RENAL LECTURE NOTES Flashcards
Blood Vessels
l ___________ – most richly vascularized part;
receives 90% of total renal blood supply
l Renal artery–> interlobar arteries –>arcuate arteries –>interlobular arteries–> l Afferent arterioles enter glomerular tuft; subdivide into 20 to 40 capillary loops
l Capillary loops merge to exit as efferent arterioles
Cortex
What is the blood flow of the kidney?
l Renal artery–> interlobar arteries –>arcuate arteries –>interlobular arteries–> l Afferent arterioles enter glomerular tuft; subdivide into 20 to 40 capillary loops
Note: l Capillary loops merge to exit as efferent arterioles
Blood Vessels
l Efferent arterioles from superficial nephrons form _____________
peritubular vascular network
l Deeper juxtamedullary glomeruli give rise to ____________
vasa recta
l Vasa recta descend as straight vessels to supply _____________
outer and inner medulla
l Anastomosing network of capillaries lined by fenestrated endothelium invested by two layers of epithelium
l Visceral epithelium – part of the capillary wall; separated from endothelial cells by a basement membrane
l Parietal epithelium – lines the urinary space (cavity in which plasma filtrate first collects)
Glomeruli
____________– part of the capillary wall; separated from endothelial cells by a basement membrane
)
l Visceral epithelium
____________ – lines the urinary space (cavity in which plasma filtrate first collects
l Parietal epithelium
Glomerular capillary wall – filtering membrane and consists of:
- Endothelial cells
- Glomerular basement membrane (GBM)
– lamina densa,
lamina rara interna
and externa
- Visceral epithelial cells (podocytes)
– foot processes and filtration slits
- Mesangial cells – lie between capillaries; basement membrane-like mesangial matrix
§ Contractile, phagocytic, capable of proliferation, lay down both matrix and collagen, secrete biologically active mediators
§ Important players in many forms of glomerulonephritis
Mesangial cells:
Glomeruli Major characteristics of normal glomerular filtration:
§ High permeability to water and small solutes
§ Impermeability to proteins (albumin)
– glomerular barrier function (size- and chargedependent)
________________- is important for the maintenance of glomerular barrier function
l Proteins located in slit diaphragm control glomerular permeability
l Mutations in genes encoding proteins give rise to nephrotic syndrome
l Visceral epithelial cell (slit diaphragm)
_______________
: l Reabsorption of 2/3 of filtered Na, H2O, glucose, K, phosphate, amino acids and proteins
l Vulnerable to ischemic damage
l Toxins are frequently reabsorbed rendering it susceptible to chemical injury
Tubules Proximal tubules
Tubules Juxtaglomerular apparatus:
l JG cells – modified smooth muscle cells in the media of afferent arteriole; produce renin
l Macula densa
l Lacis cells or nongranular cells – resemble mesangial cells
________- – modified smooth muscle cells in the media of afferent arteriole; produce renin
JG cells
_________________– resemble mesangial cells
Lacis cells or nongranular cells
l Normal cortex: compact interstitial space occupied by peritubular capillaries and fibroblast-like cells
l Expansion of the cortical interstitium is abnormal (edema or inflammatory cells)
Interstitium
___________– elevation of BUN and creatinine levels;
related to decreased GFR
Azotemia
_________– hypoperfusion of the kidneys (hemorrhage, shock, volume depletion, CHF) that impairs renal function in the absence of parenchymal damage
l Prerenal
____________– urine flow obstruction below the level of kidney
l Postrenal
___________
l Azotemia with S/Sx
l Characterized by failure of renal excretory function and metabolic and endocrine alterations
Uremia
Principal Systemic Manifestations
of CRF and Uremia
