Understanding Renal Physiology

Understanding Renal Physiology  332e: Cellular and Molecular Biology of the Kidney Harrison's PCT:  ~60% of filtered NaCl and water,  ~90% of filtered bicarbonate and most critical nutrients i.e glucose and AA. Mechanism:  both cellular and paracellular transport mechanisms.  Anatomy: The apical membrane has an expanded surface area available for reabsorptive work created by a dense array of microvilli called the brush border, and leaky tight junctions enable high-capacity fluid reabsorption. Key Features: Na and Water Low Oncotic Pressure, and Low Hydrostatic Pressure in Peritubular Capillaries Na gradient by Basolateral Na/K ATPase keep intracellular Na Low Aquaphorin 1 in both basolateral and apical sides HCO3 Carbonic Anhydrases is present in brush border and in tubular cytoplasm; Acetozolamide work here to alkalinize urine Acid Secretion: 2 mechanisms Generation and diffusion of NH3 in tubular lumen that binds to H+ secreted by Na/H transport in apical membrane Cellular K+ inversely modulates Proximal Tubular Amino genesis; High intracellular K in Hypoaldosteronism causes Type IV RTA Filtered HPO42- also binds H+ to form titratable urinary acid Most PO43- is reabsorbed (mediated by PTH) SGLT2 Saturable Process 180-200 mg / dL Excretion of organic acids (urate, ketoacids, protein bound drugs i.e penicillins, cephalosporins, salicylates) and bases (Epi, Norepi, Dopamine, histamine, Acetylcholine) Probenecid inhibits organic acid reabsorption Cimetidine Trimethoprim competes with bases for its secretion Increase in Cr, but no change in GFR Amino-Acids (eg. cystine, lysine, arginine, ornithine etc) Mutations of such protein causing AA reabsorption causes cysteinuria  Peptide Hormones and Albumin Impaired acidification of endocytic vesicles by defective Cl- causes Dent Disease Macula Densa (Ref: Chapter 7. Vander’s Renal Physiology, 8e) Helps regulate 1. Renin Production 2. Tubuloglomerular Feedback Mechanism Flow is sensed by Cilia projecting into the tubular lumen  If more fluid sensed by Cilia, it decreases the GFR to restore it to an appropriate Level to maintain normal filtered load Na-K-2Cl channel sense Na+. If more Na+, it suppresses Renin, leading to decreased Aldosterone, leading to more Na+ excretion.  Sodium Reabsorption  332e: Harrison's PCT: 60% of filtered NaCL Descending LO]oH: 0% NaCl (Usually highly water permeable) Thin Ascending LoH: Usually minimal Na is reabsorbed Thick Ascending LoH: 15-20 % of Filtered NaCl  Cortical DT: 5% of Filtered NaCl Collecting Duct (4-5% of NaCl) Cortical Collecting Duct:  P cell Type A cell Type B cell Inner Medullary Collecting Duct: Cells resemble Principal Cells of CCD ANP or Renal Natriuretic Peptide inhibit Na reabsorption Usually transports Urea back to the interstitial Water Reabsorption Water Balance NEJM 2015 5 Key proteins/mediators involved in water balance: Table 1 of NEJM 2015 AVP: 3 main ways of action V2 receptor acts chiefly in the  principal cells of the renal collecting duct,  the connecting tubule cells,  the distal convoluted tubule cells, and  the cells of the thick ascending limb of Henle  V1a receptors: Renal Medullary Vasculature (Vasa Recta) Vasopressin regulated Urea Channels  Descending LoH Inner Medullary Collecting Duct  Pathological condition: Central or Nephrogenic DI  Na+K+2Cl- Channels (Thick ascending LoH) Pathological condition: Type 1 Barters syndrome  Thiazide Sensitive NaCl- Channels Pathological condition: Gitelman's syndrome  Aquaporin: Figure 4 of NEJM 2015 for Aquaporin 2, 3, and 4 -1 PCT, Thin Descending LoH,  -2 Collecting Tubule, CD -3 Collecting Tubule, CD -4 Collecting Tubule, CD ENaC Pathological condition: Type 1 Pseudohypoaldosteronism Water absorptions along with either NaCl or Urea or Osmolal Gradient. PCT: 60% of filtered NaCL Potassium Reabsorption 3 concepts in understanding potassium physiology What increases the aldosterone production other than hypovolumia activating RAAS.  