肾小球疾病Glomerular Diseases
丁小强复旦大学附属中山医院
Pathological changes -- glomerular injury
Clinical manifestations --proteinuria / hematuria
Pathological changes -- glomerular injury
Clinical manifestations --proteinuria / hematuria
A group of diseases
Complicated causes & mechanisms
Various clinical manifestations
Different prognosisMultiple treatment
Complicated causes & mechanisms
Various clinical manifestations
Different prognosisMultiple treatment
• primary glomerular diseases
• secondary glomerular diseases
• hereditary glomerular diseases
Immune mechanismsHumoral
Cell-mediated
Immune mechanismsHumoral
Cell-mediated
Non-immune mechanismsNon-immune mechanisms
InflammationInflammation
Glomerular diseasesGlomerular diseases
A. Immune mechanisms
(A)deposits of Circulating Immuno-Complex (CIC)
circilation antigen+ antibody
CIC kidney CIC/deposits
antigen extrinsic drugs--nonhomologous serum, penicillin foods—xenogenic protein pathogen—specific serotypes streptococci,
HBV, HCV
intrinsic nucleus ( SLE) cytoplasm ( ANCA ) cellular membrane antigen of tumor antigen of thyroid
Why does CIC deposit in the glomeruli?
• Large area of glomerrular capillaries --more chances to contact
• Net structure of CIC --easy to deposit and settle down
• Clearance dysfunction of mesangial cells, disability of mononuclear macrophage, component or function defect of complements
Decrease clearance of CIC
(B)in situ Immunocomplex 1. Native renal antigen glomerular basement membrane + anti- glomerular basement membrane an
tibody (anti- glomerular basement membrane glomerul
onephritis)
2. Antigens trapped or planted DNA+ anti-DNA antibody (Lupus Nephritis)
Balance between the deposit and clearance of IC determines the
situation of the diseases
• Persistence of antigen
• Clearance dysfunction of mesangial cells
• disability of mononuclear macrophage
• component or function defect of complements
IC deposit > clearance
B. Cell-mediated immune mechanisms
minimal change glomerulopathy ?
C. Non –immune mechanisms
• glomerular hypertension• hyperlipidemia (LDL- Cho)• advanced glycosylation end products
(protein)
glomerulosclerosis
Inflammation• Mediators of inflammation
– A group of molecules which act as mediators of inflammation and complicated biological function
• Origin of inflammation mediators in kidney– Extrinsic Cells in kidney
• infiltrative neutrophil, lymphocyte, mononuclear macrophage , platelet
– Intrinsic cells in kidney• Mesangial cells, tubular cells, endothelial cells
Mediators of inflammation - active oxygen and active nitrogen - lipids - complements - cytokines - chemotatic factors - adhesion molecules - growth factors - vasoactive substances
To arouse or promote - proliferation of cells - accumulation of extracellular matrix - changes of histological structure - expression of immunomodulating mole
cules and adhension molecules
Effects of the inflammation mediators
Effects of the inflammation mediators
Mechanisms of Primary GNimmune non-immune
inflammationInflammatory cells
Extrinsic cells Intrinsic cells neutrophil, lymphcyte mesangial cells mononuclear macrophage epithelial cells platelet, tubular cells endothelial cells
Inflammation mediators cytokines TNF,IL-1 growth factors TGF,PDGF chemotatic factors MCP-1,IL-8 complements, vasoactive substances active oxygen and active nitrogen
Coagulation and fibrolysis system, enzyme
Glomerular injuries
Essential in the initiationEssential in the initiation
Essential in the progressive periodEssential in the progressive period
immune non-immune
initiation end stage Primary GN
Sites of pathological changes
Mesangium Mesangial cell
Mesangial matrixBasement membrane
PodocyteFoot processEndothelial cell
The peripheral portion of a glomerular lobule
Pathological changes• LM
– Mesangial cells, matrix of mesangium– Epithelial cells– Endothelial cells– Basement membrane– Loops of glomeruli
• EM – Foot process– Basement membrane– Hyperplasy of mesangium (electron-dense deposits )
• IF – Sites, appearances and types of the deposit (Ig or C)
Basical changes
•Proliferation
•Fibrosis and sclerosis
•Necrosis
•Infiltration of inflammatory cells
