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
