The Kidney Flashcards
What causes most glomerular disease
Immune mediated
What causes most tubular and interstitial diseases
Toxic or infectious
Glomerular, tubular and interstitial diseases damage what and lead to what
All four components of the kidney (glomeruli, tubules, interstitial, and blood vessels) and culminate in “end stage kidneys”
Azotomia
Elevation of BUN and creatinine levels
What causes azotemia
Decreased GFR
Prerenal azotomia
Hypoperfusion of kidneys
BUN/Cr>20
Postrenal azotemia
Obstruction distal to kidney
BUN/Cr<20
Uremia
Axotomia become associated with a constellation of clinical signs and symptoms and biochemical abnormalities
- failure of renal excretory function
- metabolic and endocrine dysfunctions resulting from renal damage
Nephritis syndrome
More hematuria/sicker
Caused by glomerular disease
Presentation nephritis syndrome
Acute onset of grossly visible hematuria or microscopic hematuria with dystrophic RBCs and red cell casts on urinalysis, diminished GFR, *mild to moderate proteinuria, and hypertension
HEMATURIA, AZOTEMIA, HYPERTENSION, AND SUB-NEPHROTIC (MILD TO MODERATE) PROTEINURIA
CLASSIC PRESENTATION OF ACUTE POSTSTREPTOCOCCAL GLOMERULONEPHRITIS
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)
NEPHRITIC SYNDROME WITH RAPID DECLINE IN GFR (HOURS TO DAYS)
SCHITTT for rapidly progressice glomerulonephritis
Stones, congenital anomalies, hemoglobinopathy, infection, intrinsic kidney disease, latrogenic/instrumentation, trauma, tumor, tb, toxins
Nephrotic syndrome
More proteinuria (>3.5g/24 hours)
Due to glomerular disease
SEVERE PROTEINURIA
Describe proteinuria of nephrotic syndrome for highly selective and poorly selective
Highly selective: consists of low molecular weight proteins in the urine like albumin and transferrin
Poorly selective: higher weight proteins in addition to albumin
Nephrotic syndrome lab values
Hypoalbuminemia
Hyperlipidemia
Lipiduria
More likely to become infected
Hypercoagulable
Hypoalbuminemia from nephrotic syndrome
Severe edema, espicially periorbital
Soft and pitting
Hyperlipidemia nephrotic syndrome
Except for decrease in HDL
Lipids in the urine can be free or oval (reabsorbed, but then released when the tubular celll died and detached)
Infection of nephrotic syndrome
Staphylococcus and pneumococcal infections
From loss of immunoglobulins in the urine
Hypercoagulable state nephrotic syndrome
Due to los of anti-coagulants (entithrombin III) in the urine
Can lead to renal vein thrombosis
Morphology nephrotic syndrome
Membranous glomerlupathy, minimal change, and FSGS (focal segmental glomerulosclerosis, mixed nephrotic/nephritic)
Subepithelial deposits !!
What causes acute kidney injury
Glomerular, interstitial, vascular or acute tubular injury
Characterization acute kidney injury
Rapid decline in GFR (hours to days) with concurrent dysregulation of electrolytes and fluid and retention of metabolic waste products that can lead to oliguria or anuria in severe cases
Acute tubular necrosis
Old term for acute kidney disease (doesn’t necessarily imply glomerular disease)
What causes chronic kidney disease
End result of all chronic renal parenchymal diseases most commonly diabetes and hypertension
What is the major cause of death from renal disease
Chronic kidney disease
How is chronic kidney disease clinically defined
Dismissed GFR that is persistently less than 60ml/min/1.73m^2 for at least 3 months and/or persistent albuminuria
End stage renal disease
GFR less than 5% of normal
Terminal stage of uremia
Renal tubular defects
Due to diseases that directly affect the tubular structures
What do renal tubular defects lead to
Polyuria, nocturia, and electrolyte dysregulation (metabolic acidosis)
UTI
Bacteriuria and pyuria (bacteria and leukocytes int he urine)
Pyelonephritis
UTI effects the kidney
Present with fever
Cystitis
UTI effects bladder
Does not present with fever
Nephrolithiasis
Renal stone associated with spasms of severe renal pain and hematuria
Often have recurrent stone formation
Primary glomerulonephritis
Disorders in which the kidney is the only or predominant organ involved
Secondary glomerular disease
When the glomerulus is affected by systemic immunological diseases such as SLE, vascular disorders such as HTN or metabolic diseases such as FABry disease
What are glomerular diseases associated with
Systemic disorders and patients who present with glomerular disease should be evaluated to underlying disorders
DM, SLE< vasculitis, amyloidosis
Glomerulopathy
No ellular inflammatory component
What are the two laters of epithelial cells (glomerulus)
Visceral (podocytes)
Parietal epithelium
Visceral epithelial cells
Incorporated into and become an intrinsic part of the capillary wall
Important for maintence of glomerular barrier function
What separated wth visceral from parietal layers
Basement membrane
Parietal epithelium
On the bowman capsule
Lines the urinary space (cavity in which plasma filtrate first collects)
Glomerular basement membrane
Thick, electron dense central layer==lamina densa
Thinner, electron lucent peripheral layers==lamina rara interna and lamina rara externa
Type IV collagen, laminae, polyanionic proteoglycans (mostly heparin sulfate), fibronectin, entactin, and several other glycoproteins
The glomerular filtration barrier has a size and charge selectivity function. Describe what is is permeable to
Smaller molecules
Cationic molecules
Albumin=smal, low molecular weight, anionic protein
Albuminuria
Nephropathy
Albumin Completely excluded from the filtrate
In most forms of __ __, loss of normal slit diaphragms is a key event in the development of proteinuria
Glomerular injury
Acute glomerular response to injury
Hypercellularity and formation of crescents
Chronic glomerular responses to injury
Basement membrane thickening, hyalinosis, and sclerosis
What is hypercellularity and when is it seen
Increase in the number of cells in the glomerular tufts
Seen with inflammatory diseases
What causes hypercellularity
Proliferation of endothelial or mesangial cells
Endocapillary proliferation
Formation of crescents
Mesangial cells
Mesenchyme derived and are contractile, phagocytes, and capable of proliferation; also capable of laying down matrix and collagen, and capable of secreting several biologically active mediators
Endocapillary proliferation:
infiltration of leukocytes with swelling and proliferation of the mesangial and endothelial cells
Formation of crescents
Accumulations of cells composed of proliferating glomerular epithelial cells and infiltrating leukocytes following an immune/inflammatory injury involving the capillary walls
- plasma proteins leak into he space that leads to the activation of coagulation factors
- activation of coagulation factors, particularly thrombin , may be a stimulus for crescent formation
BM thickening: LM
Thickening of the cap walls as seen with PAS staining
BM thickening EM
Can see three different forms
- Deposition of amorphous electron dense material, most often immune complexes (type III hypersensitivity)
- Increased synthesis of protein components of the BM (diabetic glomerulosclerisis)
- diabetes tends to show a focal nodular glomerulosclerosis with diffuse glomerulosclerosis - Formation of additional layers of the B< matrices that often occupy subendothelial locations and can be poorly organized to fully duplicate lamina densa (membranoproliferative glomerulonephritis)
Hyalinosis
Accumulation of material that is homogenous and eosinophilic by light microscopy
H build up of hyaline from circulating proteins that are transported to the ECM
End result of various forms of glomerular damage
What causes hyalinosis
Endothelial or capillary wall injury after glomerular damage occurs
What does hyalinosis cause
Obliterate the capillary lumens in the glomerular tufts
Sclerosis
Deposition of ECM collagen—stain with trichromatic stain (blue)
Typically builds up in mesangial areas (diabetic glomerulosclerosis), capillary loops or both
What can sclerosis lead to
Obliterate the capillary lumens in the glomerular tufts
__ mechanisms underlie most forms of primary glomerulopathy and many of the secondary glomerular disorders
Immune
two mechanisms of glomerular injury
Injury by antibodies reacting in situ within the glomerulus
(Major cause of glomerulonephritis)
Goodpasture syndrome
Injury to antibodies reacting in situ within the glomerulus
Immune complexes are formed locally by antibodies that react with intrinsic tissue antigen or with extrinsic antigens “planted” in the glomerulus from the circulaition
Membranous nephropathy=classic example=nephrotic syndrome (proteinuria)
Membranous nephropathy-classic example of nephrotic syndrome
Antibody binging to PLA2R present in the glomerular epithelial cell membrane is followed by complement activation and then shedding of the immune aggregates from the cell surface to form characteristic deposits of immune complexes along the subepithelial aspect of the basement membrane
LM-thickened basement membrane->membranous nephropathy
Pattern of deposition on IF in membranous nephropathy
Granular (rather than linear)=very localized antigen-antibody interaction
Immune complexes=granular
Anti-GBM -linear immunofluoresence
Who does membranous nephropathy develop in
Small number of infants fed on cows milk (planted antigen)
Antibodies to bovine albumin
Lesions contain bovine milk antigens
Good pasture syndrome
Simultaneous lung and kidney lesions (hematuria and hemoptysis)
-due to anti-GBM antibodies that cross react with other basement membranes, espicially those in the lung alveoli
Good pasture common?
Very rare,
What does good pasture cause
Severe necrotizing and crescenteric glomerular damage and the clinical syndrome of rapidly progressive glomerulonephritis
Recurrent hemoptysis our even life threatening pulmonary hemorrhage, but this is a renal disease
Glomerular injury results from
Deposition of circulating antigen antibody complexes int he glomerulus with subsequent formation of immune complexes in situ
Patterns of deposition glomerular injury IF (immunofluorescence)
Immune complexes shows a granular pattern of deposition-membranous nephropathy
Autoantibodies against components of the GBM show linear pattern of deposition
-goodpasture
Initiation of inflammatory damages that induce glomerulonephritis
Any combination of the following
- antibody-antigen deposition=type III hypersensitivity, circulating Ag-Ab(granular IF)
- antibody basement membrane =type II hypersensitivity, goodpasture (diffuse linear immunofluorescence)
- antibody-antigen planted=type II hypersensitivity, Ag stuck in glomerulus (granular IF)
- T cell damage-type IV hypersensitivity (4 Ts=touching, transplant, T, T cell mediated), reaction to Ag in endothelium
- no IF, no immune deposition
- not entirely proved
Pathogenesis of glomerulonephritis: charge and size of the ag-ab complexes makes a difference
Charge and size of the ag-ab complexes makes a difference:
-very cationic ag-ab tend to cross the GBM and stay int he subepithelial areas, typically not causing inflammatory reactions
-very anionic ag-ab do not crosss the GBM and are trapped subendothelially or are not nephritogenic
Neutral charge molecules accumulate int he mesangium
Large complexes are not typically nephrogenic
Circulating immune cells are most likely to see and be activated by complexes int he mesangium and subendothelial areas
Pathogenesis of glomerulonephritis
Charge and size
Short term injury is cleared by macrophages and the itis is limited
Long term injury (lupus) causes persistent damage that becomes chronic
Different injuries occur at different rates until GFR=30-50%, then they progress
Progression glomerulonephritis
Once the GFR gets down between 30-50% , progression is constant, irrelevant of the severity or time course of the underlying insult that caused it
Target therapy, since all diseases must funnel to one final progression mechanism
Key concepts pathogenesis of immune mediated glomerular injury
-antibody mediated immune injury is an important mechanism of glomerular damage, mainly cia complement and leukocyte mediated pathways. Antibodies may also be directly cytotoxic to cells int he glomerulus
The most common forms of antibody mediated glomerulonephritis are caused by the formation of immune complexes, which may involve either endogenous antigens (PLA2R in membranous nephropathy) or exogenous (microbial) antigens. Immune complexes show a granular pattern of deposition by IF
Autoantibodies against components of the GBM are the cause of anti-GBM antibody mediated disease, often associated with severe injury. The pattern of antibody deposition is linear by IF
Progression of glomerular disease key concepts
Progressice glomerular injury can be result of either primary or secondary glomerular injuries, of diseases that are either renal limited or systemic, and of diseases that initially involve renal structures other than glomeruli
The principal glomerular manifestation of progressive injury is focal segmental glomerulosclerosis, eventually leading to global glomerular involvement and glomerular obsolescence
Progressice injury ensues from a cycle of glomerular and nephron loss, compensatory changes that lead to further glomerular injury and glomerulosclerosis, and eventually end stage renal disease
Progressive glomerular injury is accompanied by chronic injuries to other renal structures, typically manifest as tubulointerstitial fibrosis
Activation of the alternative complement pathway
In dense deposit disease, until recently referred to as membranoproliferative glomerulonephritis (MPGN type II) and in an emerging diagnostic category of diseases broadly termed C3 glomerulopathies.
Mediators of glomerular injury
Once immune reactants or sensitized T cells have localized in the glomerulus, the mediators-both cells and molecules-are the usual suspects involved in acute and chronic inflammation
Neutrophils and monocytes infiltrate the glomerulus in certain types of glomerulonephritis
Result of activation of complement, resulting in generation of chemotactic agents (C5a), but also by Fc-mediated adherence and activation.
