Renal Physiology PDF

In the loop of Henle: 1. Water, Na+, Cl- and other ions are reabsorbed and volume of filtrate is reduced Reabsorption involves: Na/K/2Cl transporter on the apical membrane and Na/K pump on the basolateral membrane Positive lumen charge or transepithelial potential generated by back leak of K+ driv...

In the loop of Henle: 1. Water, Na+, Cl- and other ions are reabsorbed and volume of filtrate is reduced Reabsorption involves: Na/K/2Cl transporter on the apical membrane and Na/K pump on the basolateral membrane Positive lumen charge or transepithelial potential generated by back leak of K+ drives paracellular reabsorption of cations, especially Ca++ and Mg++ 2. Water and ion (e.g., Na+, Cl- ) reabsorptions are dissociated in the descending and ascending limbs 3. Cortico-medullary osmotic gradient is set up, crucial for efficient water reabsorption from the collecting duct 4. The countercurrent multiplier or exchange mechanism takes advantage of the proximity of filtrate and blood flow counter currents Passive countercurrent exchange by the vasa recta. Water and solutes are removed from the interstitium via AVR. Urea 750 Descending vas rectum Urine Concentration and Dilution; Regulation of Extracellular Fluid Osmolarity and Sodium Concentration Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 29, 371-387 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved. Ascending vas rectum The countercurrent mechanism takes advantage of the proximity of filtrate and blood flow counter currents Descending vasa recta and ascending vasa recta: transport and structure of the wall? Urine Concentration and Dilution Mechanisms Mulroney, Susan E., PhD, Netter's Essential Physiology, Chapter 19, 224-230 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved. Diuretic abuse can lead not only to hypokalemia, but also to other plasma electrolyte abnormalities such as hyponatremia, hypochloremia, hypomagnesemia, metabolic alkalosis and imbalances of calcium ions. Why Jane was losing potassium ? Diuretics – antihypertensive agents which promote urinary water loss or diuresis Diuretics decrease blood pressure = anti-hypertensive drugs The specific mechanisms underlying action of diuretics vary and involve different segments of the nephron Diuretics and their site of action Thiazide - Distal tubule NaCl Loop Na/K/2Cl Several classes of diuretics: a. loop diuretics (furosemide or lasix) work in the loop of Henle b. thiazide diuretics work in the distal tubule c. K+ sparing diuretics (amiloride, spironolactone) work in the collecting duct d. proximal tubule diuretics (acetazolamide, limited use in cases of metabolic alkalosis) Thick ascending limb Collecting ductPotassium sparing All diuretics elevate solute concentration of filtrate, promote water retention inside the tubular lumen due to hydration of solutes (i.e. ions) and increase excretion rate. Ions are hydrated by water molecules H O H Water molecule Ion O H H O H H Diuretics elevate solute concentration of filtrate Furosemide (Lasix) inhibits Na+K+-2Cl- transporter and causes retention of these ions, Ca++ and water (osmotic effect) in the tubular lumen, increasing their excretion with urine. Loop diuretics are very potent Major side effect of furosemide: 1. excessive loss of K+ ions (kaliuresis) which results in low level of plasma K+ or hypokalemia. Patients often have to take K+ supplements. 2. Ca++ and Mg ++ might be also lost because the force underlying their reabsorption, i.e. the positive charge in the lumen, decreases because of reduced K+ back leak. 3. Excessive loss of fluid might lead to the activation of renin- angiotensin–aldosterone system and metabolic alkalosis. Renal Physiology Costanzo, Linda S., PhD, Physiology, Chapter 6, 245-310 Copyright © 2018 Copyright © 2018 by Elsevier, Inc. All rights reserved. Bartter syndrome, mutations of genes coding for Na/K/2Cl transporter: symptoms similar to those which can be evoked by the abuse of loop diuretics, i.e. hypokalemia, hypercalceuria, excessive loss of fluid (polyuria) Loop diuretics decrease positive lumen charge & paracellular transport of Ca++ and Mg++ Thiazide diuretics inhibit Na/Cl symporter and reabsorption of ions in the early distal tubule, less potent than loop diuretics The side effects of thiazide diuretics, i.e. hypokalemia and hypocalciuria, are mimicked in patients with Gitelman syndrome Na+ ClH2O Both loop and thiazide diuretics cause excessive