Hassan Hassan ArganiArgani MD.MD.

Professor of NephrologyProfessor of NephrologyProfessor of NephrologyProfessor of Nephrology

Shahidbeheshti university of Medical Sciences

Normal kidneyy

Normal renal vasculature

Clinical signs of kidney disease

• Symptoms of associated disease• Renal colic and painRenal colic and pain• Hematuria

F i ( ibl t i i )• Foamy urine (possibly proteinuria)• Volume overload• Uremic syndrome: CNS, GI, CV, skin

Clinical assessment of extracellular volume

• BP and heart rate• Skin turgorg• Mucous membrane moisture• Jugular venous pressureg p• Pulmonary crackles• Third heart soundThird heart sound• Edema

CKDCKDCKDCKD

Cocesh etal. J Am Soc Nephrol 2005,16(1):180-8

Toxins retained in uremia:Low molecular weights (MW<300 D)Urea Creatinine Guanidines LipidsUrea, Creatinine, Guanidines, Lipids,Hipporic acid, indoxil sulfate, p-cresol O l t H P 4 H+ N + K+ tOxalate,Hcy, Po4, H+, Na+, K+, waterMiddle mollecules (MW=300-12000 D)Middle mollecules (MW 300 12000 D)PTH, B2 microglobuline, AGE,

High molecules (MW >12000 D)Cystatin C, Clara cell Protein,Cystatin C, Clara cell Protein, Retinol Binding Protein, Leptin

R.F AnemiaAVF }COHyperlipidemia AVF }

Fl idU id tifi d

PTH

Alteredvasopressor/NO

Fluidoverload

P i di l

Unidentifiedtoxins

HypertensionPericardialdiseases

K+

Cardiovascular Damageg

V l d l it dBioincompatibility

DialysisVolume and osmolarity and electrolyte changesAir emboli& hemolysis

E d t l diEnd-stage renal disease

Diabetic nephrosclerosisDiabetic nephrosclerosisHypertensive nephrosclerosisChronic glomerulonephritisChronic glomerulonephritisChronic interstitial nephritisPolycystic kidney diseasePolycystic kidney disease

Urine analysis

PROXIMAL TUBULAR CELL

DISTAL TUBULAR CELL

COLLECTING DUCT CELL

INTRACELLULAR LIPIDS

“OVAL FAT BODY”

FATTY CAST

CHOLESTEROL CRYSTAL

LEUKOCYTE CAST

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BACTERIAL CAST

YEAST CAST

CALCIUM OXALATE BYHYDRATED (U-pH <5.4-6.7)

CALCIUM PHOSPHATE (U-pH ≥7.0)

TRIPLE PHOSPHATE (U-pH ≥7.0)

CYSTINE

Qualitative identification of C ti tCystine stone

Sodium Nitroprosside

2,8-HYDROXYADENINE (BF)

2,8-HYDROXYADENINE (POL)

SULPHADIAZINE (POL)

AMOXYCILLIN (BF)

INDINAVIR

ACYCLOVIR

EGG OF SCHISTOSOMA HAEMATOBIUM (120-150 μm)

Normal glomerulusg

Presentation of renal diseasesPresentation of renal diseases

Glomerulopathies proteinuria/hematuriaNephrotic syndrome

Acute glomerulonephritis

Hemolytic uremic syndrome

Tubulointerstitial diseasesTubulointerstitial diseases

Nephrotic syndromeNephrotic syndrome

Negative charges on glomerular capillariescapillaries

Loss of negative chargesg g

Minimal change disease

Diffuse effacement of foot proces

PROTEINURICPROTEINURIC GLOMERULUS

Nephrotic s ndromeNephrotic syndromeDefinition:Definition:

Always presentProteinuriaHypoalbuminemia

Usually presentEdemaEdemaHyperlipidemia

Sometimes presentH t iHematuriaAzotemiaHypertension

Li id iLipiduria

Maltese cross

Pi t f hild ith h ti dPicture of a child with nephrotic syndrome

Sequence of events in nephrotic dsyndrome

Pathophysiology Clinical manifestationsPathophysiology Clinical manifestationsGlomerular injury

Increased permeability of the Heavy proteinuriaIncreased permeability of theglomerular basement membrane