What do neutrophils do
Release proteases, which cause GBM degradation; oxygen-derived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to the reductions in GFR
Macrophages and T cells
Infiltrate the glomerulus in antibody and cell mediated reactions, when activated, release a vast number of biologically active molecules
Platelets
May aggregate in the glomerulus during immune mediated injury. Their release of eicosanoids, growth factors and other medications may contribute to vascular injury and proliferation of glomerular cells. Antiplatelet agents have beneficial effects in both human and experimental glomerulonephritis
Resident glomerular cells
Particularly mesangial cells, can be stimulated to produce several inflammatory mediators, including ROS, cytokines, chemokine, growth factors, eicosanoids, NO, and endothelin. They may initiate inflammatory responses in the glomerulus even int he absence of leukocytic infiltration
Complement activation
Leads to generation of chemotactic products that induce leukocyte influx (complement neutrophil dependent injury) and the formation of C5b-C9, the membrane attack complex. C5b-c9 causes cell lysis but, in addition, stimulates mesangial cells to produce oxidants, proteases, and other mediators. Thus even in the absence of neutrophils, C5b-C9 can cause proteinuria, as has been demonstrated in experimental membranous glomerulopathy
Eicosanoids, NO, angiotensin and endothelin
Hemodynamics changes
Cytokines IL-1 and TNF
May be produced by infiltrating leukocytes and resident glomerular cells, induce leukocyte adhesion and a variety of other effects
Chemokines like monocyte chemoattractant protein 1 promote monocyte and lymphocyte influx
Growth factors such as PDGF Are involved in mesangial cell proliferation. TGF-B, CT growth factor, and fibroblast growth factor seem to be critical in the ECM deposition and hyalinization leading to glomerulosclerosis in chronic injury. Vascular endothelial growth factor VEGF seems to maintain endothelial integrity and may help regulate capillary permeability
Coagulation system
Also a mediator of glomerular damage. Fibrin is frequently present in the glomeruli and bowman space in glomerulonephritis, indicative of coagulation cascade activation, and activated coagulation factors, particularly thrombin, may be a stimulus for crescent formation
__ injury is common to many forms of both primary and secondary glomerular disease of both immune and non immune etiologies
Podocye
Podocytopathy
Diseases with disparate etiologies whose principal manifestation is injury to podocytes.
What causes podocytopathy
Antibodies to podocytes antigens; by toxins, as in an experimental model of proteinuria induced by puromycin aminonucleoside; conceivably by certain cytokines by certain viral infections such as HIV or by still inadequately characterized circulating factors, as in some cases of focal segmental glomerulosclerosis.
Podocytopathy morphology
Effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM, and functionally by proteinuria
Loss of podocytes
Have very little capacity for replication and repair
Feature of multiple types of glomerular injury including focal and segmental glomerulosclerosis and diabetic nephropathy
How can you see loss of podocytes
Specialized techniques
In most forms of glomerular injury, loss of normal slit diaphragms is key event in developing ___
Proteinuria
Functional abnormalities of the slit diaphragm cause genetics
Rare forms of nephrotic syndrome
Mutations in this components such as nephron and prodocin, without actual inflammatory damage to the glomerulus.
Focal segmental glomerulosclerosis is associated with what
Loss of renal mass
The adaptive changes in glomeruli (hypertrophy and glomerular capillary hypertension), as well as systemic hypertension, cause epithelial and endothelial injury and resultant ___
Proteinuria
The mesangial response , involving mesangial cell proliferationa nd ECM production, together with intraglomerular coagulation, causes the ____. This results in further loss of functioning nephrons and vicious circle of glomerulosclerosis
Glomerulosclerosis
What does reduction in renal mass cause
Systemic hypertension, intraglomerular hypertension, glomerular hypertrophy
Then
Mesangial cell hyperplasia/ECM deposition, intraglomerular coagulation, and epithelial/endothelial injury
Leading to
Glomerulosclerosis
What does epithelial/endothelial injury lead to
Glomerulosclerosis ad proteinuria
Intervention to interrupt glomerulosclerosis
Inhibitors of RAAS, which not only reduce intraglomerular hypertension, but also have direct effects on each of the mechanisms . They ameliorate progression of sclerosis
Key concepts progression fo glomerular disease
Progressive glomerular injury can be the result of either primary or secondary glomerular injuries of diseases that are either renal limited or systemic and of diseases that initially involve renal structures other than glomeruli
The principal glomerular manifestation of progressive injury is focal segmental glomerulosclerosis, eventually leading to global glomerular involvement and glomerular obsolescence
Progressive injury ensues from a. Cycles of glomerular and nephron loss, compensatory changes, that lead to further glomerular injury and glomerulosclerosis, and eventually end stage renal disease
Progressive glomerular injury is accompanied by chronic injuries to other renal structures, typically manifest as tubulointerstitial fibrosis
Postinfectious glomerulonephritis
Presentation, pathogenesis
NEPHRITIC syndrome
Immune complex mediated; circulating or planted antigen
Postinfectious glomerulonephritis
Light microscopy, fluorescence microscopy, electron microscopy
Diffuse endocapillary proliferation; leukocytic infiltration
Granular IgG and C3 in GBM and mesangium; granular IgA in some cases
Primarily subepithelial humps; subendothelial deposits in early disease states
Good pasture
Presentation, pathogenesis
Rapidly progressive glomerulonephritis
Anti-GBM COL4-A3 antigen
Goodpasture
Light microscopy, fluorescence microscopy, electron microscopy
Extracapilalry proliferation with crescents;necrosis
Linear IgG and C3; fibrin in crescents
No deposits; GBM disruptions; fibrin
Chronic glomerulonephritis
Presentation, pathogenesis
Chronic renal failure
Varible
Chronic glomerulonephritis
Light microscopy, fluorescence microscopy, electron microscopy
Hyalinized glomeruli, granular or negative
Membranous nephropathy
Presentation, pathogenesis
Nephrotic syndrome
In situ immune complex formation PLA2 antigen in most cases of primary disease mostly unknown
Membranous nephropathy light microscopy , fluorescence microscopy, electron microscopy
Diffuse capillary wall thickening
Granular IgG and C3; diffuse
Subepithelial deposits
Minimal change disease
Presentation, pathogenesis
Nephrotic syndrome
Unknown; loss of glomerular polyanion; podocytes injury
Minimal change disease
LM, FM, EM
Normal; lipid in tubules
Negative
Loss of foot processes; no deposits
Focal segmental glomerulosclerosis
Presentation
Path
Nephrotic syndrome; nonnephrotic proteinuria
Unknown ablation nephropathy plasma factor; podocytes injury
Focal segmental glomerulosclerosis LM FM EM
Focal and segmental sclerosis and hyalinosis
Focal; IgM+ C3 in many cases
Loss of foot processes; epithelial dehydration
Membranoproliferative glomerulonephritis type I
Clinical
Path
Nephrotic/nephrotic syndrome
Immune complex
Membranoproliferative glomerulonephritis type ILM FM EM
Mesangial proliferative or membranoproliferative patterns of proliferation; GBM thickening; splitting
IgG ++ C3;
C1q++C4
Subendothelial deposits
Dense deposit disease (MPGN type II)
Presentation
Path
Hematuria, chronic renal failure
Autoantibody; alternative complement pathway
Dense deposit (MPGN type II) LM FM EM
Mesangial proliferative or membranoproliferative patterns of proliferation; GBM thickening; splitting
Dense deposit disease (MPGN type II)
LM FM EM
Mesangial proliferative or membranoproliferative patterns of proliferation; GBM thickening; splitting
C3; no C1q or C4
Dense deposits
IgA nephropathy
Presentation, path
Recurrent hematuria or proteinuria
Unknown
IgA nephropathy LM FM EM
Focal mesangial proliferative glomerulonephritis; mesangial widening
IgA+- IgG, IgM and C3 in mesangium
Mesangial and paramesangial dense deposits
What is the most common cause of nephritic syndrome in adults
Focal segmental glomerulosclerosis
What is focal segmental glomerulosclerosis
Progressive fibrosis involving portions of some glomeruli that leads to increasing functional impairment
What does focal segmental glomerulosclerosis lead to
Proteinuria and hematuria even if the initial insult was non glomerular
What causes focal segmental glomerulosclerosis
Loss of renal mass from whatever cause (ischemia/infarction, immune mediated fibrosis) and is a result of adaptive changes
What are the adaptive changes that cause focal segmental glomerulosclerosis
Loss of renal mass results in hypertrophy of remaining glomeruli so that there is maintence of renal function (compensation)
Podocytes cant grow with the glomeruli, losing filtration barrier and resulting in increases of glomerular blood flow, filtration, and transcapillary pressure (glomerular HTN)
-often associated with systemic HTN
Proteins and cells are allowed to lead out, resulting in macrophage induced fibrosis, causing a reduction in renal mass
How treat focal segmental glomerulosclerosis
Renin angiotensin system inhibitors
Most likely diagnosis when an adult has nephrotic syndrome
Fsgs
When you see nephrotic syndrome with nephritic syndrome
Tubulointerstitial fibrosis
Fibrosis and inflammation of the tubules and interstitial opposed to the glomerulus
There is a stronger correlation between the decline of renal function and the amount of tubulointerstitial fibrosis than with the severity of glomerular injury
What causes tubulointerstitial fibrosis
Infarction of tubules, possibly from alterations of hemodynamics in the above condition (fSGS)
Activation of tubule cells and direct injury either from proteinuria or other cytokines
Activated tubules cell express adhesion molecules and elite inflammatory cells that lead to fibrosis
NEPHRITIC syndrome
Acute proliferative glomerulonephritis/post streptococcal glomerulonephritis (PSGN)/post infectious glomerulonephritis—all same
*diffuse proliferation of glomerular cells associated with influx (exudation) of leukocytes
What causes nephritic syndrome
Immune complexes
NEPHRITIC syndrome exogenous antigen induced
Post infectious glomerulonephritis
NEPHRITIC syndrome endogenous antigen induced
Nephritis of SE
Pathogenesis nephritic syndrome
Post step A (pyogenic) beta hemolytic pharyngitis OR skin infection is the original infection typically 1-4 weeks prior
Distractor-if there is a current complaint of sore throat and dry cough it is not PSGN: PSGN happens 1-4 weeks after an untreated case
What stream a pyogenic beta hemolytic strains are most commonly involved in nephritic syndrome
12,4,1 (identified by typing of the M protein of the bacterial cell walls)
Formation of antibody against pyogenic ________ results in immune complex formation in site and deposition
Exotoxin B SpeB
SpeB
Can directly activate complement
Commonly secreted by nephritogenic strains of streptococci
Has been localized to the hump like deposits in the subepithelial space characteristic of PSGN (post streptococcal glomerulonephritis)
NEPHRITIC syndrome inciting antigens are exogenously ___ from the circulation in subendothelial locations in glomerular capillary walls, leading to in situ formation of immune complexes where they elicit an inflammatory response
Planted
Describe immune deposits in nephritic syndrome
Hump like and located inthe glomeruli in the subepithelial space
LM nephritic syndrome
Enlarged and hypercellularity glomeruli : tubules often contain red cell casts; LM is not entirely specific, use IF and EM
Caused by proliferation of endothelial/mesangial cells and crescent formation in severe cases
Global and diffuse
Leads to obliterated capillary lumens
NEPHRITIC syndrome IF
Shows granular deposits of IgG and C3, and sometimes IgM in the mesangium and along the GB<
Immune complex deposits are almost universally present, they are often focal and sparse
NEPHRITIC syndrome EM
Discrete, amorphous electron dense deposit on the subepithelial side (which is the antigen antibody complex at the subepithelial cell surface) often having the appearance of humps
NEPHRITIC syndrome clinical course
Young child (6-10) with sudden/abrupt onset on malaise, fever, nausea, periorbital edema, mild to moderate HTN, oliguria, proteinuria, dysmorphic RBCs/cast and hematuria (tea colored urine) 1-2 weeks after a strep a infection
Labs nephritic syndrome
Elevated ASO titers and low serum complement levels (consumption)
Prognosis nephritic syndrome in kids
Good prognosis in kids
95% recover well as Ag-Ab is cleared with fluid/electrolyte therapy
1% develop rapidly progressive glomerulnephritis (bad)
Poor prognosis nephritic syndrome
Prolonged and persistent proteinuria/abnormal GFR
Adults nephritic syndrome
Suddenly without infection
HTN, edema, elevated BUN
Prognosis nephritic syndrome adults
60% will recover quickly and then remaining will have smoldering chronic conditions and can even progress to chronic or rapidly progressive glomerulonephritis
Post infectious glomerulonephritis
Mainly strep a,
Bacterial (staphylococcal endocarditis, pneumococcal pneumonia, and meningococcemia), viral (hep b, hep c, mumps, HIV, varicella, and mono), or parasite (toxoplasmosis, malaria)
—->same IF: granular deposits and subepithelial humps
—->post infectious glomerulonephritis due to staphylococcal infections differs by sometimes producing immune deposits containing IgA rather than IgG
Rapidly progressive (crescentic, exudative, extra-capillary) glomerulonephritis (RPcGN, RPGN)
VERY SICK
Severe glomerular injury associated with the formation of crescents in most glomeruli (crescenteric glomerulonephritis)
Rapid progression and loss of renal function
Severe oliguria and signs and symptoms of nephritic syndrome
Weill lead to renal failure in weeks to months if untreated
Crescents with RPGN
Proliferation of parietal epithelial cells lining the bowman capsule and by infiltrating monocytes and macrophages
RPGN pathogenesis
Immune
Type I RPGN
Anti-GB< antibodies that cross react with pulmonary alveolar BM as in goodpasture; anti-collagen type IV
Rare
Type I RPGN antigen
Alpha3 chain of collagen type IV
Genetics type I RPGN
HLA DRB1 (MHC class II)
Treat type I RPGN
Plasmapheresis (remove antigen/antibody from the circulation)
Type II RPGN
Immune complex as in post infectious, SLE, IgA, nephropathy, or Henolch schloen
Morphology type II RPGN
Granular pattern of immune complex formation
Cellular proliferation and crescent formation
Treat type II RPGN
Not helped by plasmapheresis, treat the underlying cause
Type II RPGN