K+ loss! In contrast to loop diuretics (e.g. lasix), thiazide diuretics increase Ca++ reabsorption and its plasma level. Patients with hypercalciuria benefit from thiazide diuretics! Diuretics and their site of action Thiazide - Distal tubule NaCl Loop Na/K/2Cl Thick ascending limb Collecting ductPotassium sparing Low plasma K+ is a typical side effect of loop and thiazide diuretics. In contrast, potassium sparing diuretics can cause hyperkalemia. They act in the late distal tubule and collecting duct. Glucose and kidney Glucose is reabsorbed only in the proximal tubule. Normally all glucose (100%) is taken into the peritubular capillaries and no glucose appears in urine. Filtered Reabsorbed Excreted Normal At threshold Far above threshold The ability of proximal tubules to reabsorb filtered glucose is limited. At normal plasma glucose levels (70-110 mg/dl, fasting values), filtered glucose should be completely reabsorbed. Reabsorption may not be complete if plasma level is increased to 180-200 mg/dl (hyperglycemia). The plasma level at which glucose first appears in urine is called glucose threshold. Low glucose threshold indicates deficient glucose reabsorption (Fanconi’s syndrome). Glucosuria is a sign of uncontrolled diabetes mellitus (although it can occur transiently in healthy people after a heavy meal). Glucose and kidney Blood glucose level in patients with diabetes mellitus is higher than normal (hyperglycemia). It means that the level of glucose in filtrate is also higher than normal. If glucose filtered load (mass that passes across filtration barrier in a unit of time) exceeds maximal capacity for its reabsorption, the cells of proximal tubule fail to remove all glucose molecules. Then glucose molecules travel with filtrate through the rest of the nephron, (i.e. along the cells of the loop of Henle, distal tubule and collecting duct which lack transporters for glucose reabsorption) and appear in urine (glucosuria). Why patient with hyperglycemia and glucosuria (diabetes mellitus) are frequently thirsty? Why do they need to urinate often? High blood glucose acts like osmotic diuretic In patients with diabetes mellitus, high plasma glucose causes osmotic movement of water out of the cells = cellular dehydration. This condition activates osmoreceptors, specialized cells that sense osmolarity, and an urge for drinking. High Glucose level in plasma High glucose level in filtrate impedes water reabsorption causing excessive urination or polyuria! H2O Dehydration Cells Overall, patients with diabetes loose not only glucose, a source of energy, but they also excrete an excessive amount of water “glued” to sugar molecules by osmotic force. Clinical application: exogenous sugars (e.g. mannitol) are used as osmotic Urine diuretics to promote urinary loss of water in patients with cerebral edema Peritoneal Dialysis System and hyperhydration. Ronco, Claudio, Critical Care Nephrology, Chapter 178, 1084-1088.e1 Copyright © 2019 Copyright © 2019 by Elsevier, Inc. All rights reserved. Diabetic nephropathy End Stage Renal Disease Endocrinology and Diabetes Kumar, Parveen, CBE BSC MD DM (HC) FRCP FRCP (Edin), Kumar & Clark's Cases in Clinical Medicine, 14, 411-460 Copyright © 2013 Copyright © 2013 Elsevier Ltd. All rights reserved. Glucose does contribute to plasma osmolarity. The following empirical formula demonstrates it clearly. Plasma osmolality (mOsm/kg) = 2([Na+ K]) + ([BUN]/2.8) + ([Glucose]/18) The formula, however, may lead to underestimation of osmolarity if additional organic solutes are present such as ketones during diabetes. How do we call two different types of epithelial cells in the distal nephron? Renal Parenchyma Collecting duct (CD) with principal cells (P) and intercalated cells (IC); C, peritubular capillaries; Tubules in the medulla. Cross section through the outer medulla shows a thick ascending limb of loop of Henle (AL) and descending thin limb of a long Henle loop (DL). Renal Anatomy Kriz, Wilhelm, Comprehensive Clinical Nephrology, Chapter 1, 2-13 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. Distal nephron = the distal tubule and collecting duct – fine balance of Na+, K+ and H2O. The role of aldosterone and ADH Two cell types: a. principal cells which reabsorb Na+ and secrete K+ b. intercalated cells which secrete H+ and reabsorb K+ Distal nephron like the ascending limb of Henle loop is water impermeable (tight junctions). Distal nephron = the distal