Renal Pathology Part 3 Flashcards Preview

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1

Nephrotic syndrome

-caused by a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins
-massive proteinuria, hypoalbuminemia, generalized edema, hyperlipidemia, lipiduria

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Highly selective proteinuria consists mostly of

low-molecular-weight proteins (albumin, transferrin)

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Poorly selective proteinuria consists of

-higher-molecular-weight globulins in addition to albumin

4

Most patients with nephrotic syndrome have

-increased blood levels of cholesterol, triglycerides, very-low-density lipoprotein, low-density lipoprotein, Lp(a) lipoprotein, and apoprotein, and there is a decrease in high-density lipoprotein concentrations in some patients
-these defects seem to be due to a combination of increased synthesis of lipoproteins in the liver, abnormal transport of circulation lipid particles, and decreased lipid cabalism
-Lipiduria follows hyperlipidemia, because lipoproteins also leak across glomerular capillary wall

5

In nephrotic syndrome, lipid appears in urine as

either free fat or as oval fat bodies, representing lipoprotein resorbed by tubular epithelial cells and then shed along with injured tubular cells that have detached from the basement membrane

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Nephrotic patients are particularly vulnerable to

infection, especially staph and pneumococcal infections, probably due to loss of immunoglobulins in the urine
-thrombotic and thromboembolic complications are also common, due in part to loss of endogenous anticoagulants in the urine
-Renal vein thrombosis is most often a consequence of the hyper coagulable state, particularly in patients with membranous nephropathy

7

In children younger than 17 years in North America, nephrotic syndrome is

almost always caused by a lesion primary to the kidney; among adults, it is often associated with a systemic disease

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The most frequent systemic causes of the nephrotic syndrome are

diabetes, amyloidosis, and SLE

9

The most important of the primary glomerular lesions of nephrotic syndrome are

minimal-change disease (most common in children in North America), membranous glomerulopathy (most common in older adults), and focal segmental glomerulosclerosis (all ages)

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Membranous nephropathy is characterized by

-diffuse thickening of the glomerular capillary wall due to the accumulation of deposits containing Ig along the sub epithelial side of the basement membrane.
-form of chronic immune complex-mediated disease

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Cases of secondary membranous nephropathy

-drugs (penicillamine, captopril, gold, NSAIDS)
-underlying malignant tumors
-SLE
-infections
-Other autoimmune disorders

12

Primary membranous nephropathy is considerd to be

-an autoimmune disease linked to certain HLA alleles (HLA-DQA1) and caused in most cases by antibodies to a renal auto antigen (phospholipase A2 receptor in adults)
-lesions ressemble experimental Heymann nephritis (megalin antigenic complex in rat podocyte)
-C5b-C9 activates glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage.
-IgG4 is main Ig deposited

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Membranous Nephropathy light microscopy

-glomeruli either appear normal in the early stages of the disease or exhibit uniform, diffuse thickening of the glomerular capillary wall

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membranous Nephropathy electron microscopy

-the thickening is seen to be caused by irregular electron dense deposits containing immune complexes between the basement membrane and the overlying epithelial cells, with effacement of podocyte foot processes.
-basement membrane material is laid down between these deposits, appearing as irregular spikes protruding form the GBM
-These spikes are best seen by silver stains, which color the basement membrane, but not the deposits, black
-in time the spikes thicken to produce domelike protrusions and eventually close over the immune deposits, burying them within a markedly thickened, irregular membrane

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Membranous Nephropathy Immunfluorescence microscopy

-granular deposits contain both immunoglobulins and complement
-as the disease advances segmental sclerosis may occur; in the course of time glomeruli may become totally sclerosed
-the epithelial cells of the proximal tubules contain protein reabsorption droplets, and there may be considerable interstitial mononuclear cell inflammation

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Membranous Nephropathy usually presents with

-insidious onset of the nephrotic syndrome or, in about 15% of patients, with nonnephrotic proteinuria
-hematuria and mild hypertension in 15-35% of patients
-nonselective proteinuria
-complete or partial remissions may occur
-progression is associated with increasing sclerosis of glomeruli, rising serum creatinine reflecting renal insufficiency, and development of hypertension
-disease recurs in up to 40% of patients who undergo transplantation for ESRD
-may have circulating antibodies to PLA2 receptor

