Renal physiology

 

Functional anatomy of the kidney

Kidneys filter about 160 - 200 L of blood per day, 20 - 25% of the cardiac output. The basic morphological unit of kidney is a nephron. Each kidney contains about 2 million nephrons. The most important function of the glomerulus is to serve as a sieve for plasma: Small ions and molecules such as water, sodium ions, glucose, and amino acids are filtered, while larger molecules such as proteins are not filtered. The proximal tubule actively reabsorbs 66% of sodium Na+ ions and water by means of so-called sodium-potassium-adenosine triphosphatase (Na+-K+-ATPase) pump, with chlorine Cl- ions passively following the sodium ions. Reabsorption of 70% calcium Ca2+ ions parallels reabsorption of the sodium ions. The Na+-K+-ATPase pump provides energy to reabsorb 100% of glucose and amino acids, 90% of bicarbonate (HCO3)- ions, and other electrolytes. Up to 50% of urea is reabsorbed as well. The thin descending limb of Henle loop reabsorbs water and drives up the osmotic pressure of NaCl. The ascending limb of Henle loop reabsorbs passively (in the thin limb) and actively (in the thick limb) 25% of Na+ ions, 20% of Ca2+ ions, but no water. The distal tubule and the collecting duct actively reabsorb most of the remaining Na+ and Ca2+ ions, so that over 99% of both ions is reclaimed, and a variable amount of water. The active reabsorption of sodium ions and water is tightly controlled by a variety of stimulating and suppressing hormones, acting primarily at the distal tubule and collecting ducts, in order to maintain blood levels of sodium and calcium within narrow limits.

By controlling the levels of blood electrolytes (such as sodium and bicarbonate ions), kidneys maintain the acidity of blood between pH 7.35 - 7.45. When the pH value falls below this level, the condition is called acidosis, and when the pH is above, it is called alkalosis. The major effect of mild acidosis is depression of the central nervous system, disorientation, and fatigue. The major effect of mild alkalosis is hyperexcitability of the nervous system, spontaneous stimulation (spasms) of muscles, and extreme nervousness.

The initial step is the formation of a plasma ultrafiltrate (plasma without cells or proteins) at Bowman's space through the action of hydrostatic pressure in the glomerular capillaries. The ultrafiltrate flows along the tubules and is modified by reabsorption (retrieval) of important solutes (sodium salts, glucose, amino acids) and most water from the lumen of the tubules back into the peritubular capillary blood. The luminal fluid is also modified by secretion (addition) of solutes from the peritubular capillaries (or from the tubule cells) into the lumen. The proximal tubules reabsorb back into the peritubular capillaries about 2/3 of the Na and water and most of the bicarbonate, glucose and amino acids filtered and the little albumin that may have filtered at the glomeruli. The medullary loop of Henle reabsorbs salts with little water making the medullary interstitium rich in solutes (hyperosmolar) and delivers a solute poor, dilute fluid to the distal tubules. Thus the loop of Henle initiates the processes of urine concentration or dilution. The distal tubules (cortical diluting segments) continue to dilute the luminal fluid through hormone stimulated transport of NaCl (aldosterone)and of Ca salts (parathormone). In the connecting segment water reabsorption becomes prominent only when antidiuretic hormone is abundant. The collecting ducts make the final fine adjustments in composition of the urine through antidiuretic hormone stimulated water and urea reabsorption, and aldosterone stimulated Na, K and H transport.

 

1. About 1.5 L/day of urine containing about 600 mOsm of solutes (mostly NaCl, KCl and urea) are excreted. These solutes may be excreted in as little as 0.5 L/day or in as much as 12 L/day depending on water availability. The amount of solute excreted depends on diet (more when high protein-K rich diets that generate much urea, or highly salted foods, are eaten).
2. The kidneys regulate volume (water content and cell volume, sodium content and ECF volume) and composition (concentrations of K, phosphate, bicarbonate, pH) of the body fluids. Through renal plasma clearance (C=UV/P) the kidneys clean the body fluids of non-volatile end products such as urea, uric acid, and creatinine. Clearance of secreted and filtered solutes can approach renal plasma flow. Other solutes such as proteins, amino acids and glucose are conserved by the normal kidney and have zero clearance. The kidney produces hormones (erythropoietin, renin-angiotensin and calcitriol). It has also metabolic functions, participating in degradation of peptides such as some hormones, in fasting gluconeogenesis and in transformations of amino acids (glutamine to NH4, synthesis of arginine and glycine).

