Renal pathophysiology

jana.babickova@gmail.com

Outline

• Intro – basic structure & physiology• Nephrotic syndrome• Nephritic syndrome• Acute renal failure• Chronic kidney disease

Gross structure and location

Kidney anatomyCapsule

Nephron

Nephron

Kidney ULTRAstructure

2D 3D

Kidney µ-structure – the renal corpuscule

Histological minimum

Kidney µ-structure – tubular segmentsHistological minimum

Kidney µ-structure – tubular segmentsHistological minimum

Glomerulus

Kidney ULTRAstructure

2D 3D

Kidney vasculature

Kidney FUNCTIONs

• Excretion (Blood filtration, reabsorption, secretion)

• Homeostasis = minerals, water, pH

• Osmolality

• Endocrine functions

Urine formation

Filtration

Reabsorption,secretion

Urine formation

Some useful terms• GFR

• Renal clearance

• Creatinine

• Urea

Glomerular filtration rate

= volume of blood filtered each minute

• cca 125mL/min

• only 1ml of the 125mL is excreted in urine

=˃ avarege output of urine is 60ml/hour

Arterioles

Glomerular vessels

GFR Renal perfusion

Afferent arterioleVasoconstriction ↓ ↓

Afferent arterioleVasodilation ↑ ↑

Efferent arterioleVasoconstriction

↑ ↓

Efferent arterioleVasodilatation

↓ ↑

Renal clearance

= volume of plasma that is completely cleared eachminute of any substance that finds its way to the urine

Urine concentration x urine flow rate ml/minPlasma concentration

Depends on Filtration, absorption, secretion

Inulin clearance = GFRCreatinine clearance ˃ GFR (secretion)Urea clearance ˂ GFR (absorption)

Clearance = GFR,e.g. inulin

Cleaeance > GFR,e.g. creatinine

Clearance < GFR,e.g. urea

Creatinine

= by product of creatine metabolism by the muscle, itsformation and release are relatively constat and proportional to muscle mass

- Filtered but not absorbed = clinically for GFR measurement

- (secreted, but minimally)

Urea

= end product of protein metabolism

↑ high protein diet↑ excessive tissue breakdown↑ rectal bleeding

Normal blood chemistry levels

Endocrine functions

• Renin

• Erythropoietin

• Vitamin D conversion

Juxtaglomerular complex

JGA – feedback control system that links changes in the GFR with renal blood flow.

= granules of inactive renin

=detection of NaCl in the tubular filtrate

RAAS

Erythropoietin• red blood cell differentiation• 89-95% is produced in the kidney (mostly fibroblasts)• anemia linked to kidney diseases!

Vitamin D

Proteinuria

• pressence of an excess serum protein in the urine

Clinical syndromes

• Nephrotic syndrome

• Nephritic syndrome

• Acute renal failure

• Chronic renal failure

Nephrotic syndrome

= constellation of clinical findngs that result from increased glomerular permeability of plasma proteins

• proteinuria > 3.5g/day• hypoalbuminemia• edema• hyperlipidemia• lipiduria• trombophilia

Nephritic syndrome

= inflammatory responses that decrease the permeability of the glomerular capillary membrane

• oliguria (↓GFR)• proteinuria• hematuria• hypertension• edema

Nephrotic vs. nephritic syndrome

•proteinuria > 3.5g/day• hypoalbuminemia• edema• hyperlipidemia• lipiduria• trombophilia

• oliguria • proteinuria• hematuria• hypertension• edema

NEPHROTIC NEPHRITIC

Nephritic vs. nephrotic syndrome

Renal failure

• Acute

• Chronic

Acute renal failure (ARF)

• rapid decrease in GFR

• accumulation of nitrogenous wastes (urea, uric acid, creatinine) = azotemia

• disruption in homeostasis of water, minerals acid-base balance

• Anuria ˂ 50 ml/day• Oliguria ˂ 500 ml/day• Polyuria ˃ 3000 ml/day

Acute renal failure (ARF)

• Pre-renal (55%)

• Renal (40%)

• Post-renal (5%)

Prerenal (ARF)

= marked decrease in renal blood flow

• hypovolemia(haemorrhagia, dehydration, burn injury)

• hypotension(shock – cardiogenic, septic, anaphylactic)

• hypoperfusion(vasoconstriction or atherosclerosis of renal artery)

Renal ARF

= damage to structures within the kidneys

• glomeruli(glomerulonephritides)

• tubuli(acute tubular necrosis)

• interstitium(tubulointerstitial nephritides)

Glomerulonephritis

= inflammatory process that involves glomerular structures

= cause: diseases that provoke proliferative inflammatory response to the endothelial, mesangial or epithelial cells

- the inflammatory process damages the capillary wall permitting red blood cells to escape into the urine = hemodynamic changes that decrease the GFR

Glomerulonephritis

= most cases have immune origin

Glomerulonephritis

= cellular changes: proliferative – increase in the cellular components sclerotic – increase in the noncellular components membranous – increase in the thickness of the GBM

= types: Acute proliferative glomerulonephritis Rapidly progressive glomerulonephritis

Acute tubular necrosis

= destruction of tubular epithelial cells with acute suppression of renal function

= the most common cause of ARF

Causes: ischemia, drug nephrotoxicity, tubular obstruction, toxins from a massive obstruction

Acute tubular necrosis

(Tubulo)interstitial nephritis

= affecting the interstitium of the kidneys surrounding the tubules

Etiology: infection, reaction to medication, pyelonephritis

Urinary tract infection (UTI)= asymptomatic bacteriuria vs. symptomatic infections

= lower urinary tract (cystitis) vs. upper urinary tract (pyelonephritis)

-E.coli, Staphylococcus saprophyticus, Proteus mirabilis... (adherent properties!)

