Renal pathophysiology.

Transcription

1 Renal pathophysiology

2 Outline Intro basic structure & physiology Nephro7c syndrome Nephri7c syndrome Acute renal failure Chronic kidney disease

3 Gross structure and loca7on

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 Excre7on (Blood filtra7on, reabsorp7on, secre7on) Homeostasis = minerals, water, ph Osmolality Endocrine func7ons

13 Urine forma7on Filtra=on Reabsorp=on, secre=on

14 Urine forma7on

15 Some useful terms GFR Renal clearance Crea7nine Urea

16 Glomerular filtra7on 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 Vasoconstric=on Afferent arteriole Vasodila=on Efferent arteriole Vasoconstric=on Efferent arteriole Vasodilata=on

19 Renal clearance = volume of plasma that is completely cleared each minute of any substance that finds its way to the urine Urine concentra7on x urine flow rate ml/min Plasma concentra7on Depends on Filtra7on, absorp7on, secre7on Inulin clearance = GFR Crea=nine clearance GFR (secre=on) Urea clearance GFR (absorp=on)

20 Clearance = GFR, e.g. inulin

21 Cleaeance > GFR, e.g. crea=nine

22 Clearance < GFR, e.g. urea

23 Crea7nine = by product of crea=ne metabolism by the muscle, its forma=on and release are rela=vely constat and propor=onal to muscle mass - Filtered but not absorbed = clinically for GFR measurement - (secreted, but minimally)

24 Urea = end product of protein metabolism high protein diet excessive 7ssue breakdown rectal bleeding

25 Normal blood chemistry levels

26 Endocrine func7ons Renin Erythropoie7n Vitamin D conversion

27 Juxtaglomerular complex = granules of inac7ve renin =detec7on of NaCl in the tubular filtrate JGA feedback control system that links changes in the GFR with renal blood flow.

28 RAAS

29 Erythropoie7n red blood cell differen7a7on 89-95% is produced in the kidney (mostly fibroblasts) anemia linked to kidney diseases!

30 Vitamin D

31 Proteinuria pressence of an excess serum protein in the urine

32 Clinical syndromes Nephro7c syndrome Nephri7c syndrome Acute renal failure Chronic renal failure

33 Nephro7c syndrome = constella7on of clinical findngs that result from increased glomerular permeability of plasma proteins proteinuria > 3.5g/day hypoalbuminemia edema hyperlipidemia lipiduria trombophilia

34 Nephri7c syndrome = inflammatory responses that decrease the permeability of the glomerular capillary membrane oliguria ( GFR) proteinuria hematuria hypertension edema

35 Nephro7c vs. nephri7c syndrome NEPHROTIC proteinuria > 3.5g/day hypoalbuminemia edema hyperlipidemia lipiduria trombophilia NEPHRITIC oliguria proteinuria hematuria hypertension edema

36 Nephri7c vs. nephro7c syndrome

37 Renal failure Acute Chronic

38 Acute renal failure (ARF) rapid decrease in GFR accumula7on of nitrogenous wastes (urea, uric acid, crea7nine) = azotemia disrup7on in homeostasis of water, minerals acidbase balance Anuria 50 ml/day Oliguria 500 ml/day Polyuria 3000 ml/day

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

40 Prerenal (ARF) = marked decrease in renal blood flow hypovolemia (haemorrhagia, dehydra7on, burn injury) hypotension (shock cardiogenic, sep7c, anaphylac7c) hypoperfusion (vasoconstric7on or atherosclerosis of renal artery)

41 Renal ARF = damage to structures within the kidneys glomeruli (glomerulonephri7des) tubuli (acute tubular necrosis) inters==um (tubulointers77al nephri7des)

42 Glomerulonephri7s = inflammatory process that involves glomerular structures = cause: diseases that provoke prolifera7ve inflammatory response to the endothelial, mesangial or epithelial cells - the inflammatory process damages the capillary wall permilng red blood cells to escape into the urine = hemodynamic changes that decrease the GFR

43 Glomerulonephri7s = most cases have immune origin

44 Glomerulonephri7s = cellular changes: Ø prolifera=ve increase in the cellular components Ø sclero=c increase in the noncellular components Ø membranous increase in the thickness of the glomerular basement membrane = types: Ø Acute prolifera=ve glomerulonephri=s Ø Rapidly progressive glomerulonephri=s

45 Acute tubular necrosis = destruc7on of tubular epithelial cells with acute suppression of renal func7on = the most common cause of ARF Causes: ischemia, drug nephrotoxicity, tubular obstruc7on, toxins from a massive obstruc7on

46 Acute tubular necrosis

47 (Tubulo)inters77al nephri7s = affec7ng the inters77um of the kidneys surrounding the tubules E=ology: infec7on, reac7on to medica7on, pyelonephri7s

48 Urinary tract infec7on (UTI) = asymptoma7c bacteriuria vs. symptoma7c infec7ons = lower urinary tract (cys77s) vs. upper urinary tract (pyelonephri7s) - E.coli, Staphylococcus saprophy2cus, Proteus mirabilis... (adherent proper=es!) - Bacterial coloniza7on of urethra, vagina, perineal area - Risk: women, children, elderly, cathetriza7on, diabetes, neurologic disorders (bladder emtying), etc.

