Vijesh Patel Renal Pathology I Function 1) removes metabolic wastes form the body 2) maintains homeostasis acid base

e equilibrium by exchanging H+ for bicarbonate (maintained by carbonic anhydrase enzyme) 3) Secretes EPO (used for RBC production) and renin (for maintaining blood pressure) o Ie. A person with a chronic renal disease cant remove H and take in bicarbonate Metabolic acidosis They will also have normocytic anemia b/c of less RBC formation They will also have increased renin excretion thus there will be Hypertension Right Left Adrenal gland: more triangular ** Adrenal gland: more semilunar ** Slightly lower Slightly higher Nephron: the functional unit of the kidney There are 1 million nephrons in each kidney Glomerulus forms a ball of capillaries inside of the bowmans capsule .. blood gets filtered out and forms ultra-filtrate which collects o Travels to the proximal convoluted tubule thick / thin descending limb Loop of henle Thick ascending limb Distal convoluted tubule Collecting duct o All are juxtamedullary nephrons which have long loops of henle used for the counter-current multiplier system Anatomy Retroperitoneal organ @ T12 to L3/4 10-12 cm in length and 150 grams in weight Consists of the medulla (inner) and the cortex (outer) o The medullar are pyramid (triangular) shaped and come to a point which form the papilla o The cortex dips into the medulla at points and is called the renal column of bertini Collecting duct papilla 10-12 minor callices 4-6 major callices renal pelvis ureter Blood supply receives 25% of cardiac output but only makes up 5% of the body weight o Renal interlobular lobar arcuate afferent glomerulus efferent vasa recta (peritubular capillary network) Vasa recta participate in the counter current multiplier system o Most of the blood goes to the cortex (90%) while the small amount goes to the medulla (10%) Juxtaglomerular apparatus JG cells: Modified smooth muscles cells that are found at the afferent arteriole Macula densa: Found in the distal convoluted tubule and are used to detect changes in the sodium levels The afferent arteriole and the distal convoluted tubule are located in close proximity o Changes in the sodium concentration affect the contraction of the afferent arteriole Blood pressure GFR more sodium is absorbed low Na @ the macula densa JG cells release renin Result is contraction of the efferent arteriole increases the pressure in the kidney Blood pressure GFR less sodium is absorbed macula densa swells (osmotically) Adenosine released Result is contraction of the afferent arteriole Normal glomerular filtration rate is 125 mL/min maintained by auto-regulation by the JG apparatus **CONSIDER: A px w/ renal disease GFR release Renin blood pressure connues to cycle b/c of no change in GFR Glomerulus Epithelial cells: 1) Parietal line the bowmans capsule; 2) Visceral line the glomerulus (podocytes/ foot processes) Endothelial cells: line the glomerulus on the inside of the capillary Mesangial cells: specific M for the kidney Mesangium / Mesangial matrix: holds the capillaries together and provides supporting framework Diagnosis: Usually most renal diseases can be diagnosed by history, physical findings, urinalysis and lab data Sometimes a renal biopsy is done when a clear diagnosis cant be made, check for improvement or adapting to transplant o A good biopsy consists of at least 5 glomerulus samples Visualizing a biopsy o Light microscopy using different stains PAS BM used in pxns with diabetes to find glycosylation of the BM Trichrome Collagen and immune complexes H&E Silver Immune complexes o Immunofluorescence microscopy Consider immune complex deposition: IgG, IgA, IgM, C3, C4 o Electron microscopy This can be used to confirm diagnosis of MCD (multiple connective tissue disorder) Normal findings o 1) Capillary walls faintly visible thickened = pathological o 2) Count the # of cells should be less than 100 o 3) The cells should be separated by a little no clustering o Other cells in the surround: Distal = cuboidal; Proximal = columnar; Interstitial space should not be prominent if so could be edema / advanced age *** Diabetes: Thickening of the BM indication of renal pathology

Vijesh Patel Glomerulus structure The capillary loops dont form a full circle, they end at the mesangial matrix Endothelial cells these are found inside o They form extensions of the cytoplasm (sausage like) and the have gaps called fenestrations BM: large concentration of heparin sulphate and proteoglycans provides a negative charge o Negative charge repels proteins thus they are not filtered through o Immune complexes tend to get deposited there
Visceral epithelial cells (podocytes) w/ filtration slits Lamina rara externa Central lamina rara Lamina rara interna Endothelial cells w/ fenestrations