Pauci immune without associated to anti-GBM complexes or immune complex, but is associated with ANCA that produce plasma of cytoplasmic staining patterns (p-ANCA and c-ANCA) as in wegners
Type II RPGN is associate with what
Vasculitis EUS, like granulomatous is with poly angiitis, formerly called wegners granulomatous is, or microscopic angiitis
Diagnosis type II RPGN
ANCA
Where is type II RPGN
Kidneys (idiopathic)
> 90% of idiopathic cases have c ANCA or pANCA in the sera
All cases of crescenteric glomerulonephritis of the pauci-immune type are manifestations of small vessel vasculitis or polyangiitis, which is limited to glomerular and perhaps peritubular capillaries in cases of idiopathic crescentic glomerulonephritis
Ok
Morphology RPN
Enlarged and pale kidneys with cortical petechial hemorrhage
Segmental glomerular necrosis next to unaffected areas
Histology RPGN
Crescents==proliferation of parietal cells, macrophages, PMN, and fibrin strands between cells, all contained within Bowman’s space
Obliterating the urinary space and compress the glomerular tuft
Activation of coagulation factors implicated in the formation of crescents
EM RPGN
Wrinkled and ruptured basement membranes
Ruptures in the GBM allow leukocytes, plasma proteins such as coagulation factors and complement, and inflammatory mediators to reach the urinary space where they trigger crescent formation
IF RPGN
Variable pattern depending on
Type 1=linear
Type 2=granular
Type 3=none
Clinical course all types of RPGN
Hematuria, red cell cast, proteinuria approaching nephrotic ranges—nephritic syndrome
Variable edema and HTN—nephritic syndrome
Rapidly progressive disease with loss of renal function that is accompanied by oliguria
Clinical course crescenteric glomerulonephritis
If they survive the acute episode, usually(more than 90%) progress to chronic glomerulonephritis
Treat RPGN type II
II-plasmapheresis, or steroids and cytotoxic drugs (anti inflammation)(poor prognosis)
What are the types of nephritic syndrome
Membranous glomerulopathy, minimal change disease, focal glomerulosclerosis
What is nephrotic syndrome
Derangement of glomerular capillaries with increased permeability to protein with resultant SEVERE proteinuria
Albumin leaks out along with proteinuria leading to decreased colloid pressure(edema)
Edema (periportal and peripheral) result from the loss of colloid pressure with subsequent ADH/aldosterone fluid retention (because all fluid is in the interstitial it looks like there is fluid depletion) exarcabating the edema
Edema with nephrotic syndrome
Soft and pitting
Most marked in the periorbital regions and dependent portions of the body
Why hyperlipidemia/hypercholesterolemia in nephrotic syndrome
Liver compensates by increasing protein synthesis; side effect is increase of lipoproteins and cholesterol
Nephrotic syndrome are at an increased risk of __
Infection
Staphylococcal and pneumococcal
*loss of immunoglobulins in the urine
Thrombotic and thromboembolic complications in nephrotic syndrome
Due to loss of endogenous anticoagulants
Renal vein thrombosis is most often a consequence of this (makes nephrotic syndrome worse) and can cause a varicocele on the left in males
Cause of nephrotic syndrome in US kids less than 17
Primary lesion of kidney
*minimal change disease most common in kids , membranous glomerulopathy most common in adults (spike and dome, lumpy) and focal segmental glomerulosclerosis (all ages)
NEPHRITIC syndrome in kids is MCD until proven otherwise. What shouldn’t you do
Don’t biopsy-challenge with steroids and see if condition improves bc MCD is exquisitely responsive to steroid therapy
What causes nephritic syndrome in adults
Systemic disease (SLE DIABETES AMYLOIDOSIS)
Loss of immunoglobulins int he urine predispose to acute pyogenic infection (staph and strep)
See Robbins 914
Membranous nephropathy
Diffuse thickening of the glomerular capillary wall due to accumulation of deposits containing immunoglobulins along the subepithelial side of the basement membrane
Critical concepts membranous nephropathy
75% are primary, the rest happen in association with other diseases
Either is idiopathic or is secondary to an immune disease
Does not respond well to corticosteroids
Pathogenesis membranous nephropathy
Chronic immune complex deposition disease, espicially IgG4 that activate the complement and MAC complex
Primary membranous nephropathy
Idiopathic-MHC susceptibility HLA-DQA1 + nephritogenic antigen (antibodies to a renal autoantigen)
Endogenous antigens primary membranous nephropathy
Phospholipase A2 receptor (PLA2R most common**), self nuclear proteins and autoantibodies, neutral endopeptidase
Exogenous antigens membranous nephropathy
Antigens that come fro Hep B or treponema
Secondary membranous nephropathy
SLE, drugs (penicillamine, captopril, gold, NSAIDS), tumors, metals (mercury), infections (hep C, B, schistosomiasis, malaria), autoimmune (thyroiditis)
Why are penicillamine and gold not used to treat RA
Membranous nephropathy
MAC membranous nephropathy
C5b-C9
Activated glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage
IgG4==poor activator of classical complement pathway but IgG4 the principal immunoglobulin deposited in cases of primary membranous nephropathy
LM membranous nephropathy
Uniform diffuse thickening of basement membrane, thick capillary loops
EM membranous nephropathy
Dense deposits in subepithelial side, with the BM forming spikes into the deposit—spike and dome
—spikes will grow out and encompasss the deposit forming domes (silver stain)
What makes up electron dense deposits in membranous nephropathy
PLA2R in primary
Unknown in secondary
IF membranous nephropathy
Granular pattern of immunoglobulin and complement
With advancement of membranous nephropathy there can be __ ___ and the glomerular can becomes ____
Segmental sclerosis
Sclerosis
What can happen to proximal tubules in membranous nephropathy
Epithelial cells can contain protein reabsorption droplets and there can be considerable interstitial mononuclear cell inflammation
Clinical membranous nephropathy
Insidious onset
Hematuria and mild HTN in 15-35%
Proteinuria is nonselective and dose not respond to corticosteroids
-nonselective proteinuria==higher molecular weight proteins in addition to albumin
-otherwise very similar to minimal change disease
Complete or partial remissions can happen
Eventual sclerosis in membranous nephropathy leds to what lab values
Elevated BUN, creatinine, and HTN—ezotemia/uremia
60% of patients will continue to have proteinuria
Can progress sometimes to renal failure, but only after 10-40 years
Circulating antibodies to PLA2 may be a useful biomarker of disease activity
Minimal change disease /lipoid nephrosis, nil disease
childhood nephrotic syndrome that is characterized by effaced foot processes on EM in MASSIVE proteinuria with a normal glomerulus on light microscopywith HIGHLY selective proteinuria
Cells of proximal tubules in minimal change disease
Laden with lipid and protein (from tubular reabsorption of lipoproteins passing through diseased glomeruli)
-lipid deposition
Why get lipid deposition in proximal tubes with Minaj change disease
Lose oncotically active protein (albumin) liver reacts in a compensatory pathway and increases synthesis of lipoproteins; these lipoproteins then lodge themselves in the proximal tubules
Lipids are absorbed and deposited in proximal tubules cells but do not damage the cell ( no necrosis) like bench jones proteins do (necrosis)
Most common cause of nephrotic syndrome in kids
Minimal change (206)
Nephrotic syndrome in kids is __ until proven otherwise….don’t biopsy why
MCD
Challenge with steroids…it is exquisitely responsive to steroids
If a kid has nephrotic syndrome and not respond to steroids
Mixed nephritic/nephrotic syndromes, papillary necrosis (analgesic nephropathy)
Steroid therapy is virtually diagnostic
MCD sometimes follows what
Respiratory infection or immunization
Characterization MCD
Effaced foot processes (podocytes) on EM with a normal LM glomerulus
Treat MCD
Responsive to corticosteroids and remits after puberty
Pathogenesis MCD
Unknown
Autoimmune
Post infection even though these changes can be seen in the absence of immune deposition or infection , immunization
Associated with atopic
K\link to Hodgkin lymphoma (presence of Reed-Sternberg cells, which are mature B cells that have become malignant , are usually large, and carry more than one nucleus..non Hodgkin can be derived from B cells or T cells can can arise in the lymph nodes as well as other organs)
NSAIDS MCD
Maybe
Ultastructural changed MCD EM
Primary visceral epithelial cell injury (podocytopathy) and studies in animal models suggest the loss of glomerular polyanions from defect to the charge barrier)
LM MCD
Normal glomerulus without any changes
EM MCD
Establishes diagnosis
Principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes
Visceral epithelial changes are completely reversible after corticosteroid therapy, concomitant remission of the proteinuria
Vacuoles and fused podocytes which are just flattened epithelium
MCD IF
Nothing no immune deposition
Clinical MCD
Despite massive proteinuria, there is a preservation of renal function without hematuria or hypertension
Nephrotic syndrome, not nephritic syndrome
SELECTIVE PROTEINURIA==mostly albumin (small
Non selective—albumin and high molecular weight proteins
Treat MCD
Corticosteroids and although may get resistance, excellent prognosis
Focal segmental glomerulosclerosis
Sclerosis of some, but not all glomeruli affecting only part of each affected glomeruli with nephrotic syndrome
Most common cause of nephrotic syndrome in adults in US, espicially black and Hispanic
Types of focal segmental glomerulosclerosis
Primary (idiopathic)
Association with other conditions like HIV, heroin addiction, sickle cell and massive obesity
Secondary event event that caused scarring like IgA nephropathy
Loss of renal tissue from congenital abnormalities, acquired cases like reflux nephropathy, or advanced stages of other renal disorder like hypertensive nephropathy
Inherited forms of nephrotic syndrome where disease is caused by mutations that encode the slit diaphragm proteins (pods in, alpha-actinin 4, and transient receptor potential calcium channel-6 TRCPC6)
Five categorizations
Primary=diagnosis
Associated with other known disorders
Secondary to antecedent other glomerular syndrome
Adaptive hemodynamics response
-patients who lose a kidney due to trauma or as a donor==traumatic changes in the remaining kidney
Inherited
How does focal segmental glomerulosclerosis differ from minimal change disease
Higher incidence of hematuria and HTN
Reduced GFR
Proteinuria is nonselective (high molecular weight proteins along with albumin)
POOR RESPONSE TO CORTICOSTEROIDS
There is 50% of developing ESRD within 10 years—long term prognosis is not excellent
Pathogenesis focal segmental glomerulosclerosis
Progression from minimal change with extra epithelial damage and sclerosis under light microscopy
Proteinuria results with subsequent entrapment of plasma proteins, resulting in hyalonisis and sclerosis of affected segments
Circulating factor and genetically determined factor-most likely
Mutations of focal segmental glomerulonephritis: all of which localize to the slit diaphragm and adjacent podocyte cytoskeleton structures
Nephrin
Podocin
Alpha actinin 4
TRP6
Apolipoprotein L1
Nephrin
genes code for cell adhesion interactions at the diaphragm and mutations in nephron genes cause a collapse of the filtration barrier
-NPHS1, chromosome 19p13
This mutation can lead to congenital nephrotic syndrome of the Finnish type
Podocin
NPHS2, chromosome 1q25-q31
AR
Steroid resistant pediatric form
Alpha actinin 4
Can be AD causes of FSGS
Insidious in onset with high rate of progression to renal insuffiency
TRP6
Mutation associated with adult onset FSGS
Apolipoprotein L1 (APOL1)
APOL1, chromosome 22
Increases the risk of FSGS in African Americans
Also associated with increased resistance to trypanosome infection
Renal ablation FSGS
After the removal of a diseased or healthy nephrotic segment caused by hypertrophy of the remaining segment
LM FSGS
Only a minority of the glomeruli may have the focal and segmental lesions;
Parts of some glomeruli are eosinophilic (hyalinosis) with sclerosis
There is collapse of the capillary loops and hyalinossi int he sclerotic segments, this may occlude the lumen
With time this will spread and lead to global sclerosis
Foam cells are commonly seen
EM FSGF
Effacement of podocytes as in minimal change disease. Focal detachment and denudation of the GBM
IF FSGS
IgM and C3 in sclerotic areas
Collapsing glomerulosclerosis
Morphologically distinct variant that involves retraction/collapse of the entire glomerular tuft, with or without additional FSGS lesions
Characteristic feature of collapsing glomerulosclerosis
Proliferation and hypertrophy of glomerular visceral epithelial cells
Causes of collapsing glomerulosclerosis
Typically associated with prominent tubular injury with formation of microcysts
Drug toxicities like pamidronate
HIV associated nephropathy-most characteristic lesion
Prognosis collapsing glomerulosclerosis
Poor prognosis
Who gets FSGS
Adults, kids, usually african American, associated with viral illness HIV HepB and Hep C
FSGS and corticosteroids
Nope
Prognosis FSGS
Some will end with rapid onset renal failure (2 years) while some may last 10 years; renal transplantation or dialysis in inevitable
Kids better prognosis
HIV and FSGS
Nephrotic syndrome and microscopic hematuria
FSGS nephrotic or nephrotic
Mostly nephrotic can be mixed
Significant;y decreases GFR with azotemia; focal IgM and C3 in mesangial distribution; hypertensive. Which of the following is of most value in terms of the diagnosis in this case
Lack of response to steroid therapy and biopsy
HIV associated nephropathy
Can directly of indirectly cause several renal complications, including acute renal failure or acute interstitial nephritis that is due to treatment of drugs, infections, thrombotic microangiopathies, post infectious glomerulonephritis, and from a severe form of the collapsing variant of FSGS called HIV associated nephropathy
Treat HIV associated nephropathy
Anti viral
Morphology HIV associated nephropathy
Focal cystic dilation of tubule segments which are filled with proteinaceous arterial, inflammation and fibrosis
Lots of tubuloreticular inclusions within endothelial cells that are modification of the ER in the cells by circulating IFN-a
——-not found in idiopathic FSGS therefore may be diagnostic for HIV associated nephropathy
A 35 year old HIV +ve male present to your SF clinic with nephrotic syndrome and microscopic hematuria. CD4 count >500. He is at most risk for infection from what
Strep p
Loss of immunoglobulins in the urine increases susceptibility to staph and strep infection (acute pyogenic )
Membranoproliferative glomerulonephritis
Not a specific disease, but an immune mediated injury due to immune deposition
Mesangial interposition==proliferation of mesangial cells into?