-Bacterial colonization of urethra, vagina, perineal area

- Risk: women, children, elderly, cathetrization, diabetes, neurologic disorders (bladder emtying), etc.

UTI - manifestations= cystitis: frequent urination (á 20min), lower abdominal or back discomfort, burning and pain (dysuria) on urination

= pyelonephritis: shaking chills, fever, constant pain in the loin area, dysuria, freqeuency and urgency, nausea, vomiting

Postrenal ARF

= obstruction of urine outflow from the kidneys

• ureter(caliculi, strictures, BUO)

• bladder(tumors, neurogenic bladder)

• urethra(prostatic hypertrophy)

Treatment – addressing the underlying cause of obstruction so that the urine flow is reestablished before permanent nephron damage occurs

Urolithiasis

= formation of stones in the urinary tract(calcium salts, uric acid, magnesium ammonium

sulphate, cystine).

• uretherolithiasis(urether)

• nephrolithiasis(kidney)

Urolithiasis

Management of ARF

Monitoring (Urine output, BUN, s-crea)

Cause???

Discontinuing of nephrotoxic drugs usage

Caloric intake

Judicious administration of fluids

Dialysis or renal replacement therapy

Animal models of ARF

• Bilateral nephrectomy

• Bilateral ischemia reperfusion injury

• Bilateral ureteral ligation

• cisplatin, adriamycin, rapamycin, glycerol, folic acid…

Chronic renal failure (CRF)

• decrease in GFR ˂ 60ml/min for a minimum of three months

• progressive & irreversible alterations of nephrons

• compensatory hypertrophy of the remaining nephrons

Regardless of cause, chronic renal failure results in loss of renal cells withprogressive deterioration of glomerular filtration, tubular reabsortivecapacity, and endocrine functions of the kidney. All forms of renal failure arecharacterized by a reduction in GFR, reflecting a corresponding reduction inthe number of functional nephrons.

CRF

CRF

• Diminished renal reserve – GFR drops to 50%(BUN & creatinine levels are in normal range)

• Renal insufficiency – GFR is between 50 – 20%(isosthenuria; anemia, polyuria, hypertension)

• Renal failure – GFR is less than 20% (edema, metabolic acidosis, hyperkalemia)

• End-Stage Renal Disease – GFR is less than 5%

Clinical manifestations• accumulation of nitrogenous wastes (Uremia)

• alterations of water, acid-base and electrolyte balance

• mineral and skeletal disorders

• renal hypertension

• anemia

• neurologic disorders (uremic encephalopathy)

•pericarditis

Treatment of CRF

• Conservative(dietary restriction & BP management)

• Dialysis

• Renal replacament therapy

Causes of CRF

• Diabetes

• Hypertension

• Glomerulonephritis (chronic)

•Polycystic kidney disease

•Chronic pyelonephritis

Diabetic nephropathy

= major complication of Diabetes

• glucose• hyperfiltration (intraglomerular hypertension)• thickening of the GBM = sclerosis• mesangioproliferative changes• microalbuminuria (30-300mg protein/day)• proteinuria• hypertension

Non-nephrotic proteinuria => nephrotic syndrome => Renal failure

Hypertension

= cause & result of kidney disease

-Associated with many changes in glomerularstructures, including sclerosis

-Increased vascular volume

-Na retention

-Impaired renin production

Polycystic kidney disease (PKD)

= cysts are fluid-filled sacs or segments of dilated nephron.

- tubular obstructions => intratubular pressureOR

- changes in the basement membrane of the tubules => predispose to cystic dilation

-PKD = hereditary disorder (PKD1, PKD2)

Chronic UTI

= Recurrent UTI (persistance or re-infection)

= Chronic UTI(obstructive uropathy or reflux flow of urine)

- Irreversible scaring

Renal fibrosis•Formation of excess fibrous connective tissue in an organ or tissue.

• Similar to wound healing probably initiates as a beneficial response to injury.

•If an injurious condition is sustained – non-functional fibrotic tissues replace the functional tissues.

•Final common pathway of virtually any progressive chronic kidney disease (inedependent of origin – diabetic nephropathy, hypertensive nephrosclerosis, IgA

nephropathy, chronic allograft nephropathy…)

•10% of adult population

Key characteristics – fibroblast expansion and extensive ECM deposition

Healthy kidney – alpha smooth muscle actin, α-SMA

Internal control - positive staining in media of vessels (VSMCs)

Renal fibrosis

Fibrotic kidney – alpha smooth muscle actin, α-SMA= MYOFIBROBLAST marker

Massive upregulation in fibrosis – marks expansion of myofibroblasts (only found in fibrotic kidneys)

Renal fibrosis

Healthy kidney – Collagen III., Col III.

Renal fibrosis

Fibrotic kidney – Collagen III., Col III.

Renal fibrosis

Healthy kidney – PAS

Tubular atrophyTubular dilation

ECMInflammation

Fibrotic kidney – PAS

Fibrotic kidney – PAS

Animal models of CKD

• 5/6 nephrectomy

• unilateral ureteral obstruction

• ischemia reperfusion injury

• Alport mice

UUO

Day

CTRL

01 3 5 10 14

0 14 21

30 minutes,

warm ischemia - 37°C

CTRL I/R

Day

Ďakujem za pozornosť

jana.babickova@gmail.com