Albuminuria

(foamy urine)Occasional hematuria

HypoproteinemiaDecreased serum albumin

Decreased peripheral Increased renal

Decreased plasma oncotic pressure

Decreased urine sodium

Peripheral and periorbital edema

capillary return Na reabsorption

Increased interstitial fluid

Decreased urine sodium

Distribution of histologic lesions in children and adults

Children AdultsMinimal 80% 20%Minimal change

80% 20%

Proliferative 15% 25%Proliferative 15% 25%

Membranous <1% 30%

Focal sclerosis 5% 25%

GlomerulonephritisGlomerulonephritis

Mesangial cell architectureg

M i l f tiMesangial function

Structural supportModulation of circulation

Matrix production and remodelinMC contractionModulation of circulation

Immune/inflammatory modulationFiltration and clearing

MC contraction Cytokine productionEndocytosisFiltration and clearing EndocytosisProtease secretion

Mesangial proliferative glomerulonephritisglomerulonephritis

Mesangial deposition of immunoglobulinimmunoglobulin

Mesangial depositsMesangial deposits

Sequence of events in acute l l h itiglomerulonephritis

Pathophysiology Clinical manifestationsPathophysiology Clinical manifestationsGlomerular injury

Inflammation of glomerular capillary bedRBC castsHematuriaInflammation of glomerular capillary bed

Decreased glomerular capillary perfusion

HematuriaProteinuria

Decreased GFR AzotemiaIncreased urine osmolalityDecreased urine sodium

Increased Na and water reabsorption

Decreased tubular fluidIncreased ECF volume Decreased urine volume- oliguria

Hypertension- CHF, encephalopathyEdema formationEdema formation

AnemiaRenal failure

RBC cast is the typical feature in iurine

Immunologic mechanisms f l l i jof glomerular injury

A tib di i t fi d l l tiAntibodies against fixed glomerular antigens- Planted antigens

Autoantigens- AutoantigensCirculating antigen-antibody complexes- Antigens unrelated to the kidney- Antigens unrelated to the kidney- Autoantigens unrelated to the kidney

T cell cytokine mediatedT cell cytokine mediated

Anti-basement membrane antibodies

Anti-GBM crescentic glomerulonephritisg p

Linear deposition of anti-GBM tib diantibodies

Circulating complexesCirculating complexes

“Single shot” serum sicknessChronic serum sicknessChronic serum sicknessTitered immune complex pformation

Immune complex nephritisp p

Acute proliferative glomerulonephritis

Immune complex depositsp p

Subendothelial depositsp

Membranous glomerulonephritisg p

Membranous pattern of immunoglobulin depositionimmunoglobulin deposition

Subepithelial deposits deposits

M di t f l l i jMediators of glomerular injury

ComplementAntibody mediated cellular cytotoxicityActivation of coagulationApoptotic signalsT cell cytokines

Antibody deposition T cell immune reaction

Immune complexes

Complement activationComplement activation

C5b-9 C5a

Mesangial cellsMacrophagesPlateletsNeutrophils

EpithelialEndothelial

OxidantsC t ki

ProteasesG h f

EicosanoidsNit i idEndothelial

MesangialCytokines Growth factors Nitric oxide

Others

Proteinuria Proteinuria, decreased GFR, inflammation.

Criteria for diagnosis of acute post streptococcal glomerulonephritispost-streptococcal glomerulonephritis

L t t i t l ti f i f ti t t1. Latent interval- time from infection to symptoms1. Not less than 5 days and not more than 28 days 2. Usually 10-21 days.

2. Documentation of preceding streptococcal infectiona) Culture of throat or skinb) Serologic changes in strep titers

3. Evidence of immunologic involvementa) Appropriate complement profile or low serum C3

4. Clinical course characteristic of post-streptococcal GNp pa) Lack of nephrotic syndrome at onsetb) Oliguria followed by a diuresis in 10-30 daysc) Edema formation and hypertension proportional to decrease in renal ) yp p p

functiond) Return of C3 to normal levels in 6-12 weeks

Non streptococcal GNNon-streptococcal GNPrimary renal disease

F l ild lif ti GNPrimary hematuriaHypocomplementemic nephritisChronic (non-specific) GN

Focal or mild proliferative GNMesangiocapillary GNFocal or diffuse irreversible GN( p )