tubule and collecting duct – fine balance of Na+, K+ and H2O. The role of aldosterone and ADH Consist of 2 cell types: a. principal cells which reabsorb Na+ and secrete K+ b. intercalated cells which secrete H+ and reabsorb K+ Distal nephron like the ascending limb of Henle loop is made of water impermeable epithelium (tight junctions). However, antidiuretic hormone (ADH) makes the cells water permeable. Aldosterone stimulates Na+-K+ ATPase, promotes Na+ reabsorption & K+ secretion Distal convoluted tubule Major transport proteins for solutes in the apical and basolateral membranes of tubular cells in specific regions of the nephron. Two types of intercalated cells Renal Physiology Bailey, Matthew A., Comprehensive Clinical Nephrology, Chapter 2, 14-27 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. Brief summary of segmental tubular transport Excretion of water and electrolytes. Water is reabsorbed in the proximal tubule together with glucose, amino acids, phosphate, sodium and bicarbonate, and from the distal nephron under the influence of arginine vasopressin and the hypertonic medulla. In the distal tubule, sodium is reabsorbed under the influence of aldosterone with associated excretion of potassium and hydrogen ions. ADH, antidiuretic hormone. (Adapted from Cumming and Swainson (1995) .) Disorders of the kidney and urinary tract Modi, Neena, Rennie and Roberton’s Textbook of Neonatology, 35, 927952 Copyright © 2012 © 2012, Elsevier Limited. All rights reserved A Case of Intrarenal Failure A 30-year-old woman presented to hospital with bilateral hand paresthesia and serum potassium level of 2.9 mmol/L (reference range [RR], 3.5–5.0 mmol/L). A normochromic, normocytic anaemia was present (haemoglobin level, 103 g/L; RR, 115– 165 g/L), and her serum creatinine level was 0.230 mmol/L. Her hypokalaemia was corrected, and she was discharged with a referral to the renal outpatient clinic. In the clinic, her blood pressure was 140/85 mmHg. Repeated laboratory tests showed: creatinine, 0.250 mmol/L; potassium, 3.1 mmol/L; bicarbonate, 17 mmol/L (RR, 23–31 mmol/L); and phosphate, 0.64 mmol/L (RR, 0.60 –1.40 mmol/L). Protein excretion was 0.9 g/day (RR, < 0.15 g/day). Urine microscopy showed no erythrocytes, casts or leukocytes. Urine pH was 7.0, with glucosuria on dipstick?. What is the problem? A Case of Intrarenal Failure A 30-year-old woman presented to hospital with bilateral hand paresthesia and serum potassium level of 2.9 mmol/L (reference range [RR], 3.5–5.0 mmol/L). A normochromic, normocytic anaemia was present (haemoglobin level, 103 g/L; RR, 115– 165 g/L), and her serum creatinine level was 0.230 mmol/L. Her hypokalaemia was corrected, and she was discharged with a referral to the renal outpatient clinic. In the clinic, her blood pressure was 140/85 mmHg. Repeated laboratory tests showed: creatinine, 0.250 mmol/L; potassium, 3.1 mmol/L; bicarbonate, 17 mmol/L (RR, 23–31 mmol/L); and phosphate, 0.64 mmol/L (RR, 0.60 –1.40 mmol/L). Protein excretion was 0.9 g/day (RR, < 0.15 g/day). Urine microscopy showed no erythrocytes, casts or leukocytes. Urine pH was 7.0, with glucosuria on dipstick. What is the problem? A renal biopsy showed acute interstitial nephritis and chronic renal damage. After taking prednisolone, an anti-inflammatory drug, and concurrent phosphate, bicarbonate and potassium supplements for 4 weeks, her serum creatinine level fell to 0.130 mmol/L. The dose of steroids was reduced gradually over 4 months and renal function remained stable. Tubulointerstitial nephritis can be idiopathic and may affect only the first segment of renal tubule. In this case, patients show symptoms very much alike to those observed in individuals with Fanconi’s syndrome caused by injury of the cells of the proximal tubule. Which of the following is expected in a patient with damaged proximal tubule? a. glucosuria b. hyponatremia (low level of Na+ in blood) c. kaliuresis (loss of K+ with urine) d. polyuria e. all of the above Causes of acute tubulointerstitial nephritis (TIN) By definition, TIN is characterized by interstitial cellular infiltrates, usually with sparing of the vessels and glomeruli, although it is noted that severe primary glomerular injury rarely occurs without concurrent tubulointerstitial injury Interstitial Nephritis Verghese, Priya S., Comprehensive Pediatric Nephrology, CHAPTER 34, 527-538 Copyright © 2008 TINU = tubulointerstitial nephritis with uveitis syndrome