Diseases of Blood VesselsDiseases of Blood Vessels

• Nearly all diseases of kidney involve blood vessels.• Kidneys involved in pathogenesis of essential and secondary hypertension• Systemic vascular disease (i.e. arteritis) also involve kidney

Benign NephrosclerosisBenign Nephrosclerosis• Sclerosis of renal arterioles and smallSclerosis of renal arterioles and small arteriesarteries

a)a) some degree of ischemia some degree of ischemiai)i) hypertension hypertension

• Renal changes associated with benign hypertension

a) always associated with hyaline arteriosclerosis

i) deposits in arterioles- extravasation of plasma proteins through injured endothelial cells; also in BM

ii) results in narrowing of lumen

• no renal insufficiency nor uremia in uncomplicated cases

a) diabetes, blacks, more severe blood pressure elevations risk of

renal insufficiency• Kidneys are atrophic• Many renal diseases cause hypertension which in turn may lead to benign nephrosclerosis.• Therefore this disease seen simultaneously with other diseases of kidney

• This disease by itself usually does not cause severe damage

a) mild oliguriab) loss (slight) of concentrating

mechanismc) decreases GFRd) mild degree of proteinuria is a

constant finding• These patients usually die from hypertensive heart disease or cerebrovascular disease rather than from renal disease• Pathogenesis

a) medial and intimal thickening. Due to:

i) age, hemodynamic changes, genetic factors, etc.

Malignant hypertensionMalignant hypertension(malignant nephrosclerosis)(malignant nephrosclerosis)

• malignant nephrosclerosismalignant nephrosclerosis is the form of orm of renalrenal

disease associated with malignant disease associated with malignant hypertension hypertension

• Less common than benign• May arise de novo (without preexisting hypertension) or may arise suddenly in patient with mild hypertension (i.e.,

essential benign hypertension)• Frequent cause of death from uremia

• Factors:a) initial event – some form of vascular

damage to kidneyb) result is increased permeability of

small blood vessels to fibrinogen and other plasma proteins, endothelial injury

and platelet depositsc) This leads to appearance of fibrinoid necrosis in small arteries and

arterioles and intravascular thrombosis

d) platelets (platelet derived growth factors) and plasma cause intimal hyperplasia of vessels resulting in hyperplastic arteriosclerosis, which is typical of malignant hypertension

e) narrowing of renal afferent arteriole (i.e., progressive ischemia)

stimulates angiotensin II production (ischemic- induced) with renin secretion increased. Aldosterone also increased.

i) self perpetuating cycle- constriction (Angio II) vasoconstriction ischemia

renin etc.

• Diastolic pressure > 130 mmHg, papilledema, encephalopathy, CV disorders, renal failure

a) often, early symptoms due to intracranial pressurei) headache, nausea, vomiting,

visual impairmentsb) hypertensive crisis

i) loss of consciousness, convulsions

ii) proteinuria and hematuria (micro- or macro-) • 90% deaths due to uremia• 10% deaths due to CV or cerebral disorders (hemorrhage)

This is a different kind of arteriosclerosis. This is hyperplastic arteriolosclerosis, which most often appears in the kidney in patients with malignant hypertension. The arteriolar wall is markedly thickened and the lumen is narrowed. Arteriosclerosis, or "hardening of the arteries" is a generic term that includes atherosclerosis, arteriolosclerosis, and medial calcific sclerosis.

Renal Artery StenosisRenal Artery Stenosis

• Unilateral is uncommon cause of hypertension

a) ~ 70 % due to atheromatous plaque at origin of renal artery

i) second leading cause is fibromuscular dysplasia of

renal artery (hyperplasia of all layers)

- More common in women - Tend to occur in younger groups (20-30 yrs)

b) potentially curable form of hypertensioni) related to degree of stenosis

- caused primarily by renin secretion

- ACE inhibitors show marked in arterial blood pressure

- revascularization• Ischemic kidney shows signs of diffuse ischemic atrophy• Patients present usually resembling essential hypertension• arteriography required to localize stenotic lesion• 70-80 % cure rate

Thrombotic MicroangiopathiesThrombotic Microangiopathies

• Clinical syndromes• Widespread thrombosis in microcirculation (a/c)• Damage to endothelial cells !!• Diseases:

a) childhood hemolytic-uremia syndrome (HUS)

b) Thrombotic thrombocytopenic purpura• Most follow intestinal infection (E. coli)• Disease is one of main causes of acute renal failure in children• Vasoconstriction (decreased NO, increased endothelin-1, decreased PGI2)

