Editing Kidney functions

==Kidney functions==

===The National Kidney Disease Education Program===
*300K+ people have end stage kidney disease.
*It is expensive to take care of end stage kidney disease: 28 billion in 2010 (8% of the Medicare/caid budgets).
*11% of the US population has chronic kidney disease.
*Testing and therapy for chronic kidney disease are inadequately applied.

===Homeostasis===
*Claude Bernard suggested the idea of homeostasis: "constancy of the internal milieu is the essential condition to a free life".
*Walter Canon developed the idea of homeostasis and gave it said name.
*Homer Smith explains why the kidney filters everything and then has to reabsorb most of it.
**"Recognizing that we have the kind of blood we have because we have the kind of kidneys we have, we must acknowledge that our kidneys constitute the major foundation of our physiological freedom."
*Recall that mammal (and all land animals) came from sea animals.
*The kidneys have evolved from an environment where there was too much water (sea) to an environment where there is too little water (land).
**And many diverse animals keep their ions (Na, K, Ca, Mg, and Cl) at very consistent proportions.

===Drinking urine is good for you===
*Drinking urine is NOT good for you!

===Kidney functions===
*The kidneys have many functions, all of which focus on homeostasis of the fluid.
*The kidneys regulate the osmotic pressure of the body fluids by retaining or losing water.
*The kidneys regulate concentrations of 8 major ions / molecules: Na, K, Mg, Ca, Cl, HCO3- (and therefore H+), phosphate (PO3-) and sulfate (SO4-).
*The kidneys eliminate waste products and foreign compounds (think drugs and urea).
*The kidneys regulate extraceullar fluid volume.
*The kidneys regulate arterial blood pressure.
*The kidneys have specialized metabolic functions:
**Gluconeogenesis
**Degradation of polypeptide hormones
*The kidneys add important substances to the blood:
**Erythropoietin
**1,25OH VitD (calcitriol)
**Prostaglandins and thromboxane
**Renin
**Kallikrein

===Erythropoietin===
*Erythropoietin (EPO) is released by cells of the renal cortex in response to hypoxia.
*EPO (erythropoietin) acts on the bone marrow to increase RBC proliferation, matruation and release.
*As more RBCs are made, oxygen carrying capacity goes up.
*In chronic renal disease, too little EPO is generated by the kidney and anemia results.
*In blood doping, EPO was used to increase oxygen carrying capacity until we became able to determine the difference between endogenous and exogenous EPO.
*Treatment of anephritic patients with EPO is far more effective than the cycles of transfusion that would otherwise be required.

===Vitamin D===
*Vitamin D is hydroxylated once at the liver and once at the kidney.
**Recall that 7-dehydrocholesterol is obtained from the diet, converted to vitamin D3 at the skin, hydroxylated at the 25 position at the liver, and then at the 1 position in the kidney.
*'''The kidney adds the second hydroxyl group at the 1 position.'''
*'''Calcitriol (1,25OH vit D) is the biologically active form of vitamin D.'''
**Cacitriol causes increased Ca absorption at the gut and increased Ca mobilization at the bone (by potentitiating PTH's action, from the parathyroid).


*In renal disease, vitamin D is not hydroxylated well and so the body has '''too little biologically active vitamin D (calcitriol)'''.
**As the kidney fails, increased phosphate in the blood (''hyperphosphatemia'') and decreased renal tubular mass lead to decreased ability of the kidney to hydroxylate 25OH VitD to calcitriol (1,25 vit D3).


*Decreased calcitriol generation has a '''series of effects (literally, a series)''':
**This results in '''poor calcium absorption at the gut'''.
**Because there is poor Ca absorption at the gut, there is also '''hyperparathyroidism''' as the parathyroid works overtime to signal to the gut and bone to keep the Ca levels high despite poor absorption.
**And because the parathyroid is calling on the bone to release lots of Ca to keep serum levels normal, the bone becomes demineralized (bone disease).
**Finally, there is vascular calcification.
 Why is there calcium calcification?
 "Patients with chronic kidney disease are at risk for vascular calcification because of multiple risk factors that induce vascular smooth muscle cells to change into a chondrocyte or osteoblast-like cell; high total body burden of calcium and phosphorus due to abnormal bone metabolism; low levels of circulating and locally produced inhibitors; impaired renal excretion; and current therapies." per [http://jasn.asnjournals.org/content/19/2/213.full JASN]