Fluid and Electrolytes:
l Dehydration
l Edema
l Hyperkalemia
l Metabolic acidosis
Calcium Phosphate and Bone:
l Hyperphosphatemia
l Hypocalcemia
l Secondary hyperparathyroidism
l Renal osteodystrophy
Hematologic:______________
l Anemia l Bleeding diathesis
Cardiopulmonary:
l HPN
l CHF
l Cardiomyopathy
l Pulmonary edema
l Uremic pericarditis
Gastrointestinal:
l Nausea and vomiting l Bleeding l Esophagitis, gastritis, colitis
Neuromuscular: l
Myopathy l Peripheral neuropathy l Encephalopathy
Dermatologic:
l Sallow color
l Pruritus
l Dermatitis
CLINICAL MANIFESTATIONS OF RENAL DISEASES l Acute nephritic syndrome
l Nephrotic syndrome
l Rapidly progressive glomerulonephritis –
l Acute renal failure –
l Chronic renal failure
_____________________ – nephritic syndrome with rapid decline (hours to days) in GFR
Rapidly progressive glomerulonephritis
______________ – oliguria or anuria with recent onset azotemia; can result from glomerular, interstitial, vascular or acute tubular injury
Acute renal failure
___________ – prolonged S/Sx of uremia; end result of all chronic renal parenchymal diseases
Chronic renal failure
Polyuria, nocturia, electrolyte disorders – ______________
renal tubular defects
l Bacteriuria and pyuria – _______________
UTI
l Renal colic, hematuria – ___________________
nephrolithiasis
l Asymptomatic hematuria or proteinuria ________________
– subtle glomerular abnormalities
GLOMERULAR DISEASES Primary Glomerulopathies:
l Acute proliferative glomerulonephritis – postinfectious, other
l Rapidly progressive (crescentic) glomerulonephritis
l Membranous glomerulopathy
l Minimal change disease
l Focal segmental glomerulosclerosis
l Membranoproliferative glomerulonephritis
l IgA nephropathy
l Chronic glomerulonephritis
GLOMERULAR DISEASES
Systemic Diseases with Glomerular Involvement:
l SLE
l DM l
Amyloidosis
l Goodpasture syndrome
l Microscopic polyarteritis/polyangiitis
l Wegener granulomatosis
l Henoch-Schönlein purpura
l Bacterial endocarditis
GLOMERULAR DISEASES
Hereditary Disorders:
l Alport syndrome
l Thin basement membrane disease
l Fabry disease
Clinical Manifestations
Glomerular Syndromes:
l Nephritic syndrome
l Rapidly progressive glomerulonephritis
l Nephrotic syndrome
l Chronic renal failure
l Isolated urinary abnormalities: hematuria and/or subnephrotic proteinuria
Histologic Alterations
l Hypercellularity
l Basement membrane thickening
l Hyalinization and sclerosis
Histologic Alterations
- Hypercellularity
l Cellular proliferation of mesangial or endothelial cells
l Leukocytic infiltration
l Formation of crescents
l Proliferating parietal epithelial cells and infiltrating leukocytes
l Fibrin as well as tissue factor, IL-1, TNF, interferon- γ elicit crescentic response
Histologic Alterations –BM Thickening
Light microscopy: l________________
Electron microscopy:
__________________
__________________
Thickening of capillary walls (PAS stain)
- l Deposition of amorphous electron-dense material (immune complexes, fibrin, amyloid, cryoglobulins, abnormal fibrillary protein)
- l Thickening of the basement membrane in diabetic glomerulosclerosis
__________________
l Accumulation of homogeneous and eosinophilic materia
l l Hyalin - plasma proteins from circulating plasma into glomerular structures
l Consequence of endothelial or capillary wall injury;
end result of glomerular damage
l A common feature of FSGS
Hyalinosis:
_______________
l Accumulation of extracellular collagenous matrix
l Mesangium (DM) or capillary loops
l May result in obliteration of capillary lumina in affected glomeruli
Sclerosis:
_________ underlie most forms of primary glomerulopathy and many of the secondary glomerular disorders
Immune mechanisms
Immune Mechanisms of Glomerular Injury
l Antibody-Mediated Injury
l In Situ Immune Complex Deposition