• Although the various diseases have diverse etiologies, 2 predominant factors

a) endothelial injury and activation, leading to vascular thrombosis and,

b) platelet aggregationc) both of these causing vascular obstruction and

vasoconstriction1.-1.- Endothelial injuryEndothelial injury• activation can be initiated by a variety of agents, while some remain elusive

a) denuding the endothelial cells, exposes vascular to thrombogenic subendothelium

i) NO, PGI2, enhance platelet aggregation and

vasoconstriction

ii) vasoconstriction also initiated via endothelial derived endothelin-1

iii) activation of endothelial cells increases adhesiveness to

platelets, etc.iv) endothelial cells elaborate

large multimers of vW factor platelet aggregation2.- Platelet Aggregation2.- Platelet Aggregation• serum factors causing platelet aggregation

a) large multimers of vW factor (secreted by endothelial cells)

i) usually cleaved by ADAMTS-13 (vW factor-cleaving metalloprotease)

HUS/TTPHUS/TTP

1.- Classic childhood HUS (> 75% following infection)• bloody diarrhea intestinal infection

a) verocytotoxin-releasing bacteriai) Verocytotoxin-producing strains

of E. coli (eg 0157:H7 or 0103);

ii) Similar to Shigella toxin.iii) undercooked hamburgeriv) “petting” zoos

• characterized:a) sudden onset (post GI or influenza infection) b) hematemesisc) melenad) severe oliguriae) hematuriaf) hemolytic anemia

(microangiopathic)g) hypertension in > 50% of cases

• Pathogenesisa) related to Shigella toxin

i) affects endothelium- adhesion of leukocytes- endothelin and NO- endothelial lysis (in presence

of cytokines such as TNF)ii) these changes favor thrombosis

and vasoconstrictioniii) verocytotoxin can directly bind

to platelets and cause activation• most patients recover in few weeks, with proper care (i.e., dialysis, etc); < 5% lethality

2.- Adult HUS• associated with:

a) infectioni) typhoid feverii) E. coli septicemiaiii) etx or shiga toxiniv) viral infections

b) antiphospholipid syndromei) SLEii) similar to

membranoproliferative GN but w/out immune complex deposits

c) complication of pregnancy (“postpartum renal failure”

d) vascular renal diseasei) systemic sclerosisii) malignant hypertension

e) chemotherapeutic and immunosuppressive drugs

i) mitomycinii) cyclosporineiii) bleomyciniv) cisplatinv) radiation Tx

3.- Familial HUS• recurrent thromboses (~ 50 lethality)• deficit of complement regulatory protein

a) Factor H

4.- Idiopathic Thrombotic Thrombocytopenic Purpura• Manifested by:

a) thrombi in glomerulib) feverc) hemolytic anemiad) neurologic symptomse) thrombocytopenic purpura

• defect in ADAMTS-13 (acquired or inherited)

a) normally cleaves large vW multimers

i) large vW factors promote platelet aggregation• more common in women• most patients < 40 years

• neurologic involvement is dominant feature• renal involvement in ~ 50% of patients

a) eosinophilic thrombi in glomerular capillaries, interlobular artery

and afferent arteriolesb) similar changes as with HUS

• exchange transfusion and steroid Tx mortality rate to < 50%

Other vascular disordersOther vascular disorders• Atherosclerotic renal disease

a) bilateral stenosisi) fairly common in older adultsii) cause of chronic ischemia

• Atheroembolic renal diseasea) via atheroma in older patients with severe atherosclerosis

• Sickle cell diseasea) vasa recta plugging by sickled cells

i) hematuriaii) renal concentrating

mechanismiii) patchy papillary necrosisiv) proteinuria

• Diffuse cortical necrosisa) uncommon

i) obstetric emergencyii) septic shockiii) following extensive surgery

b) glomerular and arteriolar microthrombi

c) unilateral or patchy involvement are compatible with survival

• Renal infarctsa) favored sites for infarcts

i) “end organ” nature of vasculature

b) most infarcts due to embolii) via left ventricle/atria as result

of MI- mural thrombosis

Cystic DiseasesCystic Diseases

• Common and difficult to diagnose• In adult polycystic disease – major cause of chronic renal failure• Confused with malignant tumors

• Simple cysta) Innocuous lesionb) Occur as single or multiple cystsc) Usually 1-5 cm diameterd) Clear fluid, smooth membrane, gray

glistening

e) Single layer of cuboidal cells f) Usually confined to cortex g) No clinical significance