 

RENAL HEMODYNAMICS

  1. Anatomy:

    Interlobar, arcuate, interlobular arteries
    Afferent and efferent arterioles
    Glomerular capillaries, mesangial cells and matrix
    Renal veins
  2. Pressures and Resistances: 

    Site of major pressure drop (DP) is in the afferent arterioles: from 100 to 45 mm Hg

    In the efferent arterioles, DP is from 45 in glomerular capillaries to 20 mm Hg at peritubular capillaries. 

    Because of the resistance of the intrarenal veins, pressure drops from 20 in peritubular capillaries to 5 mm Hg in the renal vein.

    The total DP is from 100 in aorta (slightly less in interlobular arteries) to 5 mm Hg in renal vein.

    Note that the glomerular capillaries and the peritubular capillaries have low resistance (because there are so many of them in parallel) and therefore have low pressure drop.
  3. Magnitude of Renal Blood Flow:

    There is a large renal blood flow (RBF) at rest, equivalent to 1/5 of CO (1 L/min) to an organ that weighs less than 1% of body weight. Per unit mass, RBF at rest is higher than that to heart muscle or brain.
  4. Measurement of Renal Blood Flow:

    Clearances of p-aminohippurate Cp=V(Up)/(Pp), of Hippuran, or of Diodrast are about 80-90% of RPF and approximate the renal plasma flow (RPF). These clearances are called effective renal plasma flow and are less than the true RPF because (1) plasma flow through renal connective and adipose tissue is not included and (2) incomplete extraction of solutes from rapidly flowing blood in peritubular capillaries precludes total secretion of all the PAH present in the blood perfusing the tubules.

    To measure RPF accurately, the concentration of PAH in the renal venous plasma (RVp) must also be known: RPF=V (Up-RVp)/(Pp-RVp). This requires cateterization of the renal vein, a feasible but not a common procedure.

    Note that RBF can be calculated from RPF by the equation RBF = RPF/(1 - hematocrit).
  5. Roles served by Renal Blood Flow: 

    Sustain filtration and excretion of end products such as urea, creatinine etc.

    Achieve rapid changes in body fluids volumes and composition through changes in renal excretion of water and solutes.

    Serve a hemodynamic reserve function (1 L/min) in case if extreme emergency (shock).   That is, the RBF can be reduced to very low levels to help sustain the blood flow in other organs (brain, heart, etc.).  However, if kidney blood flow remains low for too long, renal damage will result.

    Deliver sufficient oxygen and nutrients to the kidneys; usually plentiful.
  6. Regulation of RBF:

    Autoregulation (intrinsic) occurs at MAP between 70 and 210 mmHg when pressure changes but blood flow (and filtration rate) are nearly constant.

    Autoregulation is by myogenic and tubulo-glomerular feedback (TGF) mechanisms. It occurs at the afferent arterioles

    Myogenic autoregulation depends on stretch activated ion channels in vascular smooth muscle that, when stretched, allow Ca ions to enter and induce contraction.

    TGF occurs between macula densa (MD) cells and cells of the afferent arteriole (juxtaglomerular apparatus).  When fluid delivery and NaCl transport at MD increase (as with increased GFR or decreased PT reabsorption), there are increases in cell Na and Ca and release of arachidonic acid metabolites and adenosine that act on vascular smooth muscle cells of the afferent arteriole, causing contraction and reduced blood flow.  The opposite happens when delivery and transport at the MD are decreased.

    Renin-angiotensin system. Renin is produced at granular cells of afferent arterioles. It is released in response to decreases in renal perfusion pressure (decreased stretch reduce cell calcium which promotes renin release), by sympathetic stimulation through renal nerves and by reduced flow and transport at MD cells (which reduce cell calcium, decrease arachidonic acid release and in turn reduce cell Ca in afferent arterioles).

    Renin is a protease that react with angiotensinogen (renin substrate) to produce Angiotensin I (10 amino acids) which is converted to Angiotensin II (8 amino acids) by the endothelial angiotensin converting enzyme (ACE).