Extents of Injuries primary GN glomerular injuries—only
or dominating changes secondary GN glomerular injuries— a pa
rt of systematic diseases diffuse impaired glomeruli>50% focal impaired glomeruli <50% global impaired capillary loops of
a glomerule >50% segmental impaired capillary loops of
a glomerule <50%
Pathological types of primary GN
• Minimal change glomerulonephritis
• Focal segmental lesions
• Diffuse glomerulonephritis
• Unclassified glomerulonephritis
1. Minor Lesions of glomeruliNo specific lesionsLM—mild proliferation of mesangial cells and accumulation of ECMS
• minimal change disease , MCD
• mild mesangial proliferative GN
• recovery stage of endocapillary GN
• others
MCD (left)normal ,(right) fusion & effacement of foot processes
2. Focal and Segmental Lesions
1) focal and segmental proliferative
glomerulonephritis
2) focal and segmental glomerulosclerosis
segmental glomerulonephritis
3. Diffusive glomerulonephritis
(1) membranous nephropathy -- MN
(lesions in GBM)
MN (left) normal,(right)subepithelial deposits of IC(D), thickening of GBM,formation of spikes (S), fusion of foot processes
(2) proliferative glomerulonephritis
• mesangial proliferative GN
( lesions in mesangium)
– IgA nephropathy
– Non-IgA nephropathy
• domonating IgG deposit
• IgM nephropathy
MsPGN (left)normal, (right)proliferation of mesangial cells and matrix and electron-dense deposits (D)
• endocapillary proliferative GN ( lesions in mesangium & endo
thelial cells)
endocapillary proliferative GN (left) normal, (right) endothelial(E) & mesangial(M) cell proliferation and subepithelial humplike dense deposits(D)
• mesangiocapillary GN or membranoproliferative GN (lesions in mesangium & GBM)
• dense desposit GN (electron-dense deposits)
MmPGN (left) normal, (right) proliferation of mesngium (M),electron-dense deposits(D), and subendothelial mesangial cytoplasm interposition ( I )
• crescentic GN or extracapillary GN
Crescentic GN (left) normal, (right) splitting of GBM, leakage of fibrin(F), proliferation of epithelial cells,(E), infiltration of mononuclear macrophages(P), formation of crescents
(3) sclerosing GN
4.unclassified glomerulonephritis
Characters of lesions in GN Proliferative changesProliferative changes
MsPGNMsPGN
IgANIgAN
IgMNIgMN
OthersOthers
Including segmental proliferativIncluding segmental proliferative GNe GN
MmPGNMmPGN
Crescentic GNCrescentic GN
Endocapillary proliferative GN
Proliferative changesProliferative changes
MsPGNMsPGN
IgANIgAN
IgMNIgMN
OthersOthers
Including segmental proliferativIncluding segmental proliferative GNe GN
MmPGNMmPGN
Crescentic GNCrescentic GN
Endocapillary proliferative GN
Non- proliferative changesNon- proliferative changes
FSGSFSGS
MCDMCD
MNMN
Non- proliferative changesNon- proliferative changes
FSGSFSGS
MCDMCD
MNMN
•Proliferation of mesangium can presents in varied types of GN
•Proliferation and subsequent stiffness of mesangium may be the results of varied types of GN
FSGS • primary--later-phase of the disease its
elf• secondary-- later-phase of other types
of GN•Crescents can presents in different types of GN
Clinical manifestations
Proteinuria– Urinary protein test — positive
– Urinary protein excretion rate 150mg/d
Charge barrier of glomerule1.Epithelial cells 2. GBM 3. Endothelial cells 4. Filtrated substances
Filtration barrier
mechanisms of production of proteinuria
机 制 性 质
肾小球滤过 肾小管重吸收 中、高分子 低分子
肾小球性蛋白尿
肾小管性蛋白尿
Moderate/high MW moleculesModerate/high MW molecules
mechanismsmechanismsmechanismsmechanisms molecular wieghtsmolecular wieghtsmolecular wieghtsmolecular wieghts
filtration from filtration from GlomeruliGlomerulifiltration from filtration from GlomeruliGlomeruli
Readsorption Readsorption from tululesfrom tululesReadsorption Readsorption from tululesfrom tulules
Low MW Low MW moleculesmoleculesLow MW Low MW moleculesmolecules
Glomerular proGlomerular proteinuriateinuria
Tubular proteiTubular proteinurianuria
Glomerular proGlomerular proteinuriateinuria
Tubular proteiTubular proteinurianuria
filtration barrierproperties charge- size- selective selective
Selective albumin impaired normalproteinuria (moderate MW molecules)
