Renal

1. Renal 生理科 許明志 PhD, RPh hsumj@mail.cmu.edu.tw Office hours: 星期三早上(8-12),

2. Contents • Overviews of Renal function • Assessment of renal function • Regulation of Renal blood flow (RBF) & Glomerular filtration rate (GFR) • Solutes and water homeostasis • Acid-base balance

3. Body fluid osmolality & volume • Maintain the normal cell volume is essential for cardiovascular system (through regulation of NaCl and H2O) • Electrolyte balance: Na+, K+, Cl- , HCO3-, H+, Ca++, PO43-（intake = excretion）Positive balance (intake > excretion)、Negative balance • Acid-balance balance: Lung & kidneys • Excreteion (metabolites, foreign substances): Urea（aa）,Uric acid (nucleic acid), Creatinine（muscle creatine）, end product of hemoglobin , drugs, pesticides, chemical ingested • Endocrine organ • Renin(RAAS) 調整血壓, 以及Na+, K+平衡, • calcitriol（Vitamin D3 之代謝物: 在GI幫助鈣的吸收 及鈣骨骼之deposition) • Erythropoietin (when erythrocyte production): 通常慢性腎衰竭會產生anemia

4. 腎功能之改變-1 • Decreased ability to excrete Na+ → ↑ECF → hypertension（occasionally, the patients have high plasma renin and angiotensin level → produce even further ↑↑ECF, and arteriolar vasoconstriction → HP） • Inability of kidney to produce NH4+ →↓capacity to excrete H+ in urine → metabolic acidosis

5. 腎功能之改變-2 • ↑K+（become excessive）→ hyperkalemia（acidosis ↑↑hyperkalemia）高鉀 • Acidosis in renal failure patients further ↑hyperkalemia • Patients with renal failure can produce membrane depolarization and cardiac failure

6. 腎功能之改變-3 • Renal failure causes ↓ECF ionic calcium concentration（hypocalcemia）低鈣 • ↓ECF calcium（hypocalcemia） • ↓excrete PO4-3 ↑ECF PO4-3 → ↓ECF Ca++（Ca++ x PO4-3 = 35-45） • Reduce the ability of the kidney to active vitamin D →↓absorb calcium from GI • Reduced [Ca+2]ECF promotes increased release of Parathyroid hormone（PTH）,

7. ☆ 無法製造NH4+ ※

8. Diseases related with construction

9. Nephrotic syndrome • Causes: Increased permeability of the glomerular capillaries to proteins • Incidence: Proteinuria: protein excretion • Indicting kidney disease (protein in urine) • Develop edema and hypoalbuminemia

10. Nephrin • A transmembrane protein, a major component of the slit diaphragm • Gene mutation leads to the abnormal or absent slit diaphragms • Develop massive proteinuria and renal failure • So, Nephrin plays essential role in the formation of the normal glomerular filtration barrier

11. Alport’s syndrome • Hematuria (blood in the urine) and progressive glomerulonephritis (inflammation of glomerular capillaries) • 1-2% of cases of end-stage renal failure • Cause: defects in type IV collagen, a major component of the glomerular basement membrane • Result: basement membrane fails to serve as the barriers.

12. Nephrolithiasis (kidney stone) • 80-90%: calcium salts • Uric acid, magnesium-ammonium acetate • Cysteine • Formed by crystalization in a supersaturated urinary milieu. • 如果ureter is blocked with kidney stone, reflex constriction of the ureter around the stone elicits severe flank pain.

13. Micturition • Process of emptying the urinary bladder • Progressive filling of the bladder • Stretches the bladder wall and triggers a reflex initiated by stretch receptors • Micturition reflex

14. Assessment of renal function

15. Renal clearance Based on Fick principle

16. Pxa ; Pxv： 表示 substance X in renal artery and renal vein plasma 之濃度 RPFa RPFv：renal plasma flow rates In artery and vein Ux：[X] in urine V：urine flow rate Pxa (mg/ml) × Cx = Ux (mg/ml) × V (ml/min) Cx = clearance of substance X Cx =（Ux × V）/ Pxa Fick Principle = Mass balance Pxa ~ Ux x V正比關係

17. Mass of X excreted per unit of time Cx = Plasma concentration of X Ux * V Cx = Px Assessment of renal functionRenal Clearance (Cx) 的概念 • A volume of plasma from which all the substance (substance x) has been removed and excreted into the urine per unit of time (Unit : volume/time)

18. Renal Clearance(Cx) 的概念 3 and 4 are patients with kidney diseases Ratio = Urea in Urine/Plasma Urea concentration Ratio is a reliable index as renal function (normal = 70)