    Angiotensin II is a potent vasoconstrictor, preferentially of the efferent arteriole, reducing RBF but maintaining or increasing filtration.  It also acts on the adrenal cortex inducing release of aldosterone (a hormone that stimulates sodium reabsorption), and in the proximal tubule stimulating Na-HCO3 reabsorption.

    At higher plasma levels AII contracts mesangial cells (which decreases filtration) and causes generalized vasoconstriction including the afferent as well as the efferent arteriole, which helps maintain central arterial blood pressure at the sacrifice of RBF and filtration.
  7. Other vasoactive agents in the kidney:

    Vasoconstrictors such as endothelin and AVP reduce RBF. AVP reduces the medullary blood flow in particular and by acting on mesangial cells may also reduce filtration.

    Vasodilators such as prostaglandins, nitric oxide and natriuretic peptides counteract and limit the effect of vasoconstrictors. Their absence or blockade may lead to hypertension, profound renal vasoconstriction and reduced filtration.

COUNTERCURRENT SYSTEM and the LOOP OF HENLE

1.  The Loop of Henle establishes medullary hyperosmolarity

The ascending limb of the loop of Henle transports solutes (NaCl) out of the tubule lumen with little or no water, generating an hyperosmotic medullary interstitium and delivering an hyposmotic tubule fluid to the distal tubule. This is called the "single effect".

The osmolarity of the interstitium rises progressively from cortex to medulla and papilla through multiplication of the "single effect" by countercurrent flow in the branches of the loop: The single effect in fluid processed by loop segments located near the tip of the papilla occurs in fluid already subject to the single effect when the fluid was in loop segments located closer to the cortex.

Countercurrent exchange of solutes between ascending and descending vasa recta (the renal medullary capillaries) minimizes solute washout from the medullary interstitium.

2.    The countercurrent system permits forming a concentrated urine

In the presence of ADH, which increases water permeability, the hyposmotic fluid that enters the distal tubule (DT) from the thick ascending limb (TAL) looses most of its water by osmotic equilibration with the surrounding cortical interstitium along the CNT and cortical collecting duct (CCD). It also continues loosing NaCl through reabsorptive transport along DT, CNT and CCD, until the tubule fluid becomes isoosmotic with plasma, by the end of the CCD.

The relatively small amount of isoosmotic fluid that flows into the medullary collecting ducts losses progressively more and more water to the hyperosmotic medullary and papillary interstitia and is finally excreted as hyperosmotic, highly concentrated urine.

3.  The countercurrent system permits forming a dilute urine

In the absence of ADH, the hyposmotic fluid that enters the DT from the loop of Henle, continues to be diluted by transport of NaCl via NaCl (thiazide sensitive) cotransporters into DT cells and via Na channels (amiloride sensitive) along the CD. Water reabsorption is limited so that the tubule fluid becomes more and more dilute along DT, CNT and collecting ducts (CCD, OMCD and IMCD), until it is excreted as a large volume of hyposmotic urine.

4.  Mechanism of hyperosmotic reabsorption in the TAL

There is apical Na-K-2Cl reabsorptive cotransport with K recycling through apical K-channels, and basolateral transport of Na via the Na-K-ATPase and of Cl via Cl- channels, in the water impermeable epithelium of the TAL.

A lumen positive electrical potential difference is generated by the luminal Na-K-2Cl cotransporter operating in parallel with channels that allow K to recycle into the lumen. The lumen positive potential drives passive paracellular reabsorption of more Na+ and of other cations (Mg++, Ca++)

The higher the delivery of Cl (Km=50 mM), the higher the activity of the luminal Na-K-2Cl cotransporters and the higher the rate of hyperosmotic Na reabsorption at the TAL.

5.  Mechanism for hyperosmotic reabsorption in the tAL (thin ascending limb)

Water abstraction along the early part of the thin descending limb (tDL) is driven by the high osmolarity (at least half due to urea) present in the medullary interstitium. In the deep nephrons, water reabsorption increases the tubule fluid osmolarity (up to 1200 mOsm/L) and the Na concentration (up to 300 mEq/L) by the bend of the loop.

Along the water impermeable tAL, Na diffuses from the tubule lumen into the medullary interstitium driven by its concentration gradient and some urea enters from the interstitium into the lumen; the osmolarity decreases as the fluid ascends along the tAL.

