Renal pathophysiology.

Transcription

1 Renal pathophysiology

2 Outline Intro basic structure & physiology Nephrotic syndrome Nephritic syndrome Acute renal failure Chronic kidney disease

3 Gross structure and location

4 Kidney anatomy Capsule

5 Nephron

6 Nephron

7 Kidney µ-structure the renal corpuscule Histological minimum

8 Kidney µ-structure tubular segments Histological minimum

9 Kidney µ-structure tubular segments Histological minimum Glomerulus

10 Kidney ULTRAstructure 2D 3D

11 Kidney vasculature

12 Kidney FUNCTIONs Excretion (Blood filtration, reabsorption, secretion) Homeostasis = minerals, water, ph Osmolality Endocrine functions

13 Urine formation Filtration Reabsorption, secretion

14 Urine formation

15 Some useful terms GFR Renal clearance Creatinine Urea

16 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

17 Arterioles

18 Glomerular vessels GFR Renal perfusion Afferent arteriole Vasoconstriction Afferent arteriole Vasodilation Efferent arteriole Vasoconstriction Efferent arteriole Vasodilatation

19 Renal clearance = volume of plasma that is completely cleared each minute of any substance that finds its way to the urine Urine concentration x urine flow rate ml/min Plasma concentration Depends on Filtration, absorption, secretion Inulin clearance = GFR Creatinine clearance GFR (secretion) Urea clearance GFR (absorption)

20 Creatinine = byproduct of creatinine metabolism by the muscle, its formation and release are relatively constant and proportional to muscle mass - Filtered but not absorbed = clinically for GFR measurement - (secreted, but minimally)

21 Urea = end product of protein metabolism high protein diet excessive tissue breakdown rectal bleeding

22 Normal blood chemistry levels

23 Endocrine functions Renin Erythropoietin Vitamin D conversion

24 Juxtaglomerular complex = granules of inactive renin =detection of NaCl in the tubular filtrate JGA feedback control system that links changes in the GFR with renal blood flow.

25 RAAS

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

27 Vitamin D

28 Proteinuria pressence of an excess serum protein in the urine

29 Clinical syndromes Nephrotic syndrome Nephritic syndrome Acute renal failure Chronic renal failure

30 Nephrotic syndrome = constellation of clinical findngs that result from increased glomerular permeability of plasma proteins proteinuria > 3.5g/day hypoalbuminemia edema hyperlipidemia lipiduria trombophilia

31 Nephritic syndrome = inflammatory responses that decrease the permeability of the glomerular capillary membrane oliguria ( GFR) proteinuria hematuria hypertension edema

32 Nephrotic vs. nephritic syndrome NEPHROTIC proteinuria > 3.5g/day hypoalbuminemia edema hyperlipidemia lipiduria trombophilia NEPHRITIC oliguria proteinuria hematuria hypertension edema

33 Nephritic vs. nephrotic syndrome

34 Renal failure Acute Chronic

35 Acute renal failure (ARF) rapid decrease in GFR accumulation of nitrogenous wastes (urea, uric acid, creatinine) = azotemia disruption in homeostasis of water, minerals acidbase balance Anuria 50 ml/day Oliguria 500 ml/day Polyuria 3000 ml/day

36 Acute renal failure (ARF) Pre-renal (55%) Renal (40%) Post-renal (5%)

37 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)

38 Renal ARF = damage to structures within the kidneys glomeruli (glomerulonephritides) tubuli (acute tubular necrosis) interstitium (tubulointerstitial nephritides)

39 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

40 Glomerulonephritis = most cases have immune origin

41 Glomerulonephritis = cellular changes: Ø proliferative increase in the cellular components Ø sclerotic increase in the noncellular components Ø membranous increase in the thickness of the glomerular basement membrane = types: Ø Acute proliferative glomerulonephritis Ø Rapidly progressive glomerulonephritis

42 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

43 Acute tubular necrosis

44 (Tubulo)interstitial nephritis = affecting the interstitium of the kidneys surrounding the tubules Etiology: infection, reaction to medication, pyelonephritis

45 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,

46 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

47 Postrenal ARF = obstruction of urine outflow from the kidneys ureter (calculi, 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

48 Urolithiasis = formation of stones in the urinary tract (calcium salts, uric acid, magnesium ammonium sulphate, cystine). uretherolithiasis (urether) nephrolithiasis (kidney)

49 Urolithiasis

50 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

51 Animal models of ARF Bilateral nephrectomy Bilateral ischemia reperfusion injury Bilateral ureteral ligation cisplatin, adriamycin, rapamycin, glycerol, folic acid

52 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 with progressive deterioration of glomerular filtration, tubular reabsortive capacity, and endocrine functions of the kidney. All forms of renal failure are characterized by a reduction in GFR, reflecting a corresponding reduction in the number of functional nephrons.

53 CRF

54 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%

55 pericarditis 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)

56 Treatment of CRF Conservative (dietary restriction & BP management) Dialysis Renal replacament therapy

57 Causes of CRF Diabetes Hypertension Glomerulonephritis (chronic) Polycystic kidney disease Chronic pyelonephritis

58 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

59 Hypertension = cause & result of kidney disease - Associated with many changes in glomerular structures, including sclerosis - Increased vascular volume - Na retention - Impaired renin production

60 Polycystic kidney disease (PKD) = cysts are fluid-filled sacs or segments of dilated nephron. - tubular obstructions => intratubular pressure OR - changes in the basement membrane of the tubules => predispose to cystic dilation - PKD = hereditary disorder (PKD1, PKD2)

61 Chronic UTI = Recurrent UTI (persistance or re-infection) = Chronic UTI (obstructive uropathy or reflux flow of urine) - Irreversible scaring

62 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

63 Renal fibrosis Healthy kidney alpha smooth muscle actin, α-sma Internal control - positive staining in media of vessels (VSMCs)

64 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)

65 Renal fibrosis Healthy kidney Collagen III., Col III.

66 Renal fibrosis Fibrotic kidney Collagen III., Col III.

67 Healthy kidney PAS

68 Fibrotic kidney PAS Inflammation Tubular atrophy ECM Tubular dilation

69 Fibrotic kidney PAS

70 Animal models of CKD 5/6 nephrectomy CTRL UUO unilateral ureteral obstruction Day ischemia reperfusion injury CTRL I/R Alport mice 30 minutes, warm ischemia - 37 C Day

71 Thank you for your attention