Non-selective albumin &proteinuria high MW proteins impaired impaired
* Mixed proteinuria: moderate/high MW or moderate/low MW;glomerular &tubular proteinuris
quantity
Mild < 1.5g/d
Moderate 1.5-3.5g/d
severe > 3.5g/d 或 50mg/kg/d
hematuria• RBC >3 个 /HP
(fresh, 10 ml sample, 1500rmp centrifuge for 5 min, sediment observation)
• gross hematuriaRed color of urine, 1ml blood /1L urine
hematuria RBC from glomeruli
squeezing through GBM
dismorphic RBC
Phase-contrastmicroscopy• dismorphic RBC>50 % Hypothesis:glomerular bleeding• dismorphic RBC>70% Final diagnosis:glomerular bleeding
Urinary RBC volume distribution curve
•dissymmetry curve•MCV of urinary RBC<that in blood
Urinary RBC volume distribution curve
•dissymmetry curve•MCV of urinary RBC<that in blood
changing when passing tubules with different osmosis
changing when passing tubules with different osmosis
edema fluid retention in tissue spaces peripheral edema fluid retention in serous cavity glomerular diseases
GFR large amount of urinaryprotein lostIntrinsic RAS & Aldosterone hypoalbuminemia
water & sodium filtration colloid osmotic pressure water & sodium readsorption
primary water & sodium retention secondary water & sodium retention
Effective circulation blood volumn edema
Effective circulation blood volumn
Hypertension glomerular diseases
primary water & stimulus, such asischemiasodium retention
Volumn-dependent vessoconstrictive vessodilatory substances substances
RAS,Ald PGI2,PGE2
vessoactive substances-dependent
Hypertension
Clinical types of GN
• Glomerulonephropathy • Confined concept
• leading manifestation: proteinuria, with/without hematuria
• Extensive concept• glomerular diseases ( disorders )
• Glomerulonephritis• leading manifestation: hematuria, with/without p
roteinuria
Nephrotic syndrome
1. Large-amount proteinuria > 3.5g/d
2. hypoalbuminemia < 30g/L
3. edema
4. hyperlipidemia
1+2 ---essential
severe edemasevere edema hyperlipidemiahyperlipidemia
hypoalbuminemiahypoalbuminemia
Large-amount proteinuria
Large-amount proteinuria
Center
key
Essential for diagnosis
Intake of protein
Ingestion from GI
synthesis in liversynthesis in liver
lost through urineNS
lost through urineNS
consumptionconsumption
Mechanisms of hypoalbuminemiaMechanisms of hypoalbuminemia
Cl i ni cal mani festati on of GNmanifestation
initiation hematuria proteinuria edema,hypertension renal failure
GN急性 综合征 acute 100% 100% frequent resumabl eGN急进性 综合征 acute 100% 100% frequent ARF
GN慢性 综合征 latent frequent frequent frequent CRF
GN *隐匿性 综合征 latent frequent <1g/d (-) (-)
Linkage of clinical manifestation and pathological changes (1)
Pathological proliferative non-proliferativechanges MsPGN MCD MmPGN MN* Endocapillary PGN FSGS Crescentic GN
Clinical hematuria - proteinuria - certain certain, sometimesManifestation nephritis syndrome nephrotic syndrome
proteinuria - hematuria - possible occasional *
Linkage of clinical manifestation and pathological changes (2) clinical pathological AGN endocapillary PGN possible NS RPGN crescentic GN possible NS CGN nephritis syndrome MsPGN 2 MmPGN 2 nephritis syndrome FSGS 2 +nephrotic syndrome MN2 NS MCD 1
Acute Glomerulonephritis
Etiology• Streptococcus -hemolytic streptococcus,
group A, type XII, nephritogenic strains•antigen
•components of cytoplasm & membrane•frequently CIC, sometimes ‘planted antigen’
• Others• other bacteria, such as staphylococcus epidermidis• viruses• parasites
Pathological changes• Endocapillary Proliferative GN
• Acute phase
• Proliferation of endothelial & mesangium
• Recovery phase
• Only mesangium proliferation, sometimes minor lesion
Clinical Manifestation
1.Epidemiology: primarily children, sometimes adults & the aged
2. Preliminary infection
frequently tonsillitis,upper respiratory infectionLatent period:1-3 w
occasionally skin infectionLatent period:longer,but less than 4w
3.Nephritis syndrome(1)hematuria 100% , 40% are gross hematuria(2)proteinuria frequent , <20% are nephrotic syndrome(3)edema >90%(4)hypertension 80%(5)renal failure mild,acute renal failure
4.Laboratory findings (1) acute phase of infection of Strep.
