Renal Flashcards
Renal development
The kidneys arise from the embryological intermediate mesoderm. The homeobox genes Lim-2 and Pax-2 are involved in early kidney development. The three sequential progenitors of the kidney, which are derived from the nephrogenic cord, are the: Pronephros, Mesonephros, Metanephros.
Pronephros
The pronephros develops in week 4, is non-functional, and degenerates.
Mesonephros
The mesonephros develops and functions as an temporary kidney in week 4-8. The mesonephric duct, which connects the mesonephros to the cloaca, derives: Wolffian duct in the male genitourinary tract (e.g. vas deferens, epididymis, seminal vesicles); Ureteric bud (caudal end of the mesonephric duct); Trigone of the bladder (caudal end of the mesonephric duct)
Metanephros
The metanephros develops in week 5 and begins functioning around week 10 ultimately giving rise to the adult kidney. The fetal metanephros is located in the sacral region, and ascends in the adult kidney to T12 - L3. The metanephros is composed of the ureteric bud and the metanephric mesoderm. The aberrant interaction between these 2 tissues may result inn several congenital malformations of the kidney
Metanephric mesoderm
The metanephric mesoderm gives rise to metanephric vesicles, which become S-shaped renal tubules, ultimately forming: Renal glomerulus, Renal capsule (Bowman’s capsule), Proximal convoluted tubule, Loop of Henle, Distal convoluted tubule, Connecting tubule (connects the distal convoluted tubule to the cortical collecting duct - don’t confuse with collecting tubules)
Ureteric bud
The ureteric bud penetrates the metanephric mesoderm and branches to give rise to the: Collecting duct, Minor calyx, Major calyx, Renal pelvis, Ureter. The urinary system and genital system meet at the common urogenital sinus, eventually becoming the urinary bladder and external genitalia.
Ureteropelvic junction
he ureteropelvic junction (UPJ) is the last portion of the developing ureter to canalize. Thus, the UPJ is most common site of obstruction during fetogenesis leading to hydronephrosis.
Potter sequence
Potter phenotype is caused by the Potter sequence occurring sequentially: Bilateral renal agenesis leads to failure of fetal renal excretion, causing oligohydramnios, resulting in decreased amniotic fluid. This causes multiple anomalies (Potter phenotype) and early death. The POTTER sequence phenotype is associated with: Pulmonary hypoplasia, Oligohydramnios, Twisted face, Twisted skin, Extremity defects, Renal failure (in utero). Common deformations observed in the Potter sequence phenotype include: Facial deformities (e.g. Potter facies, flattened “parrot beak” nose, low-set ears, micrognathia); Limb deformities (e.g. rocker-bottom feet, talipes equinovarus).
Oligohydramnios
Oligohydramnios fails to provide the fetus with adequate amniotic fluid necessary to mature the lungs, leading to pulmonary hypoplasia with severe respiratory failure and early neonatal death. Oligohydramnios allows contact of fetal skin with amnion creating amnion nodosum (nodules of fetal squamous epithelial cells on placental surface). Maternal abdominal ultrasonography may detect bilateral renal agenesis during the prenatal period. Potter’s phenotype can also be caused by: Autosomal recessive polycystic kidney disease (ARPKD) and posterior urethral valves
Horseshoe kidney
Horseshoe kidney occur when the right and left kidneys fuse (90% are fused at the inferior pole; 10% are fused at the superior pole). Horseshoe kidneys become trapped under the inferior mesenteric artery (at vertebral level L3). Patients with horseshoe kidneys have normal renal function. Horseshoe kidneys may compress ureters, potentially causing: Ureteropelvic junction obstruction, Hydronephrosis, Renal stones, Infection. Horseshoe kidney is associated with the following chromosomal aneuploidy syndromes: Edwards syndrome, Down syndrome, Patau syndrome, Turner syndrome. Horseshoe kidney can rarely be associated with renal cancer, especially Wilms tumor.
Multicystic dysplastic kidney
Multicystic dysplastic kidney occurs due to an abnormal interaction between ureteric bud and the metanephric mesenchyme. Multicystic dysplastic kidney renders the affected kidney nonfunctional. Gross examination of a multicystic dysplastic kidney shows a kidney composed of macroscopic cysts compressing dysplastic renal parenchyma composed primarily of connective tissue. Most patients with multicystic dysplastic kidney have unilateral disease, which is asymptomatic. Patients have compensatory hypertrophy of contralateral kidney. Patients with bilateral multicystic dysplastic kidneys have no renal function, resulting in oligohydramnios and Potter’s syndrome. Bilateral multicystic dysplastic kidney disease is incompatible with life. Multicystic dysplastic kidney is often associated with an atretic proximal ureter. Multicystic dysplastic kidney is most often diagnosed via prenatal ultrasound.