l Circulating Immune Complex Deposition
l Cytotoxic Antibodies
l Cell-Mediated Immune Injury
l Activation of Alternative Complement Pathway (occurs in dense deposit disease)
______________
l In these forms of injury, antibodies react directly with intrinsic tissue antigen, or antigens “planted” in the glomerulus from the circulation
l Anti-GBM antibody induced nephritis
l Heymann nephritis (membranous glomerulopathy)
Immune Complex Deposition Involving Intrinsic and in Situ Renal Antigens
________________
l Antibodies are directed against intrinsic fixed antigens that are normal components of the GBM proper
l Anti-GBM antibodies cross-react with other BM: Goodpasture syndrome
l GBM antigen is a component of the noncollagenous domain of the alpha 3-chain of collagen type IV
Anti-GBM Antibody-Induced Nephritis:
l Diffuse linear staining for the antibodies by immunofluorescent techniques
l Characterized by severe crescentic glomerular damage and the clinical syndrome of RPGN
Anti-GBM Antibody-Induced Nephritis:
Immune Complex Deposition Involving Intrinsic and in Situ Renal __________________________
l Antibodies react in situ with antigens not normally present in the glomerulus but are “planted” there
l Cationic molecules; DNA, nucleosomes, other nuclear proteins; bacterial products; large aggregated proteins; immune complexes l Granular staining pattern by IF microscopy
Antigens Antibodies against Planted Antigens:
_____________
l Presence of numerous electron-dense granular deposits (immune reactants) along the subepithelial aspect of basement membrane
l Membranous glomerulopathy
Heymann Nephritis:
Circulating Immune Complex
Nephritis
l Glomerular injury is caused by the trapping of
circulating Ag-Ab complexes within glomeruli
l Abs have no immunologic specificity for
glomerular constituents
l Complexes localize within the glomeruli due
to their physicochemical properties and
hemodynamic factors
l Antigens that trigger formation of circulating immune
complexes may be endogenous (SLE) or exogenous
(infections)
l Microbial antigens include bacterial products
(streptococci), HBsAg, Hepatitis C antigen, antigens
of T. pallidum, P. falciparum
l Tumor antigens also cause IC-mediated nephritis
l In many cases, inciting antigen is unknown
Circulating Immune Complex
Nephritis
Circulating Immune Complex
Nephritis
l Glomerulus:____________________
l EM:_______________
l IF: ______________
- leukocytic infiltration and proliferation of mesangial and endothelial cells
- immune complexes as
electron-dense deposits
(mesangium, subendothelial,
subepithelial) - ICs seen as granular
deposits along the basement
membrane, in mesangium or
both
Antibodies to Glomerular Cells
l Abs to mesangial cell antigens –_______________
l Abs to endothelial cell antigens – ______________
l Abs to podocyte components – _______________
- mesangiolysis and mesangial cell proliferation
- endothelial injury and intravascular thrombosis
- proteinuria
Mechanisms of Progression in Glomerular Diseases
Two major histologic characteristics of progressive renal damage:
l Focal segmental glomerulosclerosis
l Tubulointerstitial fibrosis
___________________________
l Proteinuria
l Sclerosis initiated by the adaptive change that occurs in unaffected glomeruli of diseased kidneys
l TGF-ß play a role in induction of sclerosis
l Contributing to progressive injury is the inability of podocytes to proliferate after injury
Focal Segmental Glomerulosclerosis
______________
l Component of many acute and chronic GN
l Contributes to progression in both immune and nonimmune glomerular diseases (DM)
l Factors that lead to tubulointerstitial injury: ischemia of tubule, acute and chronic inflammation in the adjacent interstitium, damage or loss of the peritubular capillary blood supply
