststreptococcal glomerulonephritis, rapidly progressive GN, membranous GN, focal glomerulosclerosis, membranoproliferative GN, IgA nephropathy...
often waxy casts are present or otherwise called broad casts in urine analysis...
the kidneys are symmetrically contracted and have diffusely granular, cortical surfaces...
on section, the cortex is thinned, and there is an increase in peripelvic fat...
in early cases, the glomeruli may still show evidence of the primary disease...however, there eventually ensues hyaline obliteration of glomeruli, transforming them into acellular eosinophilic masses...
the hyaline represents a combination of trapped plasma proteins, increased mesangial matrix, basement membrane-like material, and collagen...
b/c hypertension is an accompaniment of chronic glomerulonephritis, arterial and arteriolar sclerosis may be conspicuous...
marked atrophy
of associated tubules,
irregular interstitial fibrosis, and
lyphocytic infiltation also occur...
develops insidiously and slowly progresses to death in uremia during a span of years or possibly decades...
complaints of a loss of appetite, anemia, vomiting, or weakness...
most patients are hypertensive and sometimes the dominant clinical manifestation are cerebral or cardiovascular...
hyperkalemia and hypermagnesemia are due to decreased excretion...
1,25 dihydoxyvitamin D suppresses PTH production in patients with bone abnormalities with chronic renal failure...