Types of membranoproliferative glomerulonephritis MPGN
Type I-deposition of IgG and complement
Type II-alternative complement activation is the most important aspect and belongs to a group of C3 glomerulopathies
Type I membranoproliferative glomerulonephritis
Tends to be a mixed nephrotic/nephrotic
In adults, less common than II
Frequently associated with chronic antigenemia causing immune complex deposition (hep C with cryoglobinemia, chronic immune complex disorders such as SLE, endocarditis, certain malignancies-CLL, lymphomas, melanomas)
-when these morbid conditions are absent, makes MPGN
Type II membranoproliferative glomerulonephritis (dense deposit)
C3 found in the GB
Type I and II membranoproliferative glomerulonephritis MPGN
Proliferation in the mesangial and capillary loops and can be called mesangiocapillary glomerulonephritis
Type I pathogenesis
Immune complex deposition and activation of classical and alternative complement pathways
-C3 low in plasma serum bc it gest used up (consumption)
There is mesangial proliferation with involvement of basement membrane
LM membranoproliferative glomerulonephritis
Hypercellularity of the mesangial and capillaries
GBM is thickened and often shows a double contour or tram track appearance
- espicially evident in silver or PAS
- duplication of the basement membrane (splitting) as the result of new basement membrane synthesis in response to subendothelial deposits of immune complexes
- mesangial interposition
Creascents are present in many cases
EM membranoproliferative glomerulonephritis
Type I: Discrete subendothelial electron dense deposited (lumen side with the RBC)
Look for silver stain to give a better picture of splitting
IF membranoproliferative glomerulonephritis
IgG, IgM, and C3 in a granular pattern: early complement components are also present, indicative of immune complex pathogenesis
Who gets membranoproliferative glomerulonephritis
Adolescents and young adults
Manifestation of membranoproliferative glomerulonephritis
Nephritic and nephritic component manifested by hematuria or sometimes mild proteinuria
Prognosis membranoproliferative glomerulonephritis
Slow progressive, unremitting
50% chance of renal failure in 10 years
Treat membranoproliferative glomerulonephritis
Immune suppression
Secondary MPGN
Almost always type I: immune complex deposition and activation of classical and alternative complement pathways
Who gets secondary MPGN
Adults
What is secondary MPGN associated with
Chronic immune complex disordersL SLE, hep B, hep C with cryoglobulinemia, endocarditis, infected AV shunts, chronic visceral abscesses, HIV, schistomiasis
Alpha 1 antitrypsin defiency
Malignant disease:lymphoid tumors like chronic lymphocytic leukemia which are commonly complicated by development of autoantibodies
Dense deposit disease (MPGN type II)
Excessive activation of the alternative complement pathway and deposition int he glomerulus
Associated with C3NeF
Mutations that cause dense deposit disease
70% C3 nephritic factor autoantibodies which bind to C3 convertase and protects it from inactivation
- promotes persistent C3 activation and hypocomplementemia
- decreased C3 synthesis by the liver—-> hypocomplementemia
Also associated with mutations in factor H
Pathogenesis I dense deposit disease (MPGN type II)
Consistently decreased C3 with normal C1 and C4 levels
Decreased factor B and properdin (components of the alternative complement pathway)
C3 and properdin are deposited int he glomerulus, but not IgG
Morphology dense deposit
Predominantly mesangial proliferative pattern, but can also appear with inflammation and focal crease trim appearance
EM dense deposit
Permeation of the lamina densa of the GBM by an extremely electron dense ribbon of material-DEFINES IT
IF dense deposit
C3 is present in irregular granular or linear foci around, not in the dense deposits
-characteristic C3 deposits in the mesangial in circular aggregations (mesangial rings)without IgG
—IgG and components of the classical complement pathway (C1q and C4) are absent
—other C3 glomerulopathies can have the rings, but don’t have the despise deposits
Clinical features dense deposits
Kids and young adults
Poor prognosis
50% protests to ESRD
Reoccurs in 90% or transplant recipients, but renal failure is much less common in the allograft
IgA nephropathy (Berger disease)
Primary renal disease (can sometimes be secondary) where IgA deposits are found in the mesangium detected by immunofluorescence with recurring hematuria
MOST COMMON CAUSE OF GLOMERULONEPHRITIS WORLDWIDE
Note: systemic diseases can also cause IgA deposition in the kidneys (henoch-schonlein purpura)
Also called focal proliferative GN
IgA nephropathy association
With one particular form of IgA (IgA1) where a genetic defect (acquired or hereditary) causes glycolyslation of the hinge region
Certain types of HLA MHC-II subtype, gluten enteropathy, liver disease where there is defective hepatobiliary clearance of polymeric IgA
Pathogenesis IgA nephropathy
Antigen recognition in mucosal membranes results in formation of IgA and IgA complexes that circulate in the blood; inciting antigen is unclear
Liver decomposes polymeric IgA (usually exists as a dimer in mucosal lumen)
-liver disease can present with IgA deposition and glomerulonephritis
Some polymeric IgA (or IgA-IgG complexes) become trapped in glomerulus leading to complement activation, mesangial proliferation and glomerular injury
The complexes cause activation of alternative complement pathway—C3 is commonly found in deposits, C1q and C4 are absent
What is IgA
Mucosal defense present in low concentrations in the plasma as a monomer; liver catabolizes the polymer
Upregulation of IgA
Extra circulating that may lead to IgA nephropathy
Morphology IgA nephropathy
Microscopic changes are variable but mesangial proliferation/widening, capillary proliferation, or overt cresenteric glomerulonephritis May occur
Healing can lead to focal segmental glomerulosclerosis
Diagnose IgA nephropathy
Immunofluorescent stains for complement of IgA in the characteristic granular mesangial pattern
-will also see C3 and less IgG and IgM
What is the most common nephropathy in the world
IgA nephropathy
Who gets IgA nephropathy
Older kids young adults
How do patients present with IgA nephropathy
Gross hematuria following an infection of their respiratory of GI tract
30-40% will have microscopic hematuria, with or without proteinuria
5-10% develop acute nephritic syndrome
Bright red urine
Bleeding will last for a few days then come back every few months (recurrent hematuris)
Prognosis IgA nephropathy
Fairly benign gross morphology, bright red bleeding in urine usually following an URI
Prognosis IgA nephropathy
Prolonged progression is associated with old age, heavy proteinuria, HTN, and more glomerulosclerosis
Hereditary nephritis/Alport syndrome
Hematuria with slowly progressing proteinuria and declining renal function
Thin basement membrane lesion==benign clinical course of hematuria with mild to moderate proteinuria and normal renal function
Alport syndrome A LP O R T
A-Alport
LP-LP is a record, that you listen to, reminds you of DEAFNESS…not present in thin basement membrane lesion
O-ocular..not present in thin basement membrane
R-renal failure..not present in the thin basement membrane lesion
T-thickening of BM and type IV collagen…thin basemen mmebrane lesion==thinning of the GM
Alport syndrome
Nephritic x linked disorder involving collagen formation characterized by renal failure, auditory disturbances, and eye problems (corneal atrophy, posterior cataracts, lens dislocation)
Females with Alport
Some hematuria-not severe
Males alport
Full syndrome and progress to ESRD by 40–worse
Pathogenesis of alport
Defective in BM as result of defect in type IV collagen synthesis
- GBM made up of alpha 3,4,5 chains
- type IV collagen is found on chromosome 2,13, and X inheritance can be autosomal of X linked
Type IV collagens is crucial for function of the GBM, the lens of the eye, and the cochlea
Lack of alpha chains renders these patient immune to good pastures since they lack alpha 3 antigen
—-linked defects of alpha 5 chain of collagen IV to in X linked
Morphology alport EM
Alternating thickening and thinning glomerular basement membrane with lamination fo the lamina densa, basket weave appearance
Can stain for the alpha chains to look for the disease as affected patients will not show the defective alpha chains. Can look for the alpha 5 chain in the skin
With progression there is glomerulosclerosis, tubular atrophy, and interstitial fibrosis
Irregular thickening of BM, lamination fo lamina densa and foci of rarefaction
Most common presenting sign of alport
Gross of microscopic hematuriafreuenly accompanied by red cell casts
—-proteinuria may develop, and nephrotic syndrome rarely develops
Onset of alport
Birth, but symptoms occcur later in life
Early signs 15-20 years
With auditory and vision problems??
What is alport associated with
Vision prob and auditory prob
Basement membrane disease/benign familial hematuria
Common, asymptomatic hematuria, discovered by routine urinalysis with mild of moderate proteinuria
Prognosis thin basement membrane disease
Renal function normal fo excellent prognosis
How diagnose thin basement membrane disease
EM see diffuse thinning of glomerular basement membrane-hence thin basement membrane!
What causes thin basement membrane disease
Defect in type IV collagen formation
A-5 type IV collagen is present and there are no ocular or auditory lesions—distinct from alport
How does thin basement membrane differ from alport and IgA nephropathy
A-5 type IV collagen is normal and no ocular or auditory lesions
No IgA immune deposition in mesngium
Prognosis thin basement membrane diseseae
Good with maintence of normal renal function throughout life
Chronic glomerulonephritis
End point of all nephrotic and nephritic syndromes
This is the end point of all diseases discussed here, occuing at varying rates dependent on primary disease or arise suddenly with no history of acute glomerulonephritis
What happens to kidney in chronic glomerulonephritis
Symmetrically contracted and have diffuse granular cortical surfaces
Cortex is thinned with an increase in peri pelvic fat
Extensive hyalinization and fibrosis (obliteration) of the glomeruli, demonstrated by large amount of collagen on a trachoma stain
Bc __ is often concomitant with chronic renal failure, arterial sclerosis may be present as well-arterolnephrosclerosis?