Tubulointerstitial Fibrosis
l Hematuria, red cell casts in the urine, azotemia, oliguria, mild to moderate HPN
l Proteinuria and edema
l Glomerular diseases presenting with nephritic syndrome are characterized by inflammation in the glomeruli
l Characteristic of acute proliferative GN and is an important component of crescentic GN
l May occur in multisystem diseases: SLE, microscopic polyangiitis
Nephritic Syndrome
l Diffuse proliferation of glomerular cells with influx of leukocytes l Caused by immune complexes
l Inciting antigen may be exogenous (postinfectious glomerulonephritis) or endogenous (lupus nephritis)
Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis
l Appears 1-4 weeks after a streptococcal infection of pharynx or skin (impetigo)
l Occurs most frequently in children 6-10 years old
Poststreptococcal Glomerulonephritis
s Etiology and Pathogenesis:
l Group A ß-hemolytic streptococci
l Immunologically-mediated
l Elevated titers of Abs against streptococcal antigens
l Low serum complement levels (activation and consumption of complement components)
l Granular immune deposits in glomeruli and electron dense deposits immune complex mediated mechanism
Poststreptococcal Glomerulonephriti
Morphology:
l Enlarged, hypercellular glomeruli caused by: infiltration by leukocytes, proliferation of endothelial and mesangial cells, crescent formation
l Capillary lumen obliteration
l Interstitial edema and inflammation
l Tubules with red cell casts
Poststreptococcal Glomerulonephritis
l IF microscopy: granular deposits of IgG, IgM, and C3 in mesangium and along GBM
Poststreptococcal Glomerulonephritis
Poststreptococcal Glomerulonephritis
Electron Microscopy:
l Discrete, amorphous, electron dense deposits on epithelial side of membrane (“humps”)
l Subendothelial, intramembranous and mesangial deposits are also seen Acute proliferative glomerulonephritis.
A, Normal glomerulus.
B, Glomerular hypercellularity is due to intracapillary leukocytes and proliferation of intrinsic glomerular cells.
C, Typical electron-dense subepithelial “hump” and a neutrophil in the lumen.
Poststreptococcal Glomerulonephritis
Clinical Course:
l Malaise, fever, nausea, oliguria, hematuria 1-2 weeks after recovery from a sore throat
l Red cell casts in urine, mild proteinuria (<1 gm/day)
l Periorbital edema, mild to moderate HPN l
Elevations of antistreptococcal Ab titers; decline in serum C3 l 95% of affected children recover
l Occurs sporadically in association with bacterial infections (staph endocarditis), viral disease, parasitic infections
l Granular immunofluorescent deposits and subepithelial humps are present
Nonstreptococcal Acute Glomerulonephritis (Postinfectious Glomerulonephritis)
l A syndrome associated with severe glomerular injury
l Characterized clinically by rapid and progressive loss of renal function with severe oliguria and signs of nephritic syndrome
l If untreated, death from renal failure occurs within weeks to months
l Most common histologic picture: crescents in most of the glomeruli
Rapidly Progressive (Crescentic) Glomerulonephritis
Rapidly Progressive (Crescentic) Glomerulonephritis Classification (immunological findings) and Pathogenesis:
l Type I RPGN – anti-GBM antibody-induced disease
l Type II RPGN – immune complex-mediated disease
l Type III RPGN – pauci-immune type
Rapidly Progressive (Crescentic) Glomerulonephritis
l All 3 types may be associated with a welldefined renal or extrarenal disease, but in approximately 50% of cases, the disorder is idiopathic
l The common denominator in all types of RPGN is ______________
severe glomerular injury
Rapidly Progressive (Crescentic) Glomerulonephritis
l Linear deposits of IgG and C3 in the GBM
l Anti-GBM antibodies cross-react with pulmonary alveolar bm Goodpasture syndrome