•elevated ASO titer (some Strep. No hemolysin O)•only the marker of infection, not nephriti
s(2) acute phase of immune reactions
•serum C3 & total complements,return to normal within 8w
•blood CIC
Natural History• edema and hypertension
– disappear in one month
• hematuria, proteinuria– usually reduce in one month, resolve within
2 to 3 months– some resolve within 6 to 12 months
• C3
– return to normal in two months
DiagnosisPoints• preliminary infection &latent period• acute onset• surely hematuria, frequently edema and hypert
ension
• ASO , C3 —— dynamic change
• Self-limitation
Differential DiagnosisDiseases presented with acute nephritis syn
drome• GN secondary to infection of other pathogens
– other bacteria, viruses (Varicella-zoster virus, EB, influenza virus)
– Climax of infection or within 5 days
– Mild abnormal of urine examination
– Hypertension and edema are unusual
– Normal blood complement level
• rapidly progressive GN
• CGN
• systemic diseases
lupus nephritis
Schönlein-Henoch purpura
Indications of kidney biopsy
• Oligouria > 1w , except ECBV insufficie
nt, urinary tract obstruction, etc
• Progressive renal failure
• Unresolved in 2 months
• untypical manifestation, or with nephroti
c syndrome
Treatment1.Supportive treatment• Rest• Food & water
•Restrictive intake of•NaCl <5 g/d
• if moderate to severe edema or hypertension•Water
• if decreased urine volume •Protein
• Renal failure, but not dialysis yet
2.Treatment of infection• Penicilin for 2 w• Tonsillectomy– if recurrent attacks
of tonsillitis1) patient’s condition is stable, Upr
o<1g/d, URBC < 10/HP2) Penicilin for 2 wks before and after th
e surgery
3. Symptomatic treatment• Diuresis• Antihypertension• Dialysis
Prognosis• hematuria, proteinuria
–usually reduce in one month, resolve within 2 to 3 months–some resolve within 6 to 12 months
• 1%ARF Death
• 6%-18% CGN?
Rapidly progressive glomerulonephritisRPGN
•Rapidly progressive nephritis syndrome
•Some induced by respiratory infection
•Acute onset, rapidly progressive
•Renal failure within a few weeks to a few mont
hs
1.primary RPGN Crescentic GN2.other primary GN other pathological changes with lots of crescents3.secondary RPGN SLE, SHP, etc
RPGN Type I Type II Type III
anti-GBM IC Pauci-immuneIF linear GBM Granular GBM ( - ) deposits & mesangium deposits anti-GBM AB ( + ) C3 、 CIC 70%-80% small vessel vasculitis ANCA ( + ) the young & the middle-aged the middle-aged middle aged & aged & aged
Most frequently in ChinaMost frequently in China
Diagnosis
• Acute onset
• Rapidly progressive
• Renal failure within a few weeks to a few months
• Acute renal failure Chronic renal failure
Differential Diagnosis Rapidly progressive nephritis syndrome ——not primary RPGN
- other primary GN AGN, IgAN, etc - secondary GN Goodpasture Syndrome, LN, SHP * accompanied by crescentic GN * severe pathological changes
Diseases with ARF• ATN• AIN - definite etiology -obsolete proteinuria and hematuria - specific manifestation ATN——large quantity of renal tubular epithelial cells
in urine AIN——hypersensitiveness (rashes, fever, arthralgia)
Treatment EARLY!!!
• Aim to humoral immune mechanisms
1.plasmapheresis discard the antibodies plasm exchange immoadsorption type I, III 2.drugs glucocorticoid +cytotoxic drugs MP0.5-1.0g/d3 , repeat if necessary
CTX type II, III
symptomatic treatment
• renal failure– balance of fluid, electrolytes and acid-base– dialysis
• infection
• hypertension
Prognosis
Hardly relieve mostCRF or death
Risk factors
Type I-worst,II-worse,III-bad
Treatment not progressive & prompt
Age the aged
Chronic Glomerulonephritis
Manifestation chronic nephritis syndrome
Pathological changes except MCD,MmPGN, Crescentic GN
Clinical manifestation 1.age any age, frequently young 2.preliminary infection upper respiratory tract, intestinal tract latent period < 1 wk 3.nephritis syndrome
Hematuria,proteinuria,edemaHematuria,proteinuria,edema
Hypertension,renal failureHypertension,renal failure
uremiauremia
4.Prognosis factors (1)pathological properties (2)treatment (3)hypertension (4)infection,prerenal factors (hypotension etc) (5)nephrotoxic drugs
Points of Diagnosis
• chronic onset• proteinuria and/or hematuria• protracted and progressive
Differential Diagnosis
CGN