HTN
Clinical chronic glomerulonephritis
patients present with nonspecific complaints of loss of appetites, anemia, vomiting, or weakness
Chronic renal failure leads to uremia with characteristic changes (pericarditis/secondary hyperparathyroidism)
Edema
Prognosis chronic glomerulonephritis
Progressive renal failure, often with HTN, eventual edema, and, without dialysis or Renault ransplant , death
Lupus
Forms antibody-antigen complexes that deposit in the glomerular filtration barrier …macrophage activation leads to injury and eventual fibrosis of the glomerulus and even some vasculitides
Complication of lupus
Renal failure-hematuris, acute nephritis, nephrotic syndrome, acute and chronic renal failure, and HTN
LUPUS appearance
Wire loop appearance -systemic LOOPus
What are the 6 patterns of SLE
ClassI-Class VI
Class I SLE
Minimal mesangial lupus nephritis
Immune comple deposition in the mesangium
Seen on EM or IF only-no structural changes identified by light microscopy-a lot like MCD
Least common
Class II SLE
Mesangial proliferative lupus nephritis
CLASS III SLE
FOCAL LUPUS NEPHRITIS
-DEFINED BY INVOLVEMENT OF <50% of all glomeruli
Segmental or global involvement of the glomerulus
Affected glomeruli-swelling and proliferation of endothelial and mesangial cells associated with leukocyte accumulation, capillary ecrosis, and hyaline thrombi; also often extracapillary proliferation associated with focal necrosis and crescent formation
Presentation class II SLE
Mild hematuris and proteinuria to acute renal insuffiency
Red cell casts in urine common in active disease
Class IV SLE
Most common and severe
> 50% of all glomeruli (diffuse)
Segmental or global involvement of the glomerulus
Morph class IV SLE
Affected glomeruli==proliferation of endothelial, mesangial, and epithelial cells_> lateral crescents that fill Bowman’s space
Subendothelial immune complex deposits may create a circumferential thickening of the capillary wall, forming WIRE LOOPS streucturs on LM
Clinical class IV SLE
Hematuria, proteinuria,HTN, mild to severe renal insuffiency
Class V SLE
Membranous lupus nephritis
Diffuse thickening of the capillary walls due to deposition of subepithelial immune complexes usually accompanies by increased production of basement membrane like material
Severe proteinuria or nephrotic syndrome
Class VI SLE
Advanced sclerosing lupus nephritis
Sclerosis of more than 90% of glomeruli
End stage renal disease
Hemochromatosis Schonlein Purpura
Childhood syndrome with skin lesions, abdominal pain, intestinal bleeding, arthralgias, and renal abnormalities in 1/3
Probably related to IgA nephropathy
Renal manifestations henoch-schonlein purpura
Hematuria, nephritis syndrome, nephrotic syndrome, or some combination
Associations of henoch-schonlein purpura
Atopy
URI
Difference between henoch schonlein purpura and burgers (IgA nephropathy)
HSP is systemic and burgers is localized
Morphology henoch schonlein purpura
Renal lesions vary from mild focal or diffuse mesangial proliferation to endocapillary proliferation to crescentic glomerulonephritis
IF henoch schonlein purpura
Diagnosis is made by IdA is deposited in the renal mesangium , sometimes C3 and IgG
- very similar to IgA
- deposits can sometimes extend into the capillary loops
- pathognomonic feature by IF is the deposition of IgA, sometimes with IgG and C3 in the mesangial region, sometimes with deposits extending to the capillary loops
Presntation henoch schonlein purpura
Pruritis skin rashes on extensor surfaces of arms and legs and butt
These lesions consist of subepidermal hemorrhages and a necrotising vasculitis involving the small vessels of the dermis
Onset 3-8 with good prognosis unless ominous clinical signs (diffuse lesions, crescents, severe prolonged nephrotic syndrome)
Prognosis henoch schonlein purpura
3-8 years good! Unless ominous clinical signs (diffuse lesions, creascents, or severe prolonged nephrotic syndrome)
Glomerulonephritis associated with bacterial endocarditis and other systemic infections occurs with what infections
Rheumatic fever, endocarditis, and infected AV shunts—stsaphylococcus aureus
Morphology glomerulonephritis associated with bacterial endocarditis and other systemic infections
Circulating antigens cause immune deposition and nephritis
Clinical glomerulonephritis associated with bacterial endocarditis and other systemic infections
Range from mild to full blown RPGN
Chronic cases can have a MPGN
Diabetic nephropathy
Diffuse nodular sclerosis
Leading cause of chronic kidney failure in the US
In chapter 24
Fibrillation glomerulonephritis characteristic
Fibrillation deposits in the mesangium and glomerular capillary walls
Looks like amyloid fibrils on histology, but do not stain with Congo red
Morphology fibrillation glomerulonephritis
Selective deposition of polyclonal IgG, IgK, Igdelta light chains, and C3 on IF
Presentation fibrillation glomerulonephritis
Nephrotic syndrome, hematuria (nephritic syndrome), and progressive renal insuffiency—mixed nephrotic/nephritic
- recurs after transplants
- unknown etiology
Essential mixed cryoglobulinemia
IgG-IgM complexes (cryoglobulinemia) induce cutaneous vasculitis, synovitis, and a proliferative glomerulonephritis (typically MPGN type I)
What is essential mixed cryoglobinemia associated with
Hep C that goes on to MPGN type I
Acute tubular injury/necrosis
Clinicopathologic finding characterized morphologically by damage to tubular epithelial cells and clinically by an acutely dismissed renal function—necrosis is not always preset
Most common form of acute kidney injury/renal failure
Is acute tubular injury irreversible or reversible
REVERSIBLE
-patchiness of tubular necrosis and maintence of theintegrity of the basement membrane along many segments allow repair and recover in the precipitation cause is removed
Two types of acute tubular injury
Ischemic (trauma, sepsis, shock)
Nephrotoxic (from exogenous agents like gentamicin, contrast, heavy metals, or solvents
Why does ATI present with cases of material in the urine
Hemolytic or muscle injuries can release hemoglobin or myoglobin that can injure the kidneys
Pathogenesis I acute tubular injury
- Tubular injury and
2. Persistent and severe disturbances in blood flow
Pathogenesis ATI
Acute, severe loss of blood flow or obstruction, usually associated with trauma; can also be caused by toxins that is associated with tubular injury
Tubular epithelial cells have a high metabolic demand (constant massive resorption and NaK ATPase use)
Ischemic poisoned cells lose cell polarity due to redistribution of membrane proteins from basolateral->luminal aspect
Abnormal ion transport across the cells->increasing distal sodium delivery->vasoconstriction via tubuloglomerular feedback
Ischemic cells detach from the BM->luminal obstruction->increase Bowman’s hydrostatic pressure ->decreasing GFR
The filtrate int he lumen of the damaged tubules can lead back into the interstitium and lead to edema and more tubular damage
Hemodynamics alterations that cause reduced GFR
Intrarenal vasoconstriction_>reduced GFR and reduced O2 delivery to the functionally important tubules int he outer medulla (thick ascending limb and straight segment of the proximal tubule)
Repairing in acute tubular injury/necrosis
Some repair and healing can occur once the offending agent is removed as long as the surrounding cells are still able to proliferate and differentiate
Morphology ATI, which don’t correspond to severity!
Focal tubular epithelial cell necrosis and BM eruption with large skip areas of unaffected tubule
Rupture of BM (tubulorrhexis) and occlusion of tubular lumen by casts
Focal, nonspecific necrosis espicially at the straight portion of the proximal tubule and the thick ascending limb
Eosinophilic hyaline and pigmented granular casts in DT and CD
-casts contain mostly Tamm-Horsfall protein (urinary glycoproteins normally secreted by the cells of the ascending thick limb and DT)
Interstitial edema and accumulation of WBC in distal vasa recta
Epithelial regeneration -flattened epithelial cells with hyperchromatic nuclei and mitosis figures
Causes of AKI
Rhabdomyloysis follwing crush injuries or any condition that breaks down muscle (cocain, statins, ciclosporin, alcoholism)
-myoglobin is released and is directly nephrotoxic
Aminoglycosides (gentamycin)-directly nephrotoxic and cause in 15% of patients
Mercuric chloride leads to injured cells with large acidophilus inclusions that can become calcified
Carbone tetrachloride can lead to lipid accumulation in cells followed by necrosis
Displaying and ciclosporin and other chemotherapeutic agents
Contrast dye is hyperosmolar and in dehydrated ppl can lead to nephrotoxicity in patients with already diminished kidney function (DM)
Crystal deposition from either tumor lysis syndrome or from the ingestion of ethylene glycol (which forms oxalate and leads to calcium oxalate stons0
-BALLOONING OF PCT ISS ETHYLENE GLYCOL
Aminoglycosides are nephrotoxic..so who do we use them in
Life treating gram negative sepsis
Pyelonephritis, coadminstered with fluoroquinolones
Clinical AKI
Repair and resolution so give supportive care
NOT associated with hematuris
Three phases-initiation, maintence, recovery
Initiation phase AKI
Short period during which the nephrotoxic insult has not yet caused acute renal failure
Slight rise in BUN and decrease in urine output
Explained by a transient decrease in blood flow and declining GFR
Maintence phase AKI
Sustained decreases in urine output (oliguria), salt and water overload, rising BUN concentrations, hyperkalemia (->cardiac arrhythmia, metabolic acidosis) and other manifestations or uremia
With proper management patient will pull through
Recover phase AKI
Renal function begins to improve rapidly with resolution in a few weeks-initial polyuria as water balance is restored (excess fluid that got jammed up is now allowed to exit)
Beware of hypokalemia
Increased risk of infection
Most patients fully recover if make it here
Diagnosis ATN
Dirty worn granular casts, also called “renal failure casts”
Tubulointerstitial nephritis
A group of renal disases caused by inflammatory injuries
Insidious in onset that are manifest by azotemia
What is the difference between acute and chronic tubulointerstitial nephritis
Acute-rapid clinical onset, interstitial edema, and WBC infiltration of the interstitium and tubules with tubular injury
Chronic-infiltration with mostly mononuclear WBCs, lots of interstitial fibrosis, and lots of tubular atrophy
Difference between tubulointerstitial nephritis and glomerular disease
Absence of nephritic and nephrotic syndrome
Presence of defects in tubular function which can present as inability to concentrate urine and defects in absorption/secretion that can lead to polyuria and metabolic acidosis
Pyelonephritis and UTI cause what
Tubulointerstitial nephritis
Most common disease of the kidney
UTI-pyelonephritis
What does pyelonephritis mean
Kidney-nephritis
Pyramids-pyelo
Bladder-cystitis
Acute vs chronic pyelonephritis
Acute-cause by bacterial infection but can have a complex etiology
Chronic-dominated by bacterial infection, but can have a complex etiology
Vesicoureteral reflux or obstruction may lead to __ episodes of acute pyelonephritis
Recurrent
Bacterial pathogenesis of pyelonephritis
Gram negative bacteria via endogenous spread from enteric/coliform organisms (e coli, proteus, klebsiella, enterobacter)
Mycobacterium can cause caseating granulomatous inflammation, while fungal infections are non caseating
Can spread hematogenous lh or through ascending infection from a lower UTI (common)
Viral pyelonephritis
Polyomavirus, CMV, adenovirus if the person is immunocompromised
Pathology ascending infection pyelonephritis
Begins with colonization of the urethra (introitus) by coliform bacteria
Entrance to bladder is acheived via catheterization (males) or ascent through small urethra (women)
Stasis of urine will make it easier for bacteria to ascend
Vesicourectal reflux (VUR) or intrarenal reflux
Vesicoureteral refluc (VUR)
Allows bacteria to gain access to ureters, while stasis makes it easier
Causes of VUR
Congenital-malformed or incompetent valve(posterior urethral valves are a congenital abnormality)
Acquired-atopy of the bladder
Absence of VUR
Localized to the bladder (lower UTI-cystitis and urethritis, no pyelonephritis)
Intrarenal reflux
Infected bladder urine can be propelled up to the renal pelvis and deep into the renal parenchyma through open ducts at the tops of the papillae
- Most common in the upper and lower poles of the kidney
- occurs with each contraction of the bladder, urine exiting the urethra and ureters, pushing infection up (espicially with utflow obstruction )
Acute pyelonephritis hallmark
Patchy interstitial suppurative inflammation (focal abscesses or large wedge like areas), intratubular WBC aggregates (WBC casts on urinalysis) and tubular necrosis
Acute pyelonephritis effects the __ poles more than the __ poles
Upper and lower
Middle
What are the three complications of acute pyelonephritis
Papillary necrosis
Pyonephrosis
Perinephric abscess
Papillary necrosis
Seen in diabetics, sickle cell disease, and those with urinary tract obstruction
- typically bilateral
- distal pyramid grey white to yellow necrosis (ischemic coagulative)
- preservation of outlines of tubules with WBCs limited to the preserved and destroyed tissue
- superimposition of papillary necrosis with acute pyelonephritis->acute renal failure
Pyonephrosis
Seen when there is a total or almost complete obstruction, particularly when it is high in the urinary tract
-severe infection that totally concludes the lumen and outflow with pus that fills the renal pelvis, calicoes, and ureter
Perinephric abscess
Where the suppurative inflammation extends through the renal capsule into the perinephric tissue
After the acute phase of acute pyelonephritis we get healing. What does this look like
Neutrophilic infiltrate replaced by macrophages, plasma cells and lymphocytes
Inflammatory foci replaced by irregular scars (characterized microscopically by tubular atrophy, interstitial fibrosis, and a lymphocytic infiltrate in a patchy jigsaw pattern with intervening preserved parenchyma
Pyelonephritis scar
Almost always associated with inflammation, fibrosis, and deformation of the underlying calyx and pelvis
What is acute pyelonephritis associated with
UTI, VUR< urinary tract instrumentation (catheters), pregnancy, and DM (increased susceptibility to infection+neurogenic bladder dysfunction+more frequent instrumentation)
PREGNANCY!!