Rapidly progressive GNHereditary nephritis

S t i di ith l

Severe proliferative GN with crescentsChronic non-specific changesSystemic disease with renal

involvementAnaphylactoid nephritis

p g

Focal or diffuse proliferative lesionFocal or diffuse proliferative lesion

Lupus nephritis

Hemolytic uremic syndrome

Membranous lesionMicrothrombi in capillary loopsFocal areas of necrosisHemolytic uremic syndrome

Hypersensitivity angiitisPolyarteritis

Focal areas of necrosisPerivascular infiltrate

Renal diseases associated with a low Clow C3

Post-infectious glomerulonephritisPost-streptococcal GNSBEShunt nephritis

SLE nephritisDiffuse proliferative type

M i l ill h i iMesangial capillary nephritisA.K.A. membranoproliferative GNP ti l li d t h dPartial lipodystrophy syndrome

THROMBOTICMICROANGIOPATHY

H l ti i dHemolytic uremic syndromeDefinitionDefinition

Microangiopathic hemolytic anemiaThrombocytopeniaAzotemia

Frequently associated findings

Abdominal painBloody diarrheaOli iOliguriaHypertension

Mechanisms of Vascular InjuryMechanisms of Vascular InjuryEndothelial Activation Smooth Muscle _ Endothelial Activation

_ Stretch / Shear Forces_ Inflammation

_ Smooth Muscle Activation_ Contraction

_ Immune Response_ Activation of

Coagulation

_ Ischemia_ Hyalinosis

Autocrine g_ Platelets_ Tissue Factor

F t X

_ Autocrine regulation_ Renin - Angiotensin

_ Factor X _ g_ Cytokines, Growth

Factors

Sequence of events in hemolytic uremic syndrome

Pathophysiology Clinical manifestationsGl l i jGlomerular injury

Endothelial damage in arterioles and capillary loops

Microangiopathic hemolytic anemiaFormation of fibrin strands

Platelet consumption and utilization Thrombocytopenia

g p yHematuria and proteinuria

Formation of fibrin strandsIntravascular thrombosis

Decreased glomerular capillary perfusion

Decreased GFR Increased Na and water reabsorption Decreased urine osmolality

AzotemiaDecreased urine sodium

Oligo-anuria

Decreased urine formation Decreased urine sodium

Renal failure

Typical features of microangiopathic hemolytic anemia

Tubulo-interstitial disorders

Interstitial nephritisInterstitial nephritis

Mechanisms of tubulointerstitial i jinjury

Infectious agentsInfectious agentsToxinsImmunologic responsesImmunologic responsesObstructionIschemiaIschemia

Comparison of the clinical presentation of l l t b l di dglomerular vs tubular disorders

Gl l T b lGlomerular Tubular

Proteinuria > 1.0 gm/day < 1.0 gm/day

Urine sediment Active many RBC & Inactive few cellsUrine sediment Active many RBC & WBC casts

Inactive few cells

Urine Na FENa Low (<1%) High (>2%)

Urine osm High (>500 mosm/L) Low (<300 mosm/L)

Acid excretion Large anion gap Hyperchloremic acidosis

O COliguria Common Unusual

Edema Common Unusual

Hypertension Common UnusualHypertension Common Unusual

Chronic glomerulosclerosis

Gl l L i fGl l L i fGlomerular Lesions of Glomerular Lesions of Systemic DiseasesSystemic DiseasesSystemic DiseasesSystemic Diseases

Nonimmunologic causes of gincreased glomerular permeability

Diabetic nephropathyAmyloid

P h l f di b i h hPathology of diabetic nephropathyThickening of GBMThickening of GBMNodular mesangial sclerosis Kimmelsteil Wilson lesionKimmelsteil-Wilson lesionMesangial widening with an increase in matrixVm/VgArteriolar hyalinizationLinear fluorescenceGlomerular hypertrophy

Diabetic nephropathyDiabetic nephropathy

Normal

K-W nodules

Diabetic nephropathy

Diffuse linear deposition of IgG and albumin

Diabetic nephropathyp p y

Diffusely thickened GBM Nodular sclerosis

Natural history of diabetic nephropathyStage 1- Time of initial diagnosis

Increased GFRIncreased GFRIncreased kidney size

Stage II- The first decade (years 1-10)Stage II The first decade (years 1 10)Early structural changes (GBM, mesangium)