• Importance to differentiate from tumorsa) are fluid filled rather than solidb) have smooth contoursc) almost always avascular

• Occur in patients with end-stage renal disease who have undergone long term dialysis• Occasionally, renal adenomas or

adenosarcoma arise from these cysts

Adult polycystic kidney diseaseAdult polycystic kidney disease (autosomal dominant)(autosomal dominant)

• Multiple expanding cysts of both kidneys that eventually destroy parenchyma of kidney• Accounts for 10% of chronic renal failure• In 90% of families, PKD1 (defective gene) is located on chromosome #16

a) encodes for protein (polycystin-1), extracellular and is a cell

membrane associated proteinb) how mutations in this gene cause

cysts formation is unclear

• Polycystin 2 (PKD2 gene) mutations also cause cyst formation• No symptoms until 4th decade

a) by then, kidneys are very largeb) common complaint is “flank pain”c) hematuriad) most important complications

i) hypertension (~75% patients)ii) UTIiii) aneurysms in circle of Willis

(10- 30%) and risk for subarachnoid hemorrhage

iv) Asymptomatic liver cysts in ~30- 40%

v) fatal disease (uremia or hypertension)

vi) progresses very slowlyviii) Treatment with renal transplantation

Childhood polycystic kidney disease (autosomal recessive)

• Rare• Serious manifestations at birth and young infants may die quickly

a) pulmonary failureb) renal failure

• Numerous small cysts in cortex and medulla• Bilateral disease• Many epithelial cysts in liver• Patients who survive infancy develop liver cirrhosis (congenital hepatic cirrhosis)• Unidentified gene location on chromosome 6p

Urinary Outflow-ObstructionUrinary Outflow-Obstruction

Renal Stones• Urolithiasis: Calculus formation at any level in urine collecting system, most often arise in kidney

• Occur frequently (!1% of all autopsies)• More common in males• Familial tendency• ~75% of renal stone

a) calcium oxalateb) calcium phosphate

• 15% composed of magnesium ammonium phosphate• 10% uric acid or cystine stones• All stones composed of mucoprotein

•Cause of stones is obscurea) Supersaturation in urine of stones

constituents (exceeds solubility)b) 50% of patients forming “calcium

stones” do not have increased plasma Ca++ but do have high urine Ca++

i) most Ca++ absorbed from gut in large amounts (absorptive hypercalciuria)

ii) only 5-10% has associated hypercalcemia

- hyperparathyroidism- Vit D intoxication- Sarcoidosis (autoimmune

disease, bacterial) - productions of Vit D (toxic)

c) Magnesium ammonium Phosphate stones

i) almost always occur in patients with alkaline urine due to UTI

ii) Proteus vulgaris and Staph split urea in kidney and therefore predispose patient to urolithiasis

• Gout and diseases involved with rapid cell turnover (e.g. leukemia) lead to high uric acid levels in urine and possibility of uric acid stones• Unlike magnesium ammonium phosphate stone, both uric acid and cystine stones are more likely to form when urine is acidic (pH < 5.5)• Stone formation 80% unilateral• Hematuria and predispose to infection

HydronephrosisHydronephrosis

• Dilation of renal pelvis and calyces with atrophy of parenchyma caused by obstruction of outflow of urine• Most common causes:

a) congenital i) atresia of the urethra (absence of a normal body passage or opening from an organ to other parts of the body)

b) acquiredi) stonesii) tumorsiii) inflammationiv) spinal cord damage with

paralysis of bladderv) normal pregnancy

• Bilateral only if blocked below level of ureters• Major problems are tubular with impaired concentration mechanisms• Obstruction leads to inflammatory response a) interstitial fibrosis• Complicating pyelonephritis is common• Pain from distension of collecting system

TumorsTumors

• Most common malignant tumor is:a) renal cell carcinoma (80-85% of all

1° Ca in kidney)b) nephroblastoma (Wilms tumor)c) urothelial tumors of calyces and

pelvis• Tumor of lower urinary tract are 2x as common as renal cell Cancer

Benign tumorsBenign tumors

• Renal papillary adenomaa) arising tubular epitheliumb) common (7-22 % found on autopsy)

• Renal fibroma or harmartoma (renomedullary interstitial cell tumor)

a) firm white-gray, < 1cm, found in pyramids (fibroblast-like

cells) • Oncocytoma (large nucleoli); eosinophilic Oncocytoma (large nucleoli); eosinophilic cellscells