Preexisting renal lesions that can lead to obstruction
Who gets acute pyelonephritis
<1 and >40 males
Under 1-congenital
Over40-catheterization and prostate obstruction
Women in adult ages more common bc short urethra
Signs and symptoms of acute pyelonephritis
Dysuria/frequency with sudden onset of pain in the costovertebral angle (flank pain)
- systemic evidence of infection (fever, malaise
- localized onset of pain at the costovertebral angle
- indications of bladder and urethral irritation==dysuria, frequency, and urgency
- pyuria-leukocytes in urine
Does pyuria differentiate between uppper and lower UTI
No
WBC casts in urine indicate what
Renal involvement—casts are formed only in tubules
Culture in pyelonephritis
Pathogens
Urine n pyelonephritis
WBC (casts)
Treat pyelonephritis
Antibiotics against the cultured pathogen
Start gram -
What happens if pyelonephritis bug lives for years like indiabetics or immunosuppression, then there can be
Superimposed papillary necrosis and acute renal failure
Polyomavirus nephropathy
Reactivation of latent virus
Seen in post transplant patients who are immunosuppressed
Characterization polyomavirus nephropathy
Infection of tubular epithelial cell nuclei
LM polyomavirus nephropathy
Nuclear enlargement and intranuclear inclusions (viral cytoplasmic effect)
EM polyomavirus nephropathy
Inclusions are arrayed in crystalline like lattices
Chronic pyelonephritis and refluc nephropathy
Chronic pyelonephritis==chronic tubulointerstitial inflammation and scarring involving the calyces and pelvis
-only chronic pyelonephritis and analgesic nephropathy impact the calyces
Two forms of chronic pyelonephritis
Reflux nephropathy and chronic obstructive pyelonephritis
Morphology chronic pyelonephritis
Tubulointerstitial inflammation causes discrete, corticomedullary scares overlying dilated, blunted and deformed calyces
Reflux nephropathy
Most common pyelonephritis scarring
Who gets reflux nephropathy
Early in childhood from superimposition of UTI on congenital vesicoureteral refluc and intrarenal reflux
VUR and reflux nephropathy
VUR may be unilateral or bilateral->scarring and atrophy of one or both kidneys—>renal insuffiency
VUR can cause renal damage in the absence of infection (sterile refluc) when obstruction is severe
Chronic obstructive pyelonephritis
Obstructions predispose to infections
The recurring inflammation can lead to scarring and chronic pyelonephritis
Defective posterior urethral valves is bilateral
Calculi and unilateral obstructions of the ureter are unilateral
Morphology chronic pyelonephritis and refluc nephropathy
Irregular scarring(differs from chronic glomerulonephritis)
Coarse, discrete corticomedullary scars overlying dilated, blunted, or deformed calyces and flattening of the papillae
-SCARS ARE MOST COMMON IN THE UPPER AND LOWER POLES
Tubules atrophy in some areas and hypertrophy/dilation in others
Sclerosis of arteries in affected regions
Dilated, flattened epithelium filled with thyroid colloid (thyroidization)==chronic pyelonephritis
Carrying degrees of chronic interstitial inflammation and fibrosis in the cortex and medulla
Arcuate and interlobular vessels demonstrate obliterating intimacy sclerosis inthe scarred areas
With HTN, hyaline arteriolosclerosis is seen in the entire kidney
Glomeruli typically appear, except in advanced cases with proteinuria there is focal segmental glomerulosclerosis (FSGS)
Presentation chronic pyelonephritis and reflux nephropathy
Back/flank pain, fever, pyuria, and bacteremia
With reflux can be insidious onset without symptoms so it is found late
Patients have asymmetrically contracted kidneys with course scares
Why do people with chronic pyelonephritis and reflux nephropathy get medical attention late in disease
Onset is so slow
What is the major cause of kidney destruction in kids with severe lower urinary tract abnormalities
chronic pyelonephritis and reflux nephropathy
*reflux nephropathy is often discovered in kids when the cause of HTN is investigated
FSGS with chronic pyelonephritis and reflux nephropathy
Possible with increased scarring!
Proteinuria is a poor prognostic finding with progression to ESRD
-chronic pyelonephritis is a cause of chronic renal failure
Morphology point chronic pyelonephritis and reflux nephropathy
Dilated renal calyces and pelvises
Only chronic pyelonephritis and analgesic nephropathy effect the calyces and pelvises
Xanthogranulomatous pyelonephritis
Rare form of chronic pyelonephritis that is characterized by foam cells mixed with plasma cells, giant cells, and other WBC
What is xanthogranulomatous pyelonephritis associated with
Proteus infections and obstruction
Morphology xanthogranulomatous pyelonephritis
Lesions can sometimes produce large, yellow orange nodules that can grossly look like renal cell carcinoma
Acute tubulointerstitial nephritis
Immune mediated reaction (hypersensitivity type I and IV) to a variable number of drugs resulting in tubulitis and acute renal failure
It is the second most common cause of acute kidney injury after pyelonephritis
Is tubulointerstitial nephritis caused by drugs (allergic nephritis) dose dependent
No..related to some immune mechanism (IgE type I or T cell type IV DTH)
How do drugs cause tubulointerstital nephritis
Drugs act as a hapten until concentrated in the tubules for excretion in urine whereby activation of IgE and T/B/Plasma cells int he localized area
Morphology allergic nephritis
Pronounced edema in the interstitium
Inflammation may be greater int he medulla where the agent is more concentrated
Eosinophilsneutrophils are present in large numbers
Granulomas may b present that are non necrotizing, typically due to methicillin and thiazides
Various stages of tubular necrosis and healing
Glomeruli are normal except in some cases with NSAIDS
Clinical presentation allergic nephritis
Fever, rash, eosinophilia, and acute renal failure (increased serum creatinine and oliguria) espicially in older patients 2-40 (average 15 days after exposure to offending agent
Sometimes papillary necrosis with gross hematuria due to ischemia from compression of small vessels or renal colic due toobstruction of the ureter
What causes allergic nephritis
NSAIDS, synthetic penicillins (methicillin, ampicillin), other synthetic antibiotics (rifampin), diuretic (thiazide), allopurinol, and cimetidine
How treat allergic nephritis
Remove drug leads to recover and healing
Analgesic nephropathy
Chronic tubulointerstitial nephritis caused by phenacetin containing analgesics
Incidence is way down bc we removed phenacetin from most countries
What patients with analgesic nephropathy more likely to develop
Urothelial carcinoma of renal pelvis
Nephropathy associated with NSAIDS
Uncommon, including COX2 selective inhibitors bc kidneys express COX1 and 2
What can nephropathy associated with NSAIDS cause
AKI-from ischemia due to vasoconstriction from loss of vasodilation prostaglandins (afferent ). Usually with another volume reducing condition
Acute hypersensitivity interstitial nephritis
Acute interstitial nephritis and minimal change disease: there is injury to both the interstitium/glom and the podocytes to cause renal failure and the nephrotic syndrome
Membranous nephropathy: occurs with the nephritic syndrome
Irate nephropathy
Due to the precipitation of uric acid crystals int he renal tubules, espicially in the CD
Leads to an obstruction of the nephrons and can develop into acute renal failure
The crystal formation is enhanced by the acid nature of the Collecting tubules
Who gets urate nephropathy
Patients with leukemia’s and lymphomas that get chemo as a result of tumor lysis syndrome whereby lots of nucleic acids are released that are then converted into uric acid
What is chronic urate nephropathy
Gout
Who gets gout
Some patients with chronic hyperuricemia
What happens in gout
URIc acid crystals develop in the distal tubules, collecting ducts and the interstitium—forms distinct bore fringe NT needle like crystals which causes there to be a mononuclear response with foreign body giant cells (tophus)
What does gout lead to
Cortical atrophy and scarring
What is gout associated with
Lead exposure
Nephrolithiasis(uric acid stones) is in 22% of people with __and 42% of patients with ___ ___
Gout
Secondary hyperuricemia
Hypercalcemia and nephrocalcinosis
Disorders that involve hypercalcemia (hyperparathyroidism, multiple myeloma, VD intoxication, metastatic cancer, too much milk) can lead to formation of Ca stones and deposition of Ca in the kidney (nephrocalcinosis)
What does lots of calcinosis lead to
Chronic tubulointerstitial disease and renal insuffiency
What is the earliest functional defect of hypercalcemia and nephrocalcinosis
Inability to concentrate the urine, but there can also be tubular acidosis and salt losing nephritis
Acute phosphate nephropathy
Lots of accumulation of phosphate can occur in patients that consume lots of oral phosphate solutions in preparation for colonoscopy
- patients are not hypercalcemic
- excess phosphate load causes marked precipitation of calcium phosphate->presents as renal insuffiency several weeks later
Patients with acute and reversible injury typically recover partial renal function
Light chain cast nephropathy (myeloma kidney)
Most of the kidney damage is restricted to the tubulointerstitial part and is due to the sequels of the tumor like hypercalcemia or from the chemo/radiation therapy
Light chain cast nephropathy-bence Jones proteinuria and cast nephropathy
Due to light chain proteinuria as the bence-jones proteins (Ig light chains) are toxic to the epithelial cell and bc they form complexes with tamm horsfall proteins under acidic conditions to cause tubular obstruction and characteristic inflammation
Occurs in 70% of patients with multiple myeloma
-presence of significant non light chain proteinuria suggests AL amyloidosis or light chain deposition disease
Amyloidosis
The AL type with lambda light chains occurs in 6-24% of patients with myeloma
Light chain deposition disease
The kappa type light chains can deposit in the GBMs and mesangium in non fibrillation forms, causing glomerulopathy
Also deposits in the tubular B< to cause tubulointerstitial nephritis
Morphology light chain
Bence jones tubular casts appear pink blue amorphous masses that are sometimes concentrically laminated and fractured
These masses then expand and fill the tubular lumen
Some casts are surrounded by multi nucleate giant cells
The adjacent interstitium shows inflammation reaction
Bile cast nephropathy
Hepatorenal syndrome==impairment of renal function in patients with acute or chronic liver disease with advanced liver failure
- serum bilirubin UP—-bile cast formation
- reversibility of the renal injury depends on the severity and duration of the liver dysfunction
Morphology Chile cast nephropathy
Bile cast formation in the kidneys (cholemic nephrosis) in the distal nephron segments that can extend to the proximal segments
What does bile cast nephropathy lead to
Direct toxicity effects and obstruction of the involved nephron
-similar pattern of injury to that of myeloma protein or myoglobin casts
Nephrosclerosis
Sclerosis of the renal arterioles and small arteries associated with aging and HTN
Affected vessels have thickened walls/narrowed lumens—>focal parenchymal ischemia
Sclerosis from medial and intimacy thickening that caused ischemia
Hyaline deposition from extravasation of plasma proteins through injured epithelium
Morphology nephrosclerosis
Hyalinized arterioles with typical arteriolar changes in HTN
Kidneys are normal to small with a fine, even granularity resembling grain leather
-loss of mass is due mainly to cortical scarring and shrinking
Microscopic subscapular scars with sclerotic glomeruli alternate with preserved parenchyma
Fibropastic hyperplasia: interlobar and arcuate arteries show medial hypertrophy, duplication of the internal elastic lamina, and increased myofibroblasts tissue in the intima—>luminal stenosis
Due to narrowing lumen there is patchy ischemic atrophy with tubular atrophy and interstitial fibrosis with glomerular alterations (GBM collapse, collagen deposition in bowman, periglomerular fibrosis and total sclerosis)
Who gets nephrosclerosis
Blacks, old ppl, diabetics
Ppl with DM and HTN
Clinical presentation nephrosclerosis
Usually inconspicuous but proteinuria, decreased GFR and an increased risk towards chronic renal failure do exist i it progresses onto malignant HTN
Malignant HTN nephrosclerosis
Renal disease with typical arterial changes associated with malignant or accelerated HTN
Pathogenesis malignant HTNnephrosclerosis
Initial insult from vascular damage to the kidneys from a wide variety of etiologies
-extreme bp=endothelial cell damage, increased permeability to fibrinogen and other plasma proteins, focal death of cells ofthe vascular wall, and platelet activation ->fibrinoid necrosis->intravascular thrombosis
Hyperplastic changes (onion skinning)results from contemporary changes
Kidney becomes ischemic
Ischemia results in activation of the RAAS and exacerbation of HTN
-increased plasma levels of renin->increased HTN
Result is a vicious cycle leadin to malignant arteriosclerosis
Morphology malignant hypertension nephrosclerosis
Petechial hemorrhage on cortical surface from rupture of arterioles of glomerular capillaries
-FLEA BITTEN APPEARANCE
Fibrinoid necrosis of arterioles=smudgy eosinophilic appearance due to fibrin deposition
-none to minimal inflammation;glomerular capillaries can thrombose
Onion skinning (hyperplastic arteriolitis)=concentric duplication of the basement membrane -correlated with renal failure
Who gets malignant HTN nephrosclerosis
Black men
Ppl with HTN
Presentation malignant HTN nephrosclerosis
Systolic>200 diastolic >120 mmHg, papilledema, retinal hemorrhages, encephalopathy, cardiovascular abnormalitis, and renal failure
Early symptoms are due to increased intracranial pressure: headache, nausea, vomiting, vision problems (scotomas)
May be HTN crises with LOC and maybe convulsions
Proteinuria, maybe hematuria presents at onset with preservation of renal function
Chronic condition results in total renal failure and uremic death
Treat malignant HTN nephrosclerosis
Medical emergency requiring aggressive and prompt antihypertensive therapy to prevent irreversible renal injury
Unilateral renal artery stenosis
Old diabetic men
- responsible for 2-5% of HTN cases, curable by surgery
- HTN secondary to renal artery stenosis is caused by increased production of renin from the ischemic kidney
Second most common cause of stenosis is from fibromuscular dysplasia of the renal artery where there is fibromuscular thickening of the artery