Differential DiagnosisDifferential Diagnosis
1. AGN AGN CGN age children young&middle-aged preliminary infection frequently sometimes latent period 1-3w <1w onset acute chronic, insidious hematuria 100% sometimes no edema frequently sometimes no hypertension frequently sometimes no ASO frequently normal blood C3 frequently , persistent/normal return within 8wks prognosis resolved within 1yr protracted and progressive pathology MmPGN/MsPGN
2.Essential hypertensive nephrosclerosis
EHT CGNfirst present hypertension abnormal urinefunction injury in advance tubule glomerulehematuria occasionally frequentlynephrotic proteinuria occasionally frequentlysystemic hypertension manifestationheart, eyeground compared with kidney equal milder pathology arteriolar sclerosis
3.secondary GN SLE (1)systemic presentation (2)immune abnormolity(C,self-AB) (3)pathological changes
SHP (1)purpura (2)stomach, joint
Chronic pyelonephritis CPN CGN mechanisms infection immunesites pelvis,calices,tubule glomerulepresents of infection + Upro excretive /tubular glomerularURBC non-glomerular glomerularhypertension infrequently frequentlyedema infrequently frequentlykidney lesions tubule glomeruledysmorphosis one side two side
TreatmentTarget inhibit immune reaction halt the progression of disease
1.restrictive intake of protein
<0.5-0.8g/kg/d
protein of high biological value
pressure in glomeruli
2.Antihypertension less than 140/90mmHg , ideal target 125/83mmHg
dialation of efferent glomerular arteriole > dialation of afferent glomerular arteriole
pressure in glomeruli Upro
postpone glomerulosclerosis
ACEI/ARBACEI/ARB
3.anti-platelet
4.immunosupression
Clinical manifestation 1.Characteristics
(1)large quantity of Upro
(2)severe edema
(3)hypoalbuminemia
(4)hyperlipidemia
Nephrotic SyndromeNephrotic Syndrome
2.Others (1) thrombosis & embolism
renal veins or inferior vena cava 25% (2)infection (3)acute renal failure•Blood volumeperfusion of kidneys ischemia of kidneys, tubule necrosis•Severe glomerular lesions
•crescent formation•Severe proliferation of mesangium•Necrosis of capillary loops
•Nephrotoxic drugs•idiopathetic
1.among varied types of pathology 2.between secondary GN
( 1 ) SLE( 2 ) SHP( 3 ) DN history, hematuria, pathological changes( 4 ) amyloidosis
history of chronic infection,systemic lesions (heart, liver, GI, tongue), pathological changes (kidney, tongue, rectum)
( 5 ) MM Middle-aged/aged, ostalgia, osteonecrosis(X-ray, isotope scanning), abnormal protein (blood single-peak protein, blood and urine light chain protein,urine BJ protein)
Diagnosis & Differential DiagnosisDiagnosis & Differential Diagnosis
1. Supportive treatment 1. rest 2. Food and water (1) water & sodium restriction when with severe edema (2) protein 1-1.2g/kg/d (3) lipid restriction when with hypoalbuminemia (4) energy 30-35 Kal/kg/d
TREATMENTTREATMENT
2. symptomatic treatment 1. diuresis osmotic diuretics plasma colloid osmotic pressure tubule fluid osmotic pressure
fluid transmit from tissue readsorption of water space to blood vessels
blood volume diuretics
mannitol, dextran, albuminmannitol, dextran, albumin
diuresisdiuresis
2. Aim to proteinuria
ACEI/ARB
3. Major treatment 1. glucocorticoid mechanisms (1)immuosupression (2)anti-inflammation principles (1)sufficient dose when initiation 0.8-1.2g/kg/d reduce 2wks after Upro is negative *if Upro doesn’t reduced apparently in 8-12wksineffective (2) reduce the dose slowly 10%/2-3wks (3) sustaining treatment minimal dose:10-15mg/d , >6m-1y
Sensitivity of glucocorticoid
1mg/kg/d 8w
negative Upro positive
relapse when reduce to some dosage
Sensitivity of glucocorticoid
1mg/kg/d 8w
negative Upro positive
relapse when reduce to some dosage
sensitive sensitive
dependentdependent
ineffectiveineffective
2. immunosuppressive agents
• cytotoxic drugs alkylating agent—CTX, chlormethine, CB1348 inhibit duplication of DNA• Aza,MMF inhibit synthesis of RNA inhibit proliferation of B lymphocyte • CyA inhibit synthesis of L-2 inhibit proliferation of T lymphocyte
indications
• glucocorticoid dependent or ineffective• glucocorticoid untolerated
4. Treatment of complications
• anticoagulation, thrombolysis
• anti-infection
• balance of electrolyte
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