Ans: Hyperkalemia What happens to renal potassium secretion in hypovolumia and in hypervolumia? Ans: In both cases, there is increased potassium excretion  What is Aldosterone Paradox?  Ans: To answer this question, one has to appreciate that renal K wasting is not only dependent on Aldosterone and distal Na delivery, but also on Ang II.  Regulation of Potassium Homeostasis CJASN 2015 Regulation of Potassium Homeostasis CJASN 2015 Regulation of Potassium Homeostasis CJASN 2015 Acid/Base Balance      Acid-Base Homeostasis CJASN 2015     A acid B Bicarb  Acid-Base Homeostasis CJASN 2015 Acid-Base Homeostasis CJASN 2015 Acid-Base Homeostasis CJASN 2015 Renin  Renin Production is under regulation of 3 pathways Macula Densa Pathway Its regulation is dependent on the luminal concentration of Cl- than Na+ Intra-renal Baroreceptor Pathway As sensed by preglomerular vessels B1 adrenergic Receptor Pathway Norepinephrine in B1 receptors of Juxtaglomerular Cells cause increased renin production Reference: Chapter 26. Renin and Angiotensin Goodman & Gilman's Pharmacology 12e 3 major physiological pathways regulating renin release Goodman and Gilaman's Aldosterone Chapter 20 Ganong's Review of Medical Physiology, 24e Renin Juxtaglomerular Cells in the Kidney Release Renin Renin cleaves Angiotensinogen to Angiotensin I in liver ACE cleaves Angiotensin I to Angiotensin II Angiotensin II binds to AT1R and causes Vasoconstriction  Increased Adrenal Aldosterone Production Conditions that cause aldosterone release along with cortisol Surgery, Physical Taruma, Hemorrhage,  Anxiety Aldosterone alone (no cortisol is released) High Potassium Intake Low Sodium Intake  IVC constriction in thorax Standing Secondary hyperaldosteronism via Renin 5 Clinical Questions to understand Renal Physiology PCT:  Use of Trimethoprim, Cr goes high, do you need to adjust medications dose? Theoritically NOT. As GFR does not change.  How can you increase the serum concentration of Oseltamivir? Probenecid increases serum concentration of Oseltamiver.  How does SLGT2 inhibitor work in DM? PCT - acts in SGLT 2 channel and inhibits it.  How does intracellular hyperkalemia in hypoaldosteronism cause Type IV RTA? ? The main affect on acid base in Type IV RTA is due to lack of aldsoterone action in Principal Cells in Cortical Collecting Duct How does Acetazolamide work in Kidneys? How does Lesinurad (Zurampic) work in the treatment of Gout?  URAT1 (Ur Acid Transferase) inhibition by Lesinurad. OAT (Organic Anion Transferase) LOH How is corticomedullary osmolality gradient generated by LOH in a countercurrent multiplication? NEJM 2015 What electrolyte abnormalities occur with Loop Diuretics or in Bartter Syndrome (B for Bartter, and Bumex Channel) ? Why? Na+K+2Cl- is blocked, hence, hypokalemic , hypocholremic metabolic alkalosis (?not sure but likely due to actual loss of K+, and Cl- and not due to secondary hyperaldosteronism as aldosterone production should be affected by inhibition of NaK2Cl- channels) (Figure 1 B of NEJM 2015) Macula Densa Glomerulotubular Feedback Glomerulotubular Balance, Tubuloglomerular Feedback, and Salt Homeostasis JASN 2008 What is the effect of loop diuretics vs thiazide diuretics in glomerulotubular feedback? loop