===Prostaglandins and Thromboxanes===
*Prostaglandins and thromboxanes are made from phospholipds via cyclo-oxygenase enzymes like COX1 and COX2.
*Cyclo-oxygenase enzymes (COX1 and COX2) are constitutively activated in the kidney.
*The kidneys make lots of prostaglandins and thromboxanes which have effects on the kidney, itself.
*Prostaglandins:
**Prostaglandins increase renal blood flow.
**Prostaglandins increase Na excretion (increases water reabsorption, increases blood pressure).
**Prostaglandins increase renin release (increases water reabsorption, increases blood pressure).
***Recall that renin converts angiotensinogen to angiotensin 1 which gets converted to antiotensin 2 (by ACE in the lung) which causes blood vessels to constrict (elevates blood pressure) and causes release of aldosterone (from the glomerulosa zone of the adrenal cortex) which causes the kidney to reabsorb more Na and therefore more water (elevates blood pressure).
**Prostaglandins inhibit the actions of ADH on the kidney (decreases water absorption, decreases blood pressure).
***Recall that ADH (anti-diuretic hormone, AVP arginine vasopressin, from the '''posterior pituitary''') causes the kidney to reabsorb water.
*Thromboxanes are vasoconstrictors (increases blood pressure).

===Renin-angiotensin system===
*The overall scheme is that angiotensin is present in the blood, renin cuts it into angiotensin 1, ACE cuts angiotensin 1 into angiotensin 2.
**Note that angiotensinogen comes from the liver, renin comes from the kidney, and ACE (angiotensin converting enzyme) comes from the liver.
 Did Homor Smith explain why it makes sense that one enzyme should come from the liver and the other from the lungs?
*Angiotensin 2 is all about increasing blood pressure and therefore has effects on the vasculature (think constriction), the adrenal cortex (think aldosterone, and the brain (think thirst).
**Angiotensin 2 causes vasculature to constrict, thus increasing the blood pressure.
**Angiotensin 2 causes the adrenal cortex (the zona glomerulosa) to release aldosterone which causes the kidney to increase Na reabsorption (and therefore water reabsoprtion), thus increasing the blood pressure.
**Angiotensin 2 causes the brain to release AVP (arginine vasopressin = ADH) which causes the kidney to put more aquaporin proteins on the renal tubule epithelial cells which increases water reabsorption, thus increasing the blood pressure.


*ACE inhibitors inhibit the conversion of angiotensin 1 to angiotensin 2 and thus help keep blood pressure low (by decreasing water reabsorption mostly and also by decreasing vascular constriction).

===Renal kallikrein enzyme system===
*'''The renal-kallikrein system serves to dilate the vasculature''' (so it has mostly an opposite affect as the renin-angiotensin system, in terms of the vasculature).
*The general pathway is kininogen to kinins via kallikrein, then kinins to inactivated peptides via kininases.
**Kininogens are made primarily by the liver, but also by some other tissues.
**'''Kallikrein is made by the kidney.'''
**The active molecules are the kinins, like bradykinin.
**'''Bradykinin increases production of NO and prostaglandins''' and is therefore a potent vasodilator.
***Recall that the kidney makes lots of prostaglandins through the cyclo-oxygenase genes.


*ACE (recall that it converts angiotensin 1 to angiotensin 2 which goes on to increase blood pressure in many ways) is a kininase so it helps to increase blood pressure by getting rid of the kinins (like bradykinin) that are floating around trying to decrease the blood pressure.

===The nephron===
*The nephron is the basic structural and functional unit of the kidney.
*Each kidney is supplied by a renal artery, a renal vein, and a ureter which enter at the renal hilus.
*The outside of the kidney is the renal capsule.
*Deep to the capsule is the cortex.
*Within the cortex framework are medullary pyramids in which are the medulla.
*The beginning of the drainage structures are the minor calyces, then the major calyces, then the renal pelvis, and finally the ureter.
**The area of the renal pelvis and the calyces combined is the renal sinus.

===Blood vessels of the kidney===
*Recall that there is the cortex and medulla of the kidney.
**The cortex and medulla are histologically distinct.
**Within the medulla, we define two distinct areas: the outer medulla and the inner medulla.


*The kidney blood supply is specialized to allow the kidney to perform it's filtering duties.
*Each nephron has its own blood artery and vein.
*The overall flow is renal artery -> arcuate artery -> cortical radial artery -> afferent arteriole (one for each glomerulus) -> glomerulus (either a superficial cortical glomerulus or a juxtamedullary glomerulus) -> efferent arteriole -> peritubular arteries -> arcuate vein -> renal vein.
**The peritubular capillaries deliver oxygen to the cells of the tubule and serve to reabsorbed material from the interstitial fluid back into the blood.


**The superficial cortical glomerulus and the juxtamedullary glomerulus differ in their function and in their location within the kidney.
***The supuerficial
***The juxtamedullary glomeruli run deeper into the medulla of the kidney and therefore do more work, run straighter, and generate a large majority of the osmotic gradient....



**The descending vasa recta provide another route for blood.
***The descending vasa recta branch off the efferent arterioles (that is, distal to the glomerulus) '''of the juxtamedullary glomeruli'''.
***The descending and ascending vasa recta lie parallel to an individual tubule.