Epithelial cells these are found on the outside o Form small foot processes (podocytes) that have spaces between them called filtration slits Mesangial cells support the entire tuft b/w capillaries Tubules & Interstitium Tubules are lined by epithelial cells and can vary as you move down the nephron Interstium is usually not prominent there is little space b/w the small capillaries w/ few fibroblasts between o Edema and inflammation can cause expansion of the space ie. Chronic diseases (Advanced kidney disease) Glomerular Filtration High permeability for small solutes and water Impenetrable barrier for proteins (Glomerular barrier function) o Negatively charged BM causes repulsion created by collage type 4 and polyanionic proteoglycans (heparan sulphate) o Normally a small amount of protein leaks through (<30 mg /day) If its between 30-300mg/day its called Microalbuminuria Kidney diseases Classified into four components: 1) Glomeruli, 2) Tubules, 3) Interstitium, 4) Blood vessels o End stage disease are hard to classify b/c many components are involved Manifestations of renal disease Azotemia: biochemical abnormality o The nitrogenous wastes cannot be excreted and thus these will be higher in the blood o Elevated BUN and creatinine Uremia: clinical condition o Besides the biochemical abnormality there are systemic symptoms involving all the body organs o Findings: + Fluid electrolyte disturbance Metabolic acidosis caused by inability to absorb HCO3 and excrete H Calcium and bone metabolism Phosphate cant be excreted thus increase in level leading to calcium suppression PTH is released to mobilize calcium Bone breakdown leads to renal osteodystrophy Less vitamin D leading to bone resorption Cardiopulmonary Deposition of urea on organs leads to uremic fibrinous pericarditis, pulmonary edema, uremic pneumonitis, HT Hematopoetic Suppression of EPO leads to anemia GIT Uremic blood supresses platelet function Bleeding, gastritis, colitis Skin Uremic salts lead to purpura and itching Neuromuscular Uremic blood causes encephalopathy, seizures and coma Renal syndromes can be divided into two: o Nephritic: Present as a triad: 1) Hematuria leakage of RBC into urine; 2) HTN, 3) Proteinuriea (mild-moderate) Smokey urine w/ RBC casts caused by inflammatory infiltrate leading to capillary lumen damage RBC casts: microscopic segments in the urine produced in the DCT combined w/ Tamm Horsfall proteins Suppression of GFR (less than 40 ml/day = Oliguria) o Nephrotic: Massive amounts of protein in the urine (Greater than 3.5grams in the urine) = Proteinuria Decreased oncotic pressure fluid accumulation @ interstitial space generalized edema ANASARCA GFR = renin and aldosterone uid retenon edema protein = protein producon @ liver ( lipoproteins) Hyperlipidemia Types of proteinuria: Selective: loss of the negative charge in the glomerular BM = repulsion = protein loss Non-selective: loss of the size barrier = larger globulins can be excreted Complications: Edema (protein loss), Hypercoagubility (AT-III loss), infections (Ab loss), Iron resistant hypochromatic anemia (transferrin loss), Hypocalcemia & secondary hyperparathyroidism (vitamin D loss) Other Systemic Diseases Associated: Tumor associations (melanoma, carcinoma); Infection associations (syphilis, malaria, HBV, AIDS); Drug associations (gold, penicillamine, street heroin); Pregnancy-induced hypertension

Vijesh Patel ARF acute renal failure; abruptly occurs w/in a matter of weeks and months can be reversible CRF chronic renal failure; gradually over a period of years Definitions and terms Need to perform renal function test to find this: o Diminished renal reserve: GFR is 50% of normal o Renal insufficiency: 20-50% of normal GFR leads to anemia and HTN o Renal failure: 20-25% of normal GFR w/ uremia o End stage kidney: 5% of normal GFR Hemodialysis: Create an artificial fistula and drain the blood into dialysis machine, blood passes across a semipermeable membrane exchanging electrolytes with fluid on opposite side and then is returned back Peritoneal dialysis: Blood transfers electrolytes with a component in the peritoneum that is injected. It is then replaced after it has accumulated electrolytes Glomerular diseases Other findings: o Capillary wall necrosis (fibrinoid): severe acute capillary wall damage Necrotizing vasculitis or malignant HTN Types of GN: o Global GN all the glomerular tufts are diseased o Segmental GN a portion of the glomerular tuft is diseased o Diffuse GN most (70% or more) of the glomeruli in the given section are diseased o Focal GN some (70% or less) of the glomeruli in the given section are diseased Causes: o Most common cause are immune complexes as a result of endogenous or exogenous sources Immune complexes activation of the C cascade C5a inflammatory cells cytokines Damage o Immune complexes localize in specific locations Subepithelial deposits: Foot processes and BM Subendothelial deposits: Endothelial (sausage links) and BM