19. Assessment of renal function 利用Inulin Clearance(Cin) 求出 GFR Inulin: polymer of fructose: neither reabsorbed, secreted nor metabolized by the cells of nephron 所以每ㄧ分鐘之 Amt filtered = amt excreted Pin x GFR = Uin x V GFR = Uin x V/Pin Determine Cin = determine GFR

20. Assessment of renal function Creatinine Clearance(Ccr) Creatinine: • By product of sketeal muscle creatine metabolism • Produced at a constant rate • Endogenous, not reabsorbed but small amount of secretion in urine

21. Glomerular Filtration Rate（ GFR） • Index of kidney function • Essential in evaluating the severity and course of kidney diseases • GFR = the sum of filtration rate of all functioning nephrons • ↓GFR • 最開始同時也是唯一之臨床表徵 • 疾病正在進行 • ↑GFR（recovery）

22. GFR必須要降到很顯著才會發現Pcr下降 • GFR: 120-100 ml/min Pcr: 1.0-1.2 mg/dl

23. Glomerular filtration • GFR = 90-140 ml/min, female (80-125); after 30 GFR declines with age • The first step in the formation of urine is the production of an ultrafiltrate of the plasma at the glomerulus • The ultrafiltrate is devoid of cellular components and protein free. • Salt, organic molecules (glucose, aa), are similar as plasma

24. Ultrafiltration is driven by Starling forces across the glomerular capillaries, and changes in these factors alter the GFR. GFR and RPF are regulated by autoregulation • The force responsible for the glomerular filtration of plasma are the same as those involved in fluid exchange across all capillariry beds

25. Hydrostatic and oncotic pressure

26. Hydrostatics of glomerular filtration Filtration coefficient（Kf）: intrinsic permeability of the glomerular capillary and the glomerular surface area available for filtration

27. Determinants of glomerular filtration rate（GFR） • Starling equation • GFR = Kf× [（PGC - PBS）- πGC] • Changes in Kf: • Drugs, hormones could dilate the glomerular arterioles also increase Kf • A reduction in PGC is caused by • Decline in renal arterial pressure • Increase in afferent arteriolar resistance • Decrease in efferent arteriolar resistance • Increased PBS reduces GFR. Acute obstruction (kidney stone) of the urinary tract increase PBS

28. Regulation of renal blood flow and GFR

29. Renal Blood Flow (RBF): 1.25 L/min • 與 GFR 的速率有關 • 在近端腎小管之部位之調節電解質與水之再吸收 • Participate in the concentration and dilution of the urine • Deliver O2, nutrients and hormones to renal cells and returning CO2 and reabsorbed fluid and solutes to the general circulation • Deliver substrates for excretion in the urine

30. Renal blood flow (RBF) • Q (blood flow) = △P (arterial pressure – venous pressure of ea organ) / R (resistance) • RBF = aortic pressure – renal venous pressure/ renal vascular resistance

31. Autoregulation • Regulate the tone of afferent arteriole • Change in arterial pressure • Myogenic mechanism: 血壓上升, renal afferent arterioles is stretched, the smooth muscle contract, increase in the resistance of the arteriole offsets the increase in pressure, RBF and GFR remains constant • Change in NaCl concentration of tubular fluid • Tubuloglomerular feedback: 增加GFR, 增加NaCl in the tubule fluid in the loop of Henle, increases resistance of afferent arteriole, 接下來decrease GFR

32. Myogenic mechanism Autoregulation -不會因為血壓上升而影響RBF及GFR -achieved by changes in vascular resistance Vascular R Precisely responds to changes of arterial pressure 90-180 mmHg

33. Tubuloglomerular feedback NaCl 在tubular fluid 會被 JGA感受到, 然後JGA送訊號到 Afferent arteriole 產生 Resistance 所以GFR增加時, NaCl於 Tubular fluid增加, --------

34. N AP  1 RBF= △P/R R= k/r4 PGC: hydrostatic pressure in the glomerular capillary 2 3 4

35. 荷爾蒙及神經調控 RBF and GFR • Sympathetic nerve: binds to1 receptor, which are located mainly on the afferent arterioles • Angiotensin II : 收縮入球及出球小動脈, 所以降低 RBF 以及 GFR (出球對於AgII較敏感, 低濃度時作用於出球, 濃度高時作用於入球及出球) • Angiotensin-converting enzyme (ACE) • ACE inhibitors increase RBF and GFR • Prostaglandins • NO • Endothelin • bradykinin