diuretics increase salt excretion because they inhibit the sodium–potassium–chloride cotransporter in the macula densa, thereby blocking the feedback to the glomerulus. NEJM 2015 Cortical DTC What is the effect of thiazides or Gietelman's syndrome? Hypokalemic, Hypocholoremic Metabolic Alkalosis (?likely due to secondary hyperaldosteronism) (Figure 1 C of NEJM 2015) How does pseudohypoaldosteronism Type 2 occur? (Figure 1 C of NEJM 2015) Cortical Collecting Duct Principal Cells What is the electrolyte abnormalities in ENaC blockage, Aldosterone Receptor Antagonist or Hypoaldosteronism? (Figure 1 D of NEJM 2015) Decreased Na: Hypovolimic / Hypotension Decreased H Loss: Acidosis Decreased K Loss: Hypokalemic What is the effect of increased Luminal Na+ Channel activity i.e Liddles (L for Luminal Na Channel, and Liddles) Hyperaldosteronism ? (Figure 1 D of NEJM 2015) Increased Na: HTN Loss of K: Hypokalemic Loss of H: Alkalosis Type A (A for Acid secreting) Intercalated Cells What is the effect of non-functional Type A cells? H+ retention: Acidosis (Distal RTA) (Figure 1 E of NEJM 2015) Type B (B for Bicarbonate secreting) Intercalated Cells What happens when Type B cell function is impaired?  Chloride Wasting Metabolic Alkalosis. (Figure 1 F of NEJM 2015) Note the difference in the location of the H+, and Cl-HCO3- Channels in Type A vs Type B cells (Figure 1 E and F of NEJM 2015) What is the difference between Type 1 RTA vs Type 4 RTA? Which cells are affected?  ? Needs verification! Type A cells in Type 1 RTA Type 4 RTA is due to decreased NH3 generation in PCT due to Hyperkalemia ... Then whey do we have hyperkalemia in Type 4 RTA... Due to Hypoaldosteronism... Hence, type 4 RTA involves Prinicipal cells that have Mineralocorticoid receptors Summary, Type 4 TRA is due to hypoaldosteronism  NEJM 2015 Misc Question: What causes more net sodium loss in Urine / 24 hr Loop Diuretics or Thiazide diuretics. or What is the level of aldosterone when using Thiazide vs Loop Diuretics Answer (Needs verification): My hypothesis Macula Densa do not sense sodium when Loop diuretics is used. That leads to Increased Renin Production, leading to RAAS activation. This leads to more aldosterone production. In Thiazide diuretics, Renin production is somewhat suppressed as Macula Densa sense Sodium, leading to relatively suppressed Aldosterone.  What is the difference between Hypoaldosteronism vs Type 1 vs Type 2 Pseudohypoaldosteronism? Hypoaldosteronism Clinical Feature Hyperkalemic Hypovolumic with acidosis  Type 1 Pseudohypoaldosteronism (Table 1 Water Balance NEJM 2015) Aldosterone Resistance Mechanism Loss of functioning ENaC  No matter how high Aldosterone Level is, ENaC is inactive (i.e JUST opposite of Liddles) Clinical Features Hypotension or Hypovolumic Hyperkalemic  Metabolic Acidosis  Type 2 Pseudohypoaldosteronism (Figure 1 C of NEJM 2015) Decreased Aldosterone Production Mechanism Affect Thiazide sensitive NaCl Channel in Cortical DCT Increased function leads to more Na retention (i.e JUST opposite of Gitelmans syndrome) More Na leads to fluid excess state Leads to decreased Renin / Aldo state  Decreased Aldo leads to Hyperkalemia and Acidosis  Clinical Features Hyperkalemic HTN (Hypervolumic) with acidosis  Chemical and Physical Sensors in the Regulation of Renal Function CJASN 2015 Chemical and Physical Sensors in the Regulation of Renal Function CJASN 2015 Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion CJASN 2015 Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion CJASN 2015 Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion CJASN 2015