l Tx: Plasmapheresis to remove circulating Abs combined with steroids and cytotoxic agents
l Goodpasture antigen is a peptide within the noncollagenous portion of the α3 chain of collagen type IV
Type I RPGN:
Rapidly Progressive (Crescentic) Glomerulonephritis
l Can be a complication of any of the immune complex nephritides: postinfectious GN, lupus nephritis, IgA nephropathy, Henoch-Schönlein purpura
l IF: granular pattern of staining characteristic of immune complex deposition
l Cellular proliferation within glomerular tuft and crescent formation
l Require tx of underlying disease
Type II RPGN:
Rapidly Progressive (Crescentic) Glomerulonephritis
l Lack of anti-GBM Abs or immune complexes by IF and EM
l Most patients have circulating ANCAs that produce cytoplasmic (c) or perinuclear (p) staining patterns
l Component of systemic vasculitis – Wegener granulomatosis or microscopic polyangiitis
l In many cases, pauci-immune crescentic GN is isolated and hence idiopathic
Type III RPGN:
Rapidly Progressive (Crescentic) Glomerulonephritis
Morphology:
l Glomeruli: focal necrosis, diffuse or focal endothelial proliferation, mesangial proliferation
l Distinctive crescents - obliterate Bowman space and compress the glomerular tuft
l Fibrin strands are prominent between the cellular layers in the crescents
Rapidly Progressive (Crescentic) Glomerulonephritis
Morphology:
l EM: _____________________________________
l IF:______________________________________
- ruptures in the GBM; allows leukocytes, proteins and inflammatory mediators to reach urinary space trigger crescent formation
- granular immune deposits (immune complex-mediated cases); linear fluorescence for Ig and complement (Goodpasture syndrome); little or no deposition (pauci immune)
Nephrotic Syndrome -
Causes Primary Glomerular Disease: l
Membranous glomerulopathy
l Minimal change disease
l Focal segmental glomerulosclerosis
l Membranoproliferative glomerulonephritis
l Other proliferative glomerulonephritides (focal, pure mesangial, IgA nephropathy)
Nephrotic Syndrome -
Causes Systemic Diseases:
l DM
l Amyloidosis
l SLE
l Drugs (NSAIDs)
l Infections (malaria, syphilis, hepatitis B and C, HIV)
l Malignant disease (carcinoma, lymphoma)
l Miscellaneous (hereditary nephritis)
l Common cause of nephrotic syndrome in
adults
l Diffuse thickening of the glomerular capillary
wall and
l Accumulation of electron-dense, Igcontaining
deposits along the subepithelial
side of bm
Membranous Nephropathy
Membranous Nephropathy
Secondary Membranous Glomerulopathy: occurs in association with other systemic diseases
l Drugs (Penicillamine, Captopril, NSAIDs)
l Underlying malignant tumors (carcinomas of lung and colon; melanoma)
l SLE
l Infections (chronic hepatitis B, hepatitis C, syphilis, schistosomiasis, malaria)
l Other autoimmune disorders (thyroiditis) 85% idiopathic
Membranous Nephropathy
Etiology and Pathogenesis:
l Idiopathic membranous glomerulopathy, like Heymann nephritis, is considered an autoimmune disease linked to susceptibility genes and caused by antibodies to a renal autoantigen
l C5b-C9 activation of glomerular epithelial and mesangial cells liberate proteases and oxidants capillary wall injury protein leakage
Membranous Nephropathy
LM:
uniform, diffuse thickening of the glomerular capillary wall
Membranous Nephropathy
l BM material laid down between IC deposits, appearing as _______________ protruding from the GBM
irregular spikes
Note : l Spikes are best seen by silver stains
Membranous Nephropathy
l EM:
irregular dense deposits of immune complexes between bm and overlying epithelial cells (with effaced foot processes)
Membranous Nephropathy l
IF:
granular deposits contain both Igs and complement Characteristic granular immunofluorescent deposits of IgG along GBM.