36. Regulation of GFR and RBF • Extrinsic（神經、內分泌） • Renal sympathetic nerves（交感神經興奮 →NE →血管收縮 → ↓GFR） • α1 receptor（主要是位於入球小動脈afferent artreioles） • ↓Effective circulating volume（ECV）: hemorrhage • Fear, pain → ↓ RBF GFR • Angiotensin II（↓GFR） • Prostaglandins • PGE2，PGI2 → 擴張 → ↑GFR • NSAID ？ • Intrinsic • Autoregulation

37. Prostaglandins 正常人不會有影響May not regulate RBF and GFR in normal healthy person PGI2 PGE2 are produced locally within the kidney, and ↑RBF w/o changes of GFR---病態生理 Prevent severe and harmful vasoconstriction and renal ischemia Prostaglandin synthesis is stimulated by decreased ECV and stress, angiotensin II, and sympathetic nerves NO（endothelium-derived relaxing factor） Counteracts vasoconstriction produced by angiotensin II and catecholamines An increase in shear force acting on endothelial cells in arterioles Acetylcholine, histamine, bradykinin, ATP → increase production of NO Abnormal production of NO: Diabetes Mellitus, HP: Excess of NO production → glomerulat hyperfiltration and damage of the glomerulus Salt intake triggers NO production Regulation of renal blood flow and GFR

38. Endothelin A potent vasoconstrictor Secreted by Endothelial cell of renal vessels, Mesangial cells Distal tubular cells in response to angiotensin II, bradykinin, epinephrine, and shear stress Elevated in number of disease states（renal diseases with DM） Bradykinin Kallikrein is a proteolytic enzyme produced in the kidney Kallikrein cleaves circulating kininogen to bradykinin, a vaodilator Bradykinin is a vasodilator that acts by stimulating the release of NO and prostaglandins Regulation of renal blood flow and GFR

39. Adenosine Produced in the kidney Cause vasoconstriction of the afferent arterioles Reduce RBF and GFR Atrial Natriuretic peptide （ ANP ） Secreted by the heart rises with HP and expansion of extracellular fluid volume Cause vasodilation of afferent arteriole and vasoconstriction of efferent arterioles The net effect of ANP is therefore to produce a modest increase in GFR with little change in RBF Regulation of renal blood flow and GFR

40. Hemorrhage • Hemorrhage → ↓arterial pressure → baroreceptor reflex → ↑sympathetic nerve to the kidney → Intensive constriction of afferent and efferent arterioles →↓RBF and GFR → • ↑ Sympathetic → ↑release of epinephrine and angiotensin II → further vasoconstriction and ↓RBF GFR • Rise of vascular resistance of the kidney →↑TPR • ↑BP offset the fall in MAP caused by hemorrhage

41. Regulation of renal blood flow and GFR

42. Regulation of renal blood flow and GFR

43. Solutes and water homeostasis

44. Types of cellular transport pathway 感受到 Na+ 進來時 會增加Na+進入blood Na+ = 12 mEq/L Na+ = 145 mEq/L

45. Collecting duct: Principal cell

46. Key Acetazolamide Diamox Solute and H2O reabsorption along the nephron 1. Proximal tubule: early segment 鈉與HCO3-或 glucose, amino acids, Pi, lactateㄧ齊被吸收

47. Solute and H2O reabsorption along the nephron 2. Proximal tubule: late segment 鈉與Cl- ㄧ齊被吸收 為何此處之Cl-會較高 因為: Na+在early proximal tubule較多 再吸收的關係

48. Proximal Tubule Na+ transport • Early PT • Glucose and amino acid • Hydrogen ion：driving the reabsorption of HCO3-， • In the early PT, HCO3- is the major anion reabsorbed with Na+, and luminal HCO3- falls • 影響鈉吸收的藥物 • Phlorhizin（block Na+ - glucose cotransporter） • Digoxin（↓ Na+ K- - ATPase ） • Acetazolamide （↓H+- Na+ counter transporter → H+排出減少 → 身體偏酸）。CAI block bicarbonate reabsorption ：

49. Protein in the urine • Nephrotic syndrome • Fanconi’s syndrome:無法吸收aa, glucose, low-molecular-weight proteins.因為其他地方無法吸收, so….. • Synthesis by thick ascending limb of Henle’s loop (Tamm-Horsfall glycoprotein:由正常孕婦尿液轉化而來的Tamm-Horsfall糖蛋白會促進多型核白血球PMN的吞噬機能 )

50. Renal excretion of anions Glutamate代謝 因為organic anions競爭相同之 transporter, 因此增加PAH可以 降低penicillin之secretion