49 UTI - manifesta7ons = cys77s: frequent urina7on (á 20min), lower abdominal or back discomfort, burning and pain (dysuria) on urina7on = pyelonephri7s: shaking chills, fever, constant pain in the loin area, dysuria, freqeuency and urgency, nausea, vomi7ng

50 Postrenal ARF = obstruc7on of urine ouplow from the kidneys ureter (calculi, strictures, BUO) bladder (tumors, neurogenic bladder) urethra (prosta7c hypertrophy) Treatment addressing the underlying cause of obstruc=on so that the urine flow is reestablished before permanent nephron damage occurs

51 Urolithiasis = forma7on of stones in the urinary tract (calcium salts, uric acid, magnesium ammonium sulphate, cys7ne). uretherolithiasis (urether) nephrolithiasis (kidney)

52 Urolithiasis

53 Management of ARF Monitoring (Urine output, BUN, s-crea) Cause??? Discon7nuing of nephrotoxic drugs usage Caloric intake Judicious administra7on of fluids Dialysis or renal replacement therapy

54 Animal models of ARF Bilateral nephrectomy Bilateral ischemia reperfusion injury Bilateral ureteral liga7on cispla7n, adriamycin, rapamycin, glycerol, folic acid

55 Chronic renal failure (CRF) decrease in GFR 60ml/min for a minimum of three months progressive & irreversible altera7ons of nephrons compensatory hypertrophy of the remaining nephrons Regardless of cause, chronic renal failure results in loss of renal cells with progressive deteriora=on of glomerular filtra=on, tubular reabsor=ve capacity, and endocrine func=ons of the kidney. All forms of renal failure are characterized by a reduc=on in GFR, reflec=ng a corresponding reduc=on in the number of func=onal nephrons.

56 CRF

57 CRF Diminished renal reserve GFR drops to 50% (BUN & crea7nine 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%

58 pericardi7s Clinical manifesta7ons accumula7on of nitrogenous wastes (Uremia) altera7ons of water, acid-base and electrolyte balance mineral and skeletal disorders renal hypertension anemia neurologic disorders (uremic encephalopathy)

59 Treatment of CRF Conserva7ve (dietary restric7on & BP management) Dialysis Renal replacament therapy

60 Causes of CRF Diabetes Hypertension Glomerulonephri7s (chronic) Polycys7c kidney disease Chronic pyelonephri7s

61 Diabe7c nephropathy = major complica7on of Diabetes glucose hyperfiltra7on (intraglomerular hypertension) thickening of the GBM = sclerosis mesangioprolifera7ve changes microalbuminuria (30-300mg protein/day) proteinuria hypertension Non-nephro=c proteinuria => nephro=c syndrome => Renal failure

62 Hypertension = cause & result of kidney disease - Associated with many changes in glomerular structures, including sclerosis - Increased vascular volume - Na reten7on - Impaired renin produc7on

63 Polycys7c kidney disease (PKD) = cysts are fluid-filled sacs or segments of dilated nephron. - tubular obstruc7ons => intratubular pressure OR - changes in the basement membrane of the tubules => predispose to cys7c dila7on - PKD = hereditary disorder (PKD1, PKD2)

64 Chronic UTI = Recurrent UTI (persistance or re-infec7on) = Chronic UTI (obstruc7ve uropathy or reflux flow of urine) - Irreversible scaring

65 Renal fibrosis Forma=on of excess fibrous connec=ve =ssue in an organ or =ssue. Similar to wound healing probably ini=ates as a beneficial response to injury. If an injurious condi=on is sustained non-func=onal fibro=c =ssues replace the func=onal =ssues. Final common pathway of virtually any progressive chronic kidney disease (inedependent of origin diabe=c nephropathy, hypertensive nephrosclerosis, IgA nephropathy, chronic allograe nephropathy ) 10% of adult popula=on Key characteris=cs fibroblast expansion and extensive ECM deposi=on

66 Renal fibrosis Healthy kidney alpha smooth muscle ac=n, α-sma Internal control - posi7ve staining in media of vessels (VSMCs)

67 Renal fibrosis Fibro=c kidney alpha smooth muscle ac=n, α-sma = MYOFIBROBLAST marker Massive upregula7on in fibrosis marks expansion of myofibroblasts (only found in fibro7c kidneys)

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

69 Renal fibrosis Fibro=c kidney Collagen III., Col III.

70 Healthy kidney PAS

71 Fibro=c kidney PAS Inflamma7on Tubular atrophy ECM Tubular dila7on

72 Fibro=c kidney PAS

73 Animal models of CKD 5/6 nephrectomy CTRL UUO unilateral ureteral obstruc7on Day ischemia reperfusion injury CTRL I/R Alport mice 30 minutes, warm ischemia - 37 C Day

74 Thank you for your auen7on