Membranous Nephropathy Clinical Course:
Begins with** insidious onset of nephrotic syndrome or with non-nephrotic proteinuria (15% of patients)**
l Hematuria and mild HPN (15 - 35%)
l Nonselective proteinuria
l Indolent course
l Does not respond well to steroid
l Progression is associated with increasing sclerosis of glomeruli, rising serum creatinine and development of HPN
l Most frequent cause of nephrotic syndrome in
children
l Peak incidence: between 2 and 6 years
l Diffuse effacement of foot processes of
podocytes in glomeruli that appear virtually
normal by LM
l Sometimes follows a respiratory infection or
routine prophylactic immunization
l Most characteristic feature: response to
corticosteroid therapy
Minimal Change Disease
Minimal Change Disease
Pathogenesis:
l MCD involves some immune dysfunction,
resulting in the elaboration of a cytokine that
damages podocytes and causes proteinuria
l Nephrotic syndrome resulting from mutations in
nephrin and podocin (localized to the slit
diaphragm) illustrates that structural defects of
the podocyte are sufficient to cause marked
proteinuria in the absence of an immune injury
Minimal Change Disease
Morphology:
l LM:______________
l EM: ______________
l IF: _______________
- glomeruli normal
- no electron-dense
material; uniform and
diffuse effacement of
foot processes - no immunoglobulin
or complement deposits
Minimal Change Disease
Clinical Course:
l** Renal function remains good** despite massive proteinuria
l Highly selective proteinuria (albumin)
l** Response to corticosteroid therapy**
l** Excellent long-term prognosis**
l MCD in adults** can be associated with Hodgkin
lymphoma**
l Secondary MCD may follow NSAID therapy in
association with AIN
l Characterized by sclerosis of some, but not
all glomeruli; in the affected glomeruli, only a
portion of the capillary tuft is involved
l Accompanied by nephrotic syndrome
l Most common cause of nephrotic syndrome
in adults in the US
Focal Segmental Glomerulosclerosis
FSGS occurs in the following settings:
l HIV infection, heroin addiction, sickle cell disease,
massive obesity
l As a secondary event in focal glomerulonephritis
(reflecting glomerular scarring)
l As a component of adaptive response to loss of
renal tissue
l In certain inherited forms of nephrotic syndrome
l As a primary disease (idiopathic FSGS)
Clinical signs differ from those of MCD in the
following respects:
l Higher incidence of hematuria, reduced GFR,
HPN
l Proteinuria is more often nonselective
l Poor response to steroid
l Progression to chronic kidney disease
Focal Segmental Glomerulosclerosis
Morphology:
l EM: ______________________________
l IF:_______________________________
- l Collapse of BMs, increase in matrix and hyalinosis
l **Global sclerosis of glomeruli**, **tubular atrophy** and interstitial fibrosis (with disease progression)
- sclerotic and nonsclerotic areas show diffuse
effacement of foot processes; focal detachment of
epithelial cells with denudation of GBM - IgM and C3 in the sclerotic areas and/or
mesangium
Focal Segmental Glomerulosclerosis
Collapsing glomerulopathy
l Retraction and/or
collapse of glomerular
tuft
l Proliferation and
hypertrophy of podocytes
l Tubular microcysts
l May be idiopathic but is
the most characteristic
lesion in HIV-AN
l Poor prognosis
Focal Segmental Glomerulosclerosis
Pathogenesis:
l_______________– hallmark of FSGS due to
l Circulating cytokine
l Genetically determined defects affecting slit
diaphragm components
l Hyalinosis and sclerosis – entrapment of plasma
proteins in extremely hyperpermeable foci and
increased ECM deposition
Epithelial damage
Focal Segmental Glomerulosclerosis
Pathogenesis:
l Genetic basis:___________- gene in chromosome
19q13 encodes nephrin – component of slit
diaphragm – control glomerular permeability
l Mutations of this gene give rise to congenital
nephrotic syndrome of the Finnish type,
producing minimal change disease-like
glomerulopathy
NPHS1
Focal Segmental Glomerulosclerosis
Pathogenesis:
l ____________ gene in chromosome 1q25-q31 encodes
podocin – component of slit diaphragm
l Mutations in NPHS2 result in a syndrome of
steroid-resistant nephrotic syndrome of
childhood onset
l Podocin mutations may account for 30% of
cases of steroid-resistant NS in children
NPHS2
Focal Segmental Glomerulosclerosis
Clinical Course:
l Little tendency for spontaneous remission in
idiopathic FSGS
l Variable responses to corticosteroid therapy
l Progression of renal failure occurs at variable
rates
l Recurrences are seen in 25 to 50% of patients
receiving allografts
Membranoproliferative
Glomerulonephritis
l Characterized by alterations in the GBM,
proliferation of glomerular cells and leukocyte
infiltration
l Mesangiocapillary GN
l May present only with hematuria or proteinuria in
the non-nephrotic range or combined nephroticnephritic
syndromes
l Primary (idiopathic) or secondary
l Primary MPGN: types I and II
