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• 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