Operation of this passive mechanisms of Na reabsorption along the tAL is critically dependent on efficient medullary recirculation of urea from IMCD to interstitium, to tAL.

5.  Other functions of the Loop of Henle

Bicarbonate reabsorption through Na-H exchange

Reabsorption of cations such as Ca2+ and Mg2+

Generation of cortical to medullary gradients of gaseous NH3 and O2 and of medullary to cortical gradients of CO2 and lactic acid

Production of Tamm-Horsfall mucoprotein (casts)

Cells survive in the hyperosmotic medullary environment through slow accumulation of osmolytes (75 mM sorbitol and 25 mM glycerophosphocholine (GPC) by synthesis, and 25 mM betaine and 10 mM inositol by Na+ driven cotransport), which can be rapidly released from the cells through channels that open when the osmolarity decreases.

Hyponatremia usually results in serum hypoosmolality ( 11). Likely causes of hypoosmolar hyponatremia in this cat included hypoadrenocorticism, salt-losing nephropathy, third-space loss due to effusion, and third-space loss due to chylothorax with repeated pleural fluid drainage. The normal ACTH stimulation test and increased serum aldosterone level ruled out hypoadrenocorticism. The FC of sodium in the urine was low ( Table 1), ruling out salt-losing nephropathy. Nonrenal losses of sodium may occur with third-space losses. Renal conservation of sodium results in a FC of sodium of < 1% ( 11). Hyponatremia due to third-space losses into effusions (without drainage) is thought to occur secondarily to sodium and water retention, and impairment of free water excretion ( 10). Body cavity effusion causes a decreased effective circulating volume (ECV), despite an increase in total extracellular fluid volume (ECFV) ( 10, 12). This develops when fluid is lost within a cavity (third-space) and no longer contributes to the ECV, resulting in a relative hypovolemia.

Hypovolemia decreases glomerular filtration rate, enhances isosmotic reabsorption of sodium and water in the proximal tubules of the kidney, and decreases delivery of fluid to distal diluting sites ( 12). This impairs excretion of water. Hypovolemia also causes antidiuretic hormone (ADH) release, activation of the renin-angiotensin-aldosterone system (RAAS), and stimulation of the sympathetic nervous system. Activation of these systems also stimulates thirst, impairs free water excretion, and decreases renal tubular flow ( 10). In this cat, ADH secretion and RAAS stimulation were supported by the formation of concentrated urine (specific gravity = 1.042), an increased serum aldosterone level, and a decreased urinary sodium excretion ( Table 1). Aldosterone increases sodium reabsorption in the cortical collecting duct of the kidney by opening luminal sodium channels. Although this theory may explain the hyponatremia in this cat with the presence of effusion without drainage, hyponatremia resulting from mechanical removal of pleural fluid is the most likely explanation ( 5, 12). The cat presented with evidence of chronic effusion, based on the cytologic examination of the pleural fluid, and electrolyte abnormalities were not present prior to repeated drainage of the cat's chest, further supporting mechanical drainage as the primary cause of hyponatremia. Third-space loss into the effusion as the predominant cause, however, could not be ruled-out.

Hyperkalemia can be caused by increased intake, transcellular shifts, or by diminished urinary excretion ( 5, 13). In this cat, increased intake was unlikely in the presence of normal renal function. A cause for transcellular shifts, such as metabolic acidosis, was not supported based on normal serum bicarbonate. The normal ACTH stimulation test did not support hypoadrenocorticism as the cause of diminished urinary excretion. Diminished urinary excretion of potassium can be caused by chylothorax with repeated drainage of pleural fluid or by third space loss into effusions without drainage, and it is thought to result from an acquired defect in renal secretion of potassium ( 5, 13). A relative hypovolemia decreasing renal tubular flow is thought to cause insufficient potassium secretion.