Stage III- MicroalbuminuriaStage III MicroalbuminuriaStage IV- Onset of clinical disease (years 10-20))

ProteinuriaHypertensionDeclining GFR

Stage V- End-stage renal disease

Potential mechanismsPotential mechanisms

HyperfiltrationHypertensionypAldose-reductase

Excess glucose polyolExcess glucose polyolIncreased sorbitol/ decreased myoinositolmyoinositol

Toxicity of high glucoseNon enzymatic glycationNon-enzymatic glycation

Advanced glycation end products

AmyloidosisAmyloidosis

Crescentic glomerulonephritisCrescentic glomerulonephritis

Lightmicroscopy

IFmicroscopy

Possiblepathogenesis

Association

Crescents/ Linear IgG Anti GBM PulmonaryCrescents/necrosis

Linear IgGFibrinogen

Anti-GBMantibodies

Pulmonaryhemorrhage

Crescents/proliferation

Granular IgGComplement

Immunecomplexes

Bacterialinfectionsproliferation Complement

Fibrinogencomplexes infections

Crescents/necrosis

NegativeFibrinogen (?)

ANCA SystemicSymptoms

Cresentic Glomerulonephritis

Anti-Glomerular Basement Membrane Disease

Anti-neutrophil cytoplasmic antibodiesC-ANCA- antiproteinase 3

90% sensitivity for extended Wegener’s granulomatosis

P-ANCAVariety of antigens

MyeloperoxidaseWegener s granulomatosisGranulomatous respiratory lesionSystemic vasculitis

MyeloperoxidaseElastaseCathepsin GLysozymey

Necrotizing glomerulonephritis75% sensitivity for limited Wegener’s granulomatosis

LysozymeLactoferrinB-glucuronidaseEnolaseWege e s g a u o atos s

With or without renal involvement

Potential false positives

EnolaseBroader reactivity

MPA, NCGN, C-S, 10-20% PAN, 20% KAW IgA ANCA in HSPp

AmebiasisPropylthiouracil induced vasculitis

20% KAW, IgA, ANCA in HSPOther diseases

Inflammatory bowel diseaseA t i li diTiter varies with activity Autoimmune liver diseaseSepsisNeoplasia

Systemic Vasculitis

Pauci Immune Glomerulonephritis

RPGN- crescents

Fibrin deposition (immunofluorescence)

WHO Classification of Lupus Neprhitis, RevisedRevised

Class I Minimal mesangial lupus glomerulonephritis -mesangial deposits

Class II Mesangial proliferative LGN-with immune deposits

Class III Focal LGN (less than 50% of glomeruli) subendothelial depositsdeposits,

Class III (A) Purely active focal proliferative LGN Class III (A/C) Active and chronic lesions focal LGN:Class III (C) Chronic inactive sclerotic focal LGN( )

Class IV Diffuse segmental (IV-S) or global (IV-G) LGN - SE deposits,

Class IV (A) Active lesions: diffuse proliferative LGNClass IV (A) Active lesions: diffuse proliferative LGNClass IV (A/C) Active and chronic lesions: proliferative and

sclerotic LGNClass IV (C) Inactive with glomerular scars: diffuse sclerotic LGN

Class V Membranous LGN - subepithelial immune deposits

Class VIAdvanced sclerotic LGN

Lupus nephritis WHO Class I

Lupus nephritis WHO Class I

Lupus nephritis WHO Class II

Lupus nephritis WHO Class II

Lupus nephritis WHO Class III

Hereditary diseasesHereditary diseasesyy

Polycystic kidney disease

Alport: Molecular Genetics• 1 in 50,000 live births • X-linked form is most common (no father-son

transmission, females are carriers)transmission, females are carriers)o responsible gene is COL4α5

• X-linked form associated with esophageal leiomyomatosisleiomyomatosiso contiguous gene syndrome involving COL4α5

and COL4α6 l i f li k d h 2• autosomal recessive form linked to chromosome 2

o mutations in COL4α3 and COL4α4

Renal TransplantationRenal Transplantation

Technique of pancreas-kidney transplant with systemic drainage. The pancreas is i i i i f i i i iplaced in the right iliac fossa. The donor portal vein is anastomosed to the recipient

iliac vein, resulting in systemic drainage of pancreatic veins.

BK Virus Nephropathyp p y

DECOY CELLS BY PHASE CONTRAST

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