Duplex collecting system
Duplex collecting system is a condition in which two ureters drain a single kidney. Duplex collecting system can arise via 2 etiologies: The ureteric bud, the embryological origin of the ureter, can bifurcate before it enters metanephric blastema. Alternatively, duplex collecting system can arise when two ureteric buds reach and interact with metanephric blastema. Duplex collecting system is associated with: Vesicoureteral reflux (VUR), Ureteral obstruction, often due to a ureterocele, Urinary tract infections. Duplex collecting system is most often diagnosed via prenatal ultrasound, which often shows hydronephrosis of the affected kidney due to VUR. If a duplex collecting system isn’t diagnosed in utero, children can present with recurrent urinary tract infections.
Renal anatomy
The kidneys are located against the dorsal wall of abdomen, just beneath the diaphragm and are retroperitoneal (i.e., posterior to the peritoneum). The left kidney is usually taken during donor transplantation because it has a longer renal vein. Each kidney is divided into two regions: the outer renal cortex and the inner renal medulla.
The renal cortex
The renal cortex contains the: Glomeruli, Convoluted tubules, Cortical collecting ducts.
The renal medulla
The renal medulla contains the: Loops of Henle and Medullary collecting ducts. Projections of the renal medulla form pyramids, topped by papilla. Each papilla drains urine into a minor calyx, which convene to form a major calyx. The major calyx drains urine into the ureters, and subsequently, the bladder.
Nephron
The functional unit of the kidney is the nephron. Each kidney contains approximately one million nephrons, each with a renal corpuscle and a renal tubule. There are two types of nephrons, cortical and juxtamedullary. In contrast to cortical nephrons, juxtamedullary nephrons have: longer Loops of Henle, lower renin content, different tubular permeability properties, different postglomerular blood supply (vasa recta).
The renal corpuscle
The renal corpuscle is composed of a tuft of capillaries called the glomerulus, surrounded by the Bowman’s capsule.
The renal tubule
The renal tubule is divided into several segments in the following order (from proximal to distal): Proximal convoluted tubule, Proximal straight tubule, Thin descending limb of the loop of Henle, Thin ascending limb of the loop of Henle, Thick ascending limb of the loop of Henle, Distal convoluted tubule, Cortical collecting duct, Medullary collecting duct.
RBF (renal blood flow)
RBF (renal blood flow) is normally ~20% of cardiac output. The renal cortex receives ~90-95% of total RBF. The renal medulla receives ~5-10% of total RBF. To reach the kidney, arterial blood leaves the descending (abdominal) aorta to enter the renal artery. Note: the renal artery emerges from the descending aorta at the level of L2 (second lumbar vertebra).
Renal capillary beds
The kidney is relatively unique as it has 2 capillary beds arranged in series: glomerular capillaries and peritubular capillaries. Glomerular capillaries are high pressure, allowing filtration of solute and water out of the systemic bloodstream and into the urine. Peritubular capillaries are low pressure, allowing reabsorption of solute and water from urine into the systemic bloodstream.
Course of ureters
Ureters pass under the uterine artery and under the ductus deferens (retroparitoneal). Water (ureters) under the bridge (uterine artery, vas deferens. Gynecologic procedures involving ligation of the uterine vessels traveling in the cardinal ligament may damage ureter causing ureteral obstruction or leak.
Body fluid compartments
The 60-40-20 rule of body fluid compartments: 60% of body weight is water, 40% of body weight is intracellular fluid (ICF), 20% of body weight is extracellular fluid (ECF).
Intracellular fluid (ICF)
The major cations within the ICF are potassium and magnesium.
Extracellular fluid (ECF)
The ECF is further divided into two compartments: the interstitial fluid and the plasma. The major cation within ECF is sodium; the major anions are chloride and bicarbonate. ECF volume is measured by inulin.
Intracellular fluid (ICF)
Interstitial fluid is normally 15% of total body weight.
Plasma volume
Plasma volume is measured by radiolabeled albumin. Plasma volume is normally 5% of total body weight. Normal blood osmolality is 285 - 295 mOsm/kg H2O.