Vijesh Patel
Epi NEPHRITIC Acute diffuse proliferative GN Post streptococcal GN More common cause of nephritic syndrome in children Pathogenesis / Antibodies Proliferation of cells in the glomerulus (>100 cells) 1) 10 days after a group A Bhemolytic strep pharyngitis 2) 2 weeks after impetigo - caused by M types 1,4,12 Antigens deposit @ epithelial side - Attracts IgG-ab & C3 **N** Crescent formation parietal cells of glomerulus proliferate + M - Fibrin leads to the proliferation* Anti-glomerular BM ab Immune complex Pauci immune Young adult males Anti-BM-ab @ glomerular & pulmonary capillaries - -3 chain of type 4 collagen - Type 2 HSR S/S SubENDOthelial deposits SubEPIthelial deposits Nephritic (Triad) Oliguria (<400ml/day) Lumpy-bumpy appearance on IF ASO ters & C levels Children: Adults: 95% recover 5% go to RPGN / CGN epidemics = sporadic = *

Non-post streptococcal GN Rapidly progressive GN

Nephritic (Triad) Severe oliguria / anuria

prognosis (irreversible renal failure)

Type 1 Type 2 Type 3 Good pastures syndrome

Ie. Good pastures syndrome Ie. SLE, post infectious GN, Henoch scholein purpura Ie. Wegners, Microscopic PAN Hemoptysis, lung hemorrhage (cigarette smokers, recent URI, hydrocarbon exposure) Nephritic (Triad) Smooth linear appearance on IF Nephritic Hematuria

cANCA, pANCA + respiratory s/s, vasculitis and granulomas Most rapidly progress to renal failure / end stage kidney disease

IgA Nephropathy (Bergers disease)

Most common GN world wide Young men / children

Henoch-Schonlein Purpura (HSP) Focal proliferative GN NEPHROTIC Minimal change GN (Lipoid nephrosis)

URI w.in 1.5days (no lesions) / celiac disease / liver disease IgA production Abnormal IgA are trapped in mesangium = C activation = damage Same Proliferation of the cells + necrosis and fibrin deposits
- Like crescent but involves tuft

DDX respiratory illness (w/in 3 days) Prognosis (Slow progression to CRF)

Skin, GI tract, joint & renal involvement Nephritic

* Ass w/ SLE, endocarditis, wegners

More common cause of nephrotic syndrome in children

Occurs following a URI, recent immunization, atopic attack Type 4 HSR Abnormal cytokine circulating damages visceral epithelium - Effacement of foot processes

Selective albuminuria (los of charge) Nephrotic

Everything looks normal except for lipid droplets in the tubules - + fat stain (Trichrome = red) Children = 90% respond to corticosteroids *Ass w/ Hodgkins lymphoma Can occur secondary due to: - Drugs (NSAIDS, heavy metals) - Infections (hep B & C, malaria, leprosy, syphilis) - Diseases (malignancy, SLE) Clinical course = variable May complicate reflux nephropathy prognosis in adults - Progress to end stage in 10 years

Membranous GN

Most common cause of nephrotic syndrome in adults * Ass w/ Asians and males

Thickening of BM Immune complex deposit on BM - Epimembranous spikes hair-on-ends appearance - Suspect SLE in adults Hyalinization of the mesangium (Pink area devoid of cells) Sclerosis part of glomerulus w/ collapse of BM = hyaline deposits HIV ass w/ collapsing variant - Collapse + involvement of entire tuft Tubuloreticular inclusions in endothelial cells b/c of viral parts Proliferation + BM thickening - Immune complex deposition - Low C levels early and late - C3 nephritic factor = activation of C3 convertase = C3 levels - Normal C levels early