Aldosterone is a mineralocorticoid produced and secreted by the cells of the zona glomerulosa of the adrenal cortex. Secretion is controlled mainly by the serum potassium concentration and stimulation by the RAAS. An increase in either results in increased aldosterone secretion ( 13). Aldosterone is important for sodium and potassium regulation and maintenance of a normal intravascular volume. Aldosterone acts at the distal convoluted tubule of the kidney, increasing production of Na+-K+-ATPase, increasing the number of sodium pumps within the nephron, and facilitating potassium excretion at the luminal membrane ( 10, 12, 13). Aldosterone is the most important hormone affecting urinary potassium excretion. An increase in distal tubular flow results in enhanced potassium secretion. A decrease in distal tubular flow from relative hypovolemia, especially in conjunction with hyponatremia, impairs potassium secretion. Potassium secretion is impaired because of poor sodium delivery (decreased electrochemical gradient) and potassium saturation of the luminal fluid (decreased concentration gradient), despite normal or increased concentrations of aldosterone ( 10, 13). In this cat, hyperkalemia caused by inadequate urinary secretion of potassium was demonstrated by the inappropriately low FC of potassium in the urine ( Table 1), despite an increased serum aldosterone level. When FC is evaluated, the evaluation does not necessarily correlate with the 24-hour urinary excretion of electrolytes; however, reference values have been reported ( 1, 6, 7, 11, 14).

Urea and Creatinine

Plasma urea and creatinine are the routine markers used to evaluate renal function. Plasma urea/creatinine levels give only a rough indication of renal function as at least 75% of renal function must be lost before values rise above reference levels.

 

1. Fossum TW. Feline chylothorax. Compend Contin Educ Pract Vet 1993;25:549–567.
2. Fossum TW, Forrester SD, Swenson CL, et al. Chylothorax in cats: 37 cases (1969–1989). J Am Vet Med Assoc 1991;198:672–678. [ PubMed].
3. Birchard SJ, Smeak DD, McLoughlin MA. Treatment of idiopathic chylothorax in dogs and cats. J Am Vet Med Assoc 1998;212:652–657. [ PubMed].
4. Thompson MS, Cohn LA, Jordan RC. Use of rutin for medical management of idiopathic chylothorax in four cats. J Am Vet Med Assoc 1999;215:346–348.
5. Willard MD, Fossum TW, Torrance A, Lippert A. Hyponatremia and hyperkalemia associated with idiopathic or experimentally induced chylothorax in four dogs. J Am Vet Med Assoc 1991;199: 353–358. [ PubMed].
6. Jacobs RM, Lumsden JH, Taylor JA. Canine and feline reference values. In: Bonagura JD, ed. Kirk's Current Veterinary Therapy XIII. Philadelphia, WB Saunders, 2000:1224.
7. Osborne CA, Stevens JB, Lulich JP, Ulrich LK, Bird KA, Swanson LL. A clinician's analysis of urinalysis. In: Osborne CA, Finco DR, eds. Canine and Feline Nephrology and Urology. Baltimore: Williams & Wilkins, 1995:136–205.
8. Gores BR, Berg J, Carpenter JL, Ullman SL. Chylous ascites in cats: Nine cases (1978–1993). J Am Vet Med Assoc 1994;205: 1161–1164. [ PubMed].
9. Casley-Smith JR, Morgan RG, Piller NB. Treatment of lymphedema of the arms and legs with 5,6-benzo-[α]-pyrone. N Engl J Med 1993;329:1158–1163. [ PubMed].
10. Bisset SA, Lamb M, Ward CR. Hyponatremia and hyperkalemia associated with peritoneal effusion in four cats. J Am Vet Med Assoc 2001;218:1590–1592. [ PubMed].
11. Autran de Morais HS, Chew DJ. Use and interpretation of serum and urine electrolytes. Sem Vet Med Surg 1992;7:262–274.
12. DiBartola SP. Disorders of sodium and water: hypernatremia and hyponatremia. In: DiBartola SP, ed. Fluid Therapy in Small Animal Practice. Philadelphia: WB Saunders, 1992:57–88.
13. DiBartola SP, Autran DE Morais HS. Disorders of potassium: hypokalemia and hyperkalemia. In: DiBartola SP, ed. Fluid Therapy in Small Animal Practice. Philadelphia: WB Saunders, 1992:89–115.
14. Adams LG, Polzin DJ, Osborne CA, O'Brien TD. Comparison of fractional excretion and 24-hour urinary excretion of sodium and potassium in clinically normal cats and cats with induced chronic renal failure. Am J Vet Res 1991;52:718–722. [ PubMed].