17

Minimal Change Disease

-relatively benign disorder characterized by diffuse effacement of foot processes of visceral epithelial cells (podocytes), detectable only by electron microscopy, in glomeruli that appear virtually normal by light microscopy.
-most frequent cause of nephrotic syndrome in children, and less common in adults
-peak incidence between 2 and 6 years of age
-sometimes follows a respiratory infection or prophylactic immunization

18

Immunological Basis of Minimal Change Disease

-clinical association with respiratory infection and immunization
-response to corticosteroids and/or other immunosuppressive therapy
-association with other atopic disorders (eczema, rhinitis)
-increased prevalence of certain HLA haplotypes in patients with disease associated with atopy
-increased incidence of minimal change disease in patients with Hodgkin lymphoma

19

Ultrastructural changes of minimal change disease point to

-a primary visceral epithelial cell injury (podocytopathy), and studies in animal models suggest the loss of glomerular polyanions

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Minimal Change Disease Electron microscopy

-GBM appear normal, and no electron-dense material is deposited
-principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes, these being reduced to a rim of cytoplasm with loss of recognizable intervening slit diaphragms.
-represents simplification of the epithelial cell architecture with flattening, retraction, and swelling of foot processes
-only when effacement is associated with normal glomeruli by light microscopy!!
-reversible after corticosteroid therapy and remission of proteinuria

21

Minimal Change Disease proximal tubules

-cells are often laden with lipid and protein, reflecting tubular reabsorption of lipoproteins passing through disease glomeruli

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Clinical Features of Minimal Change Disease

-massive proteinuria but good renal function
-NO hypertension or hematuria
-highly selective proteinuria (albumin)
-dramatic response to corticosteroid therapy
-proteinuria may recur though
-in adults, associated with lymphomas and leukemias
-secondary disease from NSAID therapy

23

Focal Segmental Glomerulosclerosis (FSGS)

-most common cause of nephrotic syndrome in adults in the U.S.
-sometimes considered to be a primary disorder of podocytes
-lesion is characterized by sclerosis of some, but not all, glomeruli; and in the affected glomeruli, only a portion of the capillary tuft is involved
-frequently manifests clinically by the acute or subacute onset of nephrotic syndrome or nonnephrotic proteinuria
-hypertension, microscopic hematuria, and some degree of azotemia are commonly present when the disease is first clinically recognized

24

Focal segmental glomerulosclerosis occurs in the following setting:

-as a primary disease
-in association with other conditions such as HIV infection, heroin addiction, sickle-cell disease, and massive obesity
-as a secondary event, reflecting scarring of previously active necrotizing lesions, in cases of focal glomerulonephritis
-as a component of the adaptive response to loss of renal tissue, whether from congenital anomalies or acquired causes, or in advanced stages of other renal disorders, such as hypertensive nephropathy
-in uncommon inherited forms of nephrotic syndrome where the disease may be caused by mutations in genes that encode proteins localized to the slit diaphragm, e.g., podocin, alpha-actinin4, and TRPC6

25

Idiopathic focal segmental glomerulosclerosis accounts for

10 and 35% of cases of nephrotic syndrome in children and adults
-has increased in incidence and is not most common cause of nephrotic syndrome in adults in the U.S. (particularly Hispanic and African-American patients

26

Clinical signs of FSGS differ from minimal change disease in the following respects:

-higher incidence of hematuria, reduced GFR and hypertension
-proteinuria is more often nonselective
-there is poor response to corticosteroid therapy
-there is progression to chronic kidney disease, with at least 50% developing ESRD within 10 years

27

Hallmark of FSGS

epithelial damage

28

Hyalinosis and sclerosis in FSGS stem from

entrapment of plasma proteins in extremely hyper permeable foci and increased ECM deposition

29

Several mutations of the NPHS gene have been identified that give rise to

congenital nephrotic syndrome of the Finnish type, producing a minimal-change disease like glomerulopathy with extensive foot process effacement

30

A distinctive pattern of autosomal recessive FSGS results from

mutations in the NPHS2 gene, which encodes the protein product podocin