SubEPIthelial deposits of IgG + C3 Nephrotic - Non-selective proteinuria (high mol weight proteins lost) - May have hematuria or HTN Nephrotic - Non-selective proteinuria (high mol weight proteins lost) - MANY have hematuria or HTN Trichrome stain: collagen deposits IF: granular deposits of IgM & C3 EM: diffuse effacement of podocytes

Focal segmental glomerulosclerosis (FSGS)

More common in HIV patients More common in Afro-Americans

Membranoproliferative (Mesangiocapillary) GN Type 1 Type 2 (Linear dense deposit disease)

Adolescents and young adults

Nephrotic, Nephritic or Mixed SubENDOthelial depsoits Lamina densa deposits - Unknown composition

50% develop chronic renal failure in 10 years prognosis (benign course) * Ass w/ partial lipodystrophy which has truncal / shoulder lipid accumulation prognosis prognosis * Ass w/ chronic infections (hep B and C), SLE, Slow progression to uremia (ABOVE) death Need dialysis / renal transplant

Type 3 Secondary MPGN Chronic GN RPGN, FSGS, MPGN, MGN, IgA nephropathy, PSGN

- Tram-track appearance b/c of mesangial matrix splitting BM

SubENDOthelial depsoits SubEPIthelial depsoits

All GN end here terminal event Some evidence of primary disease

Atrophied + cortical thinning Hyaline masses accumulate - Acellular eosinophilic mass - Ghost glomeruli Arteriolar sclerosis b/c of HTN

Vijesh Patel
Hereditary Alports syndrome X-linked Involves synthesis of alpha 5 chain of Type 4 collagen - Fibrosing renal disease + eye disorder + nerve deafness Thinning of BM (150 nm or less) - Normally 300 nm Irregular thickening of BM - Reduplication of lamina densa / splitting Mucopolysaccharide + neural fat accumulation Asymptomatic hematuria DDX: good pastures - Autoimmune vs. Hereditary

Thin membrane disease Fabrys disease Secondary GN (Glomerular lesions associated w/ Systemic Diseases) DM Type 1 mostly Type 2

Prognosis

Nodular GN + Glomerulosclerosis NE glycosylation b/c of hyperglycemia leads to fibronectin + collagen deposit = capillary thickening w/ Heparan sulphate - Thickening b/c of GF + cytokines - Affect barrier function Hyperglycemia = GFR, capillary pressure = glomerular hypertrophy

Nephrotic Glomerulosclerosis: - Diffuse / Hyaline expansion of mesangial matrix - Nodular Kimmelstiel Wilson disease In periphery like Christmastree balls Diabetic nephropathy - Diabetic vascular disease b/c of microangiopathy - risk of infecons - Arteriosclerosis of efferent arteriole affects GFR Capsular drop lesion escaped plasma proteins stick to capsule Microalbuminuria Nephrotic SubEPIthelial or SubENDOthelial or BM

Prevent w/ control of blood glucose Progress to end stage renal failure w/ loss of GFR w/in 5 years Rx: Dialysis + renal transplant

Amyloidosis

Primary: Bence jones, AL - Multiple myeloma Secondary: AA - Chronic inflammatory disease, RA, chrons Class 1 normal Class 2 mesangial GN Class 3 focal proliferative GN Class 4 diffuse proliferative GN (MOST AGGRESSIVE) - 50:50 nephritic: nephrotic Class 5 membranous GN

SLE

Amorphous pink deposits in / around arteries / interstitium / glomeruli - Congo red stain (apple green birefringence) - Fibrils = 10 nm Class 4 & 5 have wire looping - SubENDOthelial deposit (type 4) - SubEPIthelial deposit (type 5) - anti-DNA + DNA complexes Fibrinoid necrosis Hematoxylin bodies - smudging appearance caused by ANA binding to nucleus Fibrillary deposits in mesangium - Dont stain w/ congo red - Fibrils = 20-30 nm Cryoglobulin (IgG-IgM complex deposits) - Precipitate at low temp, disassociate at high temp

Nephrotic

Wire loop = bad prognosis

Fibrillary & Immunotactoid glomerulonephritis Essential mixed cryoglobinemia

Nephrotic Hematuria Vasculitis Raynauds phenomenon Synovitis Focal or diffuse GN

* Ass w/ Hep C infections - May show MPGN

Vasculitis diseases PAN Wegners granulomatosis Henoch-Schonlein purpura Bacterial endocarditis