-more common in 20-30 women
What causes unilateral renal artery stenosis
CV changes (atheromaous plaques, particularly at the origin of the renal artery) that lead to a decreased renal blood flow and elaboration of ANGII via RAAS from the ischemic kidney (elevated serum renin levels)
Treat unilateral renal artery stenosis
ACE-I or ARB and surgery
Morphology unilateral renal artery stenosis
Plaque is concentrically placed
There is often superimposed thrombosis
Ischemic kidney is smaller with diffuse ischemic atrophy, crowded glomeruli, atrophic tubules, interstitial fibrosis, and focal inflammation
String of beads**
The arterioles in the ischemic kidney are typically protected from the HTN and only show mild arteriosclerosis while the other contralateral, nonischemic kidney is less protected and will show more severe arteriosclerosis
Presentation unilateral renal artery stenosis
Patients look like they have essential HTN
Bruit can be heard on the affected kidney
Elevated plasma renin, shows a response to ACE inhibitor
Arteriography is needed to find the lesion and surgery is needed for the cure
Thrombotic microangiopathies=HUS/TTP
Group of overlapping clinical manifestations
Variety of insults leads to excessive activation of platelets that deposit in small vessels, including the kidneys
Why do patients with thrombotic microangiopathies have thrombocytopenia and microangiopathic hemolytic anemia
Consumption of platelets also leads to thrombocytopenia that can shear RBCs and lead to microangiopathic hemolytic anemia
-fragmented red cell forms=evidence of hemolysis-schistocytes
Thrombi can cause microvascular occlusions leading to tissue ischemia and organ dysfunction
TPP thrombotic thrombocytopenic purpura
Will do plasmapheresis: good pasture, TPP, hyperviscousity syndrome, lupus cerebri this,
HUS hemolytic uremia syndrome
Will not do plasmapharesis
2 major triggers for HUS and TPP
HUS endothelial injury
TPP excessive platelet aggregation
Endothelial injury causing HUS pathogenesis
Typical Cause is shiga like toxin (EHEC>shigella)
Inherited forms of atypical HUS-inappropriate activation of complement
The injury to the endothelial causes there to be platelet aggregation and thrombosis within microvascular beds
- reduced endothelial production of PGI2 and NO->platelet aggregation
- increased production of endothelin1->vasoconstriction (exacerbates hypoperfusion)
TPP platelet aggregation pathogenesis
Due to large amounts of vWF from a defiency of ADAMTS13 (most often from auto-antibodies to it)
Causes of typical (childhood, epidemic, diarrhea +, classic)) HUS
E. coli hamburgers (O157:H7) containing shiga like toxin
-raw milk and person to person
Trigger-shiga like toxin induced endothelial injury
Toxin causes increase in adhesion mo;Eccles of epithelium and decreased NO synthesis
Who gets typical HUS
Kids and elderly
Presntation typical HUS
Sudden onset hematemesis and melena following a flu like prodrome
Oliguria/hematuria/hemolytic anemia may follow
Treat typical HUS
Dialysis
Prognosis typical HUS
Acute setting resolves itself, but long term prognosis is poor
- if renal failure is managed properly with dialysis, most patients recover normal Rena,l function in weeks
- long term outlook is more guarded due to renal damage and up to 90% exhibit some level of renal insuffiency 15-25 years later
Morphology typical HUS
Fibrinoid necrosis of lobular arteries
Intermesangial hemorrhage
Intima hyperplasia and thrombosis
Atypical HUS (non epidemic, diarrhea -, adults)
Worse prognosis than typical HUS since underlying conditions can be chronic and/or hard to treat
Trigger is excessive, inappropriate activation of complement
Differentiate atypical HUS from TPP
Look for normal levels of ADAMTS13
Presentation atypical HUS
Neuro signs and symptoms
Endothelial injury
Inherited mutation that causes atypical HUS
Mutation in complement regulatory proteins, most commonly in factor H (breaks down the alternative pathway C3 convertase and protects cells from damage by uncontrolled complement activation) but can also be from defects in factor I or CD46)
Age of onset atypical HUS
Any
Presentation atypical HUS
Many relapses and progression to ESRD
Antiphospholipid antibody syndrome
HUS without immune deposition
Primary or secondarily related to SLE
Atypical HUS and pregnancy
Uncomplicated delivery results in spontaneous renal failure a day to 3 months later
Grave prognosis ; recovery possible in milder cases
Vascular renal disease leading to atypical HUS
Wagner’s, scleroderma, HTN
Chemotherapy leading to HUS
Cyclosporine, bleomycin, cisplatin
Thrombotic thrombocytopenic purpura TTP
Pentax: fever, neurologic symptoms (dominant feature), microangiopathic hemolytic anemia, thrombocytopenia, and renal failure
Defiencies causing TPP
In ADAMTA14, normally regulates the function of vWF
-most commonly caused by inhibitory auto-antibodies, espicially in women
Who gets TPP
Adults over 40 unless it is inherited and then they have episodic symptoms beginning int heir adolescence
-need some other disease to get the full form out TPP
Treat TPP
Plasmapheresis
- removes antibodies and provides functional ADAMTS13
- can be treated successfully in more than 80% of patients (once was a terminal disease)
Morphology HUS/TPP
ACUTE
Patchy or diffuse cortical necrosis
Subscapular petechiae
Glomerular capillaries are occluded by thrombi comprised of aggregated platelet and fibrin
Capillary walls are thickened from endothelial swelling and subendothelial deposits of cell debris and fibrin
Mesangiolysis
Intralobular arteris show fibrinoid necrosis and occlusive thrombi
Morphology chronic HUS/TPP
Only in patties with atypical HUS or TTP
Due to continued injury and attempts to heal
Renal cortex has lots of scarring
Glomeruli are hypercellular
Tram-track BM-like in MPGN
Walls of arteries have onion skinning
All of this leads to hypoperfusion and ischemia/atrophy of the parenchyma
Atherosclerotic ischemic renal disease
Adults
Bilateral renal artery stenosis causes renal ischemia
Labs atherosclerotic ischemic renal disease
HTN may be absent but with bilateral stenosis, ANGII is usually elevated
Treat atherosclerotic ischemic renal disease
Avoid ACE-I and ARB
-decrease in ANGII willl dilate the efferent arterioles->increased RBF but a decreased GFR=acute renal failure
Surgical revascularization can prevent further decline in renal function
Atheroembolic renal disease
Emboli from atheromtous plaques proximal to renal artery (aorta, coronary angiography, abdominal aorta surgery)
Contain cholesterol crystals that appear as rhomboid clefts
Causes no problems in healthy kidneys, but infarcts lead to acute renal failure in diseased kidneys
Sickle cell nephropathy
Suckling in the vasa recta decreases concentrating ability and increases thrombosis
There can be cortical scarring and patchy papillary necrosis
Characteristics are hematuria, dilute urine (hyposthenuria; dismissed concentrating ability), and proteinuria (can sometimes progress to nephrotic syndrome)
Diffuse cortical necrosisi
Follows malignant HTN, obstetric emergencies, septic shock, and extensive surgery
Ischemia and coagulative necrosis is limited to cortex with white patchy infarcts
Thrombosis of glomerulus and arteries;typically focal
Hemorrhage may be preset that can form fibrin plugs to occlude the golermular capillaries
In bad cases it can quickly lead to sudden Anura and uremic death, but patchy or unilateral cases have a better prognosis**
Infarcts
Most are due to emboli, espicially from mural emboli int he left atrium or ventricle status post MI
Kidney is an end organ with little collateral circulation
Infarcts are white and wedge shaped initially
Within 24 hours, they are sharply demarcated, pale, yellow white , with irregular foci of hemorrhagic discoloration
Eventually the infarcts become fibrosis leaving depressed, pale, gray white scares that have a V shape
Large infarcts of one kidney are probably associated with renal artery steosis and may cause HTN
Agenesis of kidney bilateral
Bilateral incompatible with life-stillborn
Amniotic fluid is not made (oligohydramins) and the baby gets crushed when no kidney
-potter syndrome
Unilateral agenesis of kidney
Compatible with life
Good kidney will undergo compensatory hypertrophy and become enlarged; some develop sclerosis and renal failure
Renal hypoplasia
Failure of the kidneys to develop to a normal size
Unilateral>bilateral
Typically due to low birth weight and may contribute to lifetime risk of chronic kidney disease
May be indistinguishable from an acquired atrophic kidney
True hypoplastic kidney has reducedlobes and pyramids and no signs of scarring
Ectopic kidneys
Definitive metanephros develops at ectopic foci, usually on pelvic brim or within pelvis
The ectopic kidneys are usually small and asymptomatic
May cause torsion or obstruction of ureter, predisposing for infection (pyelonephritis)
Horshoe kidney (common)
Fusionof kidneys produces a horseshoe shaped structure continuous across the anterior of the aorta and inferior vena cava
Get caught by inferior mesenteric artery
Usually lower pole fusion (90%) some upper (10)
Risk for stone formation
Autosomal dominant polycystic kidney disease-ADPKD
Multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma leading to interstitial fibrosis and cause renal failure beginning in 30-40 and almost definitely by 70
Pathogenesis ADPKD genetics
AD that needs a second hit
PKD1 85% chromosome 16
PKD2. Chromosome 4
Generate cysts via polcystin 1 or 2 protein abnormality leading to proliferation of fiefferent regions of the tubules
Exact mechanism unknown, but most likely a defect in the cilia that control the mechanic sensin of Ca
PKD1 or PKD2 more severe
1
Only 45% of PKD2 have renal failure at 70
PKD1
Expressed in tubular epithelial cells, particularly those of the distal nephron
Unknown functional contains domains involved in cell cell and cell matrix interactions
PKD2
Integral membrane protein expressed in all segments of the renal tubules and may extrarenal tissues
Ca permeable cation channel
Morphology ADPKD
Bilaterally enlarged kidneys reaching enormous size (4kg)
Surface appears entirely cystic though histology reveals functional parenchyma
Arise from different regions of the tubules so cysts express variable epithelial
Cysts may be filled with a clear , serous fluid or with turbid, red to brown sometimes hemorrhagic fluid
Who gets ADPKD
Norther European descent
Progression is accelerated in black males, espicially with sickle cell and/or HTN
Presntation ADPKD
Also see extrarenal congenital anomalies
May be asymptomatic until renal insuffiency announces presence
Hemorrhage may cause flank pain (bleeding into cyst)
Excretion of blood clots can cause renal colic
Disease occasionally begins with insidious onset of hematuria followed by other features of progression fo chronic kidney disease such as proteinuria
What are extrarenal congenital anomalies found in patients with polycystic kidney disease
40% occur in the liver from biliary epithelium and are asymptomatic—polycystic liver disease
Some occur int he lungs or spleen; mitral valve prolapse and other cardiac valvular anomalies in heart
Intracranial berry aneurysms presumably arise from altered expression of polycystic in vascular smooth muscle
- account for 15% of deaths in these patients
- isolated, basilar SAH in a young patient on imaging==ADPKD
Prognosis ADPKD
Patients may survive for years with azotemia slowly progressing to uremia
40% die coronary or hypertensive disease
25% from infection
15% from a rupture berry aneurysm or hypertensive intracerebral hemorrhage
Autosomal recessive polycystic kidney disease==childhood form of polycystic kidney disease
PKHD1 (chromosome 6) codes for fibrocystin, highly expressed in adult and fetal kidney and also in liver and pancreas
Mutations disrupt the collecting tubule+biliary epithelium differentiation
Without history, this can be either recessive (kids) or dominant (adults)
Morphology AR polycystic disease
Enlarged smooth surfaced, tiny elongated cysts along the interior replace the cortex and medulla perpendicular to the cortical surface
-have a sponge like appearance when cut
Lined by cuboidal cells bc all cysts come from the collecting tubules
-ADPKD==arises from different regions of tubules
Liver has cysts associated with portal fibrosis and proliferation of portal bile ducts
Invariably bilateral
LM ARPD
Cylindrical or saccular dilation of all CT
I
Prognosis ARPD
Highly fatal in infancy, obvious renal failure in all cases
Childhood form shows smaller cysts at right angles to cortical surface
Four subsets of ARPD
Perinatal, neonatal, infantile, juvenile
Perinatal and neonatal most common
Survivors of ARPD
Develop congenital hepatic fibrosis (biliary epithelium in origin) with HTN and splenomegaly
Medullary sponge kidney/innocuous medullary cystic disease
Occurs in adults with unknown pathogenesis
Found incidentally on radiograph
Scarring is typically absent
Multiple cystic dilations that consist of cuboidal or transitional epithelium from collecting tubules
Nephronophthisis and adult onset medullary cystic disease
Group of progressice diseases that are characterized by variable numbers of cysts in the medulla, typically concentrated at the corticomedullary junction
Almost always associated with some degree of renal dysfunction
As a group, nephronophthisis complex is the msot common genetic cause of ESRD in children and young adults
Three variant of nephronophthisis and adult onset medullary cystic disease
Sporadic nonfamilial
Familial juvenile nephronophthisis
Renal retinal dysplasia
Pathogenesis nephronophthisis and adult onset medullary cystic disease
Injury begins at the distal tubules with tubular BM disruption followed by progressive atrophy of the medulla and cortex leading to interstitial fibrosis
The cortical tubulointerstital adage is the cause of the eventual renal failure
Pathogenesis nephronophthisis and adult onset medullary cystic disease
Genetics
Familial-AR
Juvenile-NPH genes make nephrocystin (JBTS-#) without a known pathogenesis
—-AD and AR form
MCKD1 or 2 defects are associated with ESRD in adults and is AD
Morphology Pathogenesis nephronophthisis and adult onset medullary cystic disease
Small kidneys with contracted granular surfaces
Large cysts at the cortico medullary junction small cysts in the cortex
Cysts are lined by flattened cuboidal epithelium with inflammation or fibrosis surrounding it
In the cortex: atrophy and thickening of the tubular B< with intestinal fibrosis
Glomerular structure is preserved