Malignant TumorsMalignant Tumors

Renal cell Ca Renal cell Ca (adenocarcinoma of (adenocarcinoma of kidney)kidney)

• Derived from renal tubular epithelial cells

a) located primarily in cortex• 2-3% of all cell Ca in adults (~30,000 cases/yr)• 6th to 7th decades in life• Male preponderance (~ 3:1)

• Higher risk in smokers (2:1) and occupational exposure to cadmium, hypertension and acute renal failure and acquired cystic disease.• 30 fold increase in susceptibility in patients with polycystic disease• Classification:

1. 1. clear cell Cancerclear cell Canceri) most common (~ 85 % renal ca)

a) most are sporadic (~ 95%), nonpapillary

b) familial links (von Hippel-Lindau [VHL])

i) autosomal dominant diseaseii) predispose to a variety of CA – hemangioblastoma of

cerebellum and retina

iii) genetic abnormality chromosome 3,

which houses the VHL gene (VHL gene acts as a tumor

suppressor gene) – clear cell CA• Clinical

a) palpable mass, hematuria (most reliable), costovertebral pain

b) great mimicker (paraneoplastic syndromes)

i) polycythemiaii) hypercalcemiaiii) hypertensioniv) Cushing syndromev) eosinophilis

• common characteristic is to metastasize prior to giving rise to symptoms

a) common site are the lungs (~ 50%) and bones (~ 30%)b) renal vein involvement (increases morbidity and mortality)

• Renal cell CA are difficult to diagnose!a) Present with hematuria in ~50% of cases

2.- Papillary renal cell Ca2.- Papillary renal cell Ca• 10-15% of all renal CA• papillary growth pattern • Multifocal and bilateral• Both sporadic and familial forms• No genetic abnormalities in chromosome 3

a) Protooncogene on chromosome 7

3- Chromophobe Renal Carcinoma3- Chromophobe Renal Carcinoma• Least common (~5% of all renal cell CA)• Cortical collecting ducts or their collated cells• Stain more darkly than clear cell CA• Lack of a lot of chromosomes (1,2,6,10,17,&21)• Have good prognosis vs clear cell and papillary

4.- Collecting duct (Bellini duct) 4.- Collecting duct (Bellini duct) carcinomacarcinoma• ~ 1% of renal epithelial cell carcinoma• arise from collecting duct in medulla

4. Wilms tumor (nephroblastoma)4. Wilms tumor (nephroblastoma)• Occurs infrequently in adults• 1/3 most common organ cancer in children <15 years, (major cause in children)

a) most common 1 renal tumor of childhoodb) usually diagnosed between ages 2-5

yrs.• Sporadic or familial in nature

a) autosomal dominantb) 3 groups at risk for developing

i) WAGR syngromeii) Denys-Drash syndrome (WT 1

gene)iii) Beckwith-Wiedemann

syndrome (WT 2 gene)

ClinicalClinical• Good outcome with early diagnosis. Tumor has tendency to easily metastasize

• major complaint is associated with large size of the tumor

a) readily palpable mass

• less common complaints includea) feverb) abdominal painc) hematuriad) intestinal obstruction

(uncommon)

Urothelial CA of renal pelvisUrothelial CA of renal pelvis• ~ 5-10% of 1~ 5-10% of 1 renal tumors originate from renal tumors originate from urothelium of renal pelvisurothelium of renal pelvis

a)a) benign renal papillomas benign renal papillomas b)b) invasive urothelial (transition cell) invasive urothelial (transition cell)

CACA• become apparent quickly (hematuria)become apparent quickly (hematuria)

a)a) usually never palpable (small) usually never palpable (small)• In 50% there may be associated bladder urothelial tumor

a) increased incidence in patients with analgesic nephropathy

b) infiltration of pelvis and calyces is common

i) prognosis not good

Urinary bladder and collecting system Urinary bladder and collecting system tumors (Renal pelvis to urethra)tumors (Renal pelvis to urethra)

• Tumors in collecting system above bladder are uncommon• Bladder Cancer more frequent cause of death than are kidney tumors

a) Bladder tumorsi) small benign papillomas (rare) ii) large invasive CAiii) most recur after removal and

kill by infiltrative obstruction of ureters rather than by metastasizing

iv) Shallow lesion have good prognosis

v) deep invasive Cancer, survival (5yr) is <20% with overall 5 yr survival at 50-60%

b) Cancer of ureters is very rarei) 5 yr survival <10%