Who gets nephronophthisis and adult onset medullary cystic disease
Affects children , suspected in unexplained renal failure with familial history
Presentpresetnation nephronophthisis and adult onset medullary cystic disease
Polyuria and polydipsia reflecting inability to concentrate urine
There is Na wasting an tubular acidosis
Prognosis nephronophthisis and adult onset medullary cystic disease
Renal failure occurs in 5-10 years
Cysts may be too small to see on radiograph
Multicystic renal dysplasia
Sporadic disorder that can be unilateral or bilateral, and almost always cystic and nephrectomy; remaining kidney functions normal
-good prognosis
Bilateral:renal failure may ultimately result
-worse prognosis
Kidneys enlarged, extremely irregularly, and multicystic
Histology multicystic renal dysplasia
Lined by flattened epithelium
Presence of islands of undifferentiated mesenchyme, often with cartilage and immature collecting ducts==characteristic feature
Acquired cystic disease (dialysis)
Caused by end stage kidney disease with prolonged dialysis
Cortical and medullary cysts that contain clear fluid but may bleed (causing hematuria) after harmonic exposure
Cysts are lined by hyperplastic or flattened tubular epithelium and often contain calcium oxalate crystals
- calcium phosphate stones are more common that calcium oxalate int he general population
- calcium oxalate stones are more common than calcium phosphate stomes in patients receiving renal dialysis
Calcium oxalate stones are ore common than calcium phosphate stones in patients receiving what
Dialysis
What is acquired cystic disease associated with
Renal cell carcinoma from the walls of cysts
What is a clinically significant complication int he setting of calcium oxalate stones ina. Patient receiving dialysis
Renal cell carcinoma
Simple renal cysts
Get mistaken for tumors bc they create awkward radiographically shadows
-differentiate them bc the cysts have:smooth contours, avascular and give fluid signals on ultrasonography
Morphsimple renal cysts (localized)
Translucent, grey, glistening, and lined by a single layered membrane (cuboidal or flattened cuboidal that can be atrophic)
Clinical simple renal cysts
May bleed into them causing acute pain and distention
Are usually small and cortical
Obstructive urinary lesion can lead to what
Infection and stone formation
Almost always leads to permanent renal atrophy (hydronephrosis or obstructive uroopathy)
Congenital anomalies leading to OUL
Posterior urethral valves Urethral strictures Mental strenuous is Bladder neck obstruction Ureteropelvic jucntion narrowing/obstruction Severe vesicoureteral refluc
Hydronephrosis
Dilation of the renal pelvis and calyces associated with progressive atrophy of the kidney due to obstruction to outflow of urine
What does hydronephrosis cause
High pressure int he pelvis is transmitted back through the collecting ducts into the cortex-> compressses renal vasculature int he medulla
Decreased medullary blood flow, but GFR persists for some time
-GFR only begins to decrease after lots of damage
Often there is significant interstitial inflammation, even int he absence of infection
Morphology hydronephrosis with sudden/complete obstruction
Sudden/complete obstruction: mild dilation of the pelvis and calyces with atrophy of the renal parenchyma sometimes
Morphology hydronephrosis intermittent/incomplete obstruction
Progressive dilation occcurs leading to hydronrphrosis
Hydronephrosis can eventually turn the kidney into what
Large, thin walled cystic structure
Presentation hydronephrosis
Most of the early symptoms are produced by the underlying cause of hydronephrosis
Acute obstruction-may provoke pain from distention
Unilateral complete or partial hydronephrosis-can remain silent for long times as the other kidney compensates
Bilateral partial obstruction-inability to concentrate urine (polyuria, nocturnal), distal tubular acidosis, renal salt wasting, secondary renal calculi, and chronic tubulointerstital nephritis with scarring and atrophy of the papilla and medulla. HTN common
Bilateral complete obstruction: oliguria/Anura: incompatible with survival unless the obstruction is relieved
-after the block is removed, the kidney can undergo post obstructive diuresis where the kidney excretes urine rich in NaCl
Urolithiasis, renal calculi, stones
Formation of solid crystals in the GU tract, most forming int he kidney as a result of increased concentration of particles that precipitate out
Cause of renal caliclui
**increased urinary concentration of the stones constituents such that it exceeds their solubility in urine (supersaturation)
Acidification of the urine and low urine flow rates may also contribute
-promotes precipitation
Postulated that stone formation is enhanced by a defiency in inhibitors of crystal formation in urine
-pyrophosphate, diphosphonate, citrate,
Calcium oxalate stones
Most common type of stone 75%
What are calcium oxalate stones associated with
Hypercaliuria, with or without hypercalcemia
When both are present, it is a result of hyperparathyroidism which can be a result of progressive kidney failure
Renal impairment of calcium reabsorption of a hyper-absorptive intestinal tract can lead to hypercalciuria without hypercalcemia
20% of calcium oxalate stones are associated with uric acid secretion
Hyperuricosuric calcium nephrolithiasis
May occur with or withou hypercalcuria
Involves nucleation of the crystal in the CD
10% of calcium oxalate stones are associated with hyperoxaluria
Primary/genetic form is less common
Overabsorption from diet (enteric hyperoxaluria) occurs even in vegetarians who have a diet rich in oxalate
Hypocituria and calcium oxalate stones
Seen in diarrhea and metabolic acidosis may also lead to calcium stones
15-20% of calcium oxalate stones have no known metabolic derrrangement!
Can also be associated with diffuse bone disease, sarcoidosis and other hypercalcemic states
Sturvite stones, made of magnesium ammonium phosphate (triple stones)
Caused by urea splitting bacteria aka an infection by proteus species and some staph
Increased ammonia from urea degradation int he tubules causes an alkylation of urine , favoring magnesium ammonium phosphate salts
Forms the largest KIDNEY STONES
STAGHORN CALCULI OCCUPYING RENAL PELVIS ARE CAUSED BY INFECTION AND ARE STRUVITE
Uric acid stones-who gets
Common in patients who have conditions predisposing to hyperuricemia, such as gout or any leukemia’s, forming at a low (acidic) urinary pH
- uric acid is insoluble in acidic uring with a pH of less than 5.5
- alkalinize the urine to solubilize the stone and pee it out-can give them bicarb
More than half don’t have hyperuricemia or increased urinary excretion of uric acid
Theses are radiolucent, unlike Ca stones
Cystine stones
Formed with genetic diseases that prevent reabsorption of proteins from the lumen
Form at low urinary pH
Morphology stones
Unilateral in renal calyx, pelvis or bladder
Cary in size (smaller in pelvis)
Smooth or jagged
Staghorn calculi are large branching stone, forming off a small stone in the pelvis, growing upwards, forming a cast of the pelvis and calyces
Who gets renal stones
Men 20-30
Familial pattern
Presntation renal stones
Renal colic : intermittent, sharp flank pain that may radiate to groin
Hematuria may be present as the stone passes and shreds the ureter
Large stones do not pass and stay in pelvis, causing obstruction->hydronephrosis
Renal stones are a predisposition for what
Infection
Renal papillary adenoma
Benign small pale yellow gray, well circumscribed nodules in the cortex
How find renal papillary adenoma
Incidental finding at autopsy
LM renal papillary adenoma
Complex, branching, papillomatous structure with complex fronds
-cells are cuboidal to polygonal in shape and have regular, small central nuclei, little cytoplasm and no atypical
EM renal papillary adenoma
Appear as Low grade papillary renal cell carcinoma ——potentially malignant
-share some immunohistochemical and cytogenic features (trisomies 7 and 17)
Potential malignancy of renal papillary adenoma
Potentially malignant at any size but espicially if greater than 3 cm—consider all adenomas as potentially malignant
> 3 cm metasticize-malignant
<3cm do not metasticise -benign
Angiomyolipoma
Benign neoplasm consisting of vessels, smooth msucle and fat from the perivascular epithelioid cells
MAY SPONTANEOUSLY. HEMORRHAGE
What is angiomyolipoma associated with
Tuberous sclerosis, loss of function mutations in TSC1 or 2 tumor suppressor genes
-characterized by lesions of the cerebral cortex that produce epilepsy./retardation, skin problems and other benign tumors
Oncocytoma
Epithelial neoplasm/tumor composed of large, eosinophilic cells with small, round, benign looking nuclei that have large nucleeoli
Where are oncocytoma
Comes from the intercalated cells of the CD
EM oncocytoma
Massive amounts of mitochondria (eosinophilic cell filled with mitochondria
Malignant oncocytoma
Benign but it can get pretty big (12cm) and cause compression syndrome
What do oncocytoma look like
Tan to brown , well circumscribed with a central scar
What is the most common renal cancer in adults
Renal cell carcinoma
Who gets renal cell carcinoma
Males 50-60
Why get renal cell carcinoma
Most idiopathic, some familial
Risk factors for RCC
SMOKING!!!
Obesity, HTN, unopposed estrogen therapy , asbestos, petroleum, heavy metals
Where are RCC
Mainly poles
Genetic RCC
VHL
Hereditary leiomyomatosis and RCC syndrome
Hereditary papillary carcinoma
Birt-I logg-Dube syndrome
VHL RCC
Nearly all patients will develop bilateral RCC and cysts if they live long enough
Cerebellar involvement too
Hereditary leiomyomatosis and RCC
AD
Mutations in FH gene (fumarate hydratase)
Cutaneous and uterine leiomyomata with an aggressive type of papillary carcinoma with increased risk for metastatic spread
Hereditary papillary carcinoma
AD
Mutations in MET protooncogenes
Many bilateral tumors with papillary histology
Birt-1 log cube syndrome
AD
Mutations in BI ID (expressed folliculin)
Skin problems , pulmonary cysts or bless, and renal tumors with a wide range of histologic subtypes
Most common type of RCC
Clear cell carcinoma more than 95% sporadic!
Mutation clear cell carcinoma
98% loss of chromosome 3 where the VHL gene is
VHL-ubiquitin lipase that targets HIF-1
Chromosomal deletion allows for high levels of HIF1 even under norms in conditions
Inappropriate expression of a number of genes turned on by HIF-1
-genes that promote angiogenesis (VEGF) and genes that stimulate cell growth (insulin like growth factor 1)
What does CCC cause
Unilateral tumors
Form from proximal tubular epithelium presuming with large clear or granular cells
Nonpapillary tumors that rare usually unilateral
What do CCC look like
Bright yellow white grey tumors
Why are CCC yellow
Foam like fat cells present in tumor
RCC shows focal cytoplasmic lipid positivity that other adenocarcinomas do not
Morphology CCC
Undifferentiated but can show some atypia
CCC are likely to invade the __ __ and may go all the way to the ___. Causing what
Renal vein
Heart
Cause a varicocele if located on the left
Papillary carcinoma
Frequently multifocal
What is papillary carcinoma associated with
Sporadic: trisomies 7 and 17, loss of Y in males
Familial:just trisomies 7 (MET pronto-oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor—scatter factor)
——not associated with 3p deletions (like VHL and CCC)
What is papillary carcinoma associated with
Dialysis associated cystic disease
Morphology papillary carcinoma
Hemorrhagic and cystic
Cuboidal or columnar epithelium arranged in papillary pattern that came from the distal convulsed tubules
-foam cells are common in the core
Little stroma but it is highly vascularized
Chromophobe renal carcinoma
Eosinophilic cytoplasm, prominent cell membrane, perinuclear halo, localized to vasculature in solid sheets
- many chromosome losses with extreme hypodiploidy
- grow from intercalated cells of the collecting ducts (like oncocytoma
Prognosis chromophobe renal carcinoma
Excellent
Xp11 translocation carcinoma
Xp11 translocation carcinoma
-young, translocation of the TFE3 gene, cells have clear cytoplasm with papillary architecture
Collecting duct (bellini duct) carcinoma)
Come from collecting duct cells in the medulla
Irregular channels lined by highly atypical epithelium with a hobnail pattern
Malignant cells that create glands enmeshed within medullary fibrotic stroma
Medullary carcinoma is morphologically smiler to neoplasm seen in patietsnw ith sickle cell trait (heterozygous)
____ changes in any type of renal cell carcinoma leads to a worse prognosis
Sarcomatoid changes
How find RCC
Often asymptomatic, discovered by CT scan or MRI for a nonrenal cause
May reach massive sizes 10cm before symptoms set in
Classic triad symptoms RCC
Hematuria, flaunt pain, mass
- hematuria is often microscopic and intermittent
- mass is often non palpable when found
_% of RCC have metasticized prior to discovery
25
Metasticize widely before symptoms!
Where do RCC go
Lungs, bones, regional LN, liver, adrenals, and brain
___ syndromes are huge in RCC
Paraneoplastic
What paraneoplastic syndromes see in RCC
Polycythemia, hypercalcemia, hypertension, Cushing, leukemoid reactions, amyloidosis and feminization/masculinazation
Why is RCC a great mimic in medicine
Tends to produce a diversity of systemic symptoms not related to the kidney
There is a high 5 year survival with RCC UNLESS
Renal vein invasion
Extension into the perinephric fat
Stage 1
Note:statins is dependent on local involvement
Only kidney involved
60-80% 5 year survival
Stage II
Kidney and fat involved
15% 5 year survival
State III
Kidney and renal vein or lymph are involved <10% 5 year survival
Treat RCC
Total nephrectomy is usually curative without metastasis, but partial nephrectomy is recommended to T1a tumors (<4cm)
VEGF tyrosine kinase inhibitors are used as adjuncts
Urothelial carcinoma of the pelvis
Some primary renal tumors come from the urothelial of the renal pelvis
Range from being papillomas to invasive urothelial (transitional cel) carcinomas
Why are urothelial carcinoma of the pelvis quickly found
Produce hematuria so they are typically small
Painless hematuria
1 risk factors urothelial carcinoma
Smoking
Presntation urothelial carcinoma
Painless hematuria
May block urine outflow and lead to hydronephrosis and flank pain
Can be multiple tumors found in other places like the bladder
Prognosis urothelial carcinoma of the pelvic
Not good as they spread through walls easily
What are urothelial carcinomas associated with
Analgesic nephropathy