Glomerular filtration barrier
The glomerular filtration barrier is made up of three layers: Capillary endothelial cells, Negatively-charged glomerular basement membrane (GBM), Podocytes. Capillary endothelial cells of glomerulus contain numerous large pores (fenestrae) that allow anything smaller than a red blood cell (RBC) size to pass through. A negatively-charged glomerular basement membrane (GBM) sits below the fenestrated glomerular endothelium. The negative charge of the GBM helps it repel small, negatively charged proteins (e.g., albumin). Heparan sulfate provides the negative charge to the GBM. The GBM is made of Type IV collagen. Podocytes line the other side of the GBM and form a tight network of foot processes (pedicles) that regulate ultrafiltration of proteins into Bowman’s space. Only ions (e.g. Na+, K+, Cl-, HCO3-) and small molecules (e.g., glucose, amino acids, peptides) pass freely through podocytes.
Renal clearance
Renal clearance indicates the volume of plasma cleared of a substance per unit time. Renal clearance is calculated by the formula: C(x) = U(x)V/P(x). Where: C(x) = clearance of substance x (mL/min), U(x) = urine concentration of substance x (mg/mL), V = urine flow rate (mL/min). P(x) = plasma concentration of substance x (mg/mL). If C(x) is less then GFR, then there is a net tubular reabsorption of X (example: Na+, glucose, amino acids, HCO3-, Cl-). If C(x) is greater then GFR, then there is net secretion of X [example: Para-aminohippurate (PAH)]. If C(x) = GFR, then there is no net secretion or reabsorption of X (example: inulin).
Glomerular filtration rate (GFR)
GFR is functionally measured by looking at inulin clearance because inulin is filtered, but neither reabsorbed nor secreted by renal tubules. GFR = C-inulin = (U-inulin x V) / P-inulin. Where: C-inulin = clearance of inulin (mL/min), U-inulin = urine concentration of inulin (mg/mL), V = urine flow rate (mL/min), P inulin = plasma concentration of inulin (mg/mL). GFR normally decreases with age. In healthy patients, this decrease in GFR is not accompanied by a rise in serum creatinine, since creatinine is derived from muscle mass, which also decreases with age. Creatinine clearance slightly overestimates GFR because creatinine is also secreted by the proximal tubules. Creatinine clearance (CCr) is used to estimate GFR: GFR ≈ CCr = UCr V / PCr.
Starling equation
Another way to express GFR is through use of Starling equation: GFR = Kf [ (Pgc – Pbs) – (Pigc – Pibs)]. Where: Kf – filtration coefficient of glomerular capillaries. Pgc – glomerular capillary hydrostatic pressure, which is constant along the length of the capillary. Pbs – Bowman’s space hydrostatic pressure. Pigc – glomerular capillary oncotic pressure. Pibs – Bowman’s space oncotic pressure. The driving force for glomerular filtration is the net ultrafiltration pressure across the glomerular capillaries. This results in an increased GFR. The value of oncotic pressure in Bowman’s space is usually zero since only a small amount of protein is filtered.
Effective renal plasma flow (eRPF)
Renal plasma flow can be approximated by measuring the clearance of paraaminohippuric acid (PAH) because it is both filtered and secreted in the proximal collecting tubule (PCT) resulting in near 100% excretion of all PAH entering the kidney. eRPF=Urine PAH*V/Plasma PAH=Clearence PAH. RBF=RPF/(1-Hematocrit). V = urine flow rate (ml/min or ml/24hr)
Renal blood flow
RBF = [ RPF / (1-Hematocrit) ]. Where: RBF = renal blood flow. RPF = renal plasma flow
Filtration fraction
Filtration fraction is the fraction of renal plasma flow (RPF) filtered across the glomerular capillaries. Filtration fraction = GFR / RPF. Normally, 20% of RPF is filtered; 80% leaves through efferent arterioles to enter the peritubular capillaries. An increase in FF leads to an increase in the protein concentration of peritubular capillary blood, which leads to increased reabsorption in the proximal tubule. A decrease in FF leads to a decrease in the protein concentration of peritubular capillary blood and decreased reabsorption of water in the proximal tubule. Prostaglandins preferentially dilate afferent arteriole (increasing RPF, GFR, so FF remains constant). NSAIDs inhibit this. Angiotensin II preferentially constricts efferent arteriole (decreasing RPF, increasing GFR so FF increases). ACE inhibitors prevents this.
Effects of afferent arteriole constriction on GFR, RPF, and FF (GFR/RPF)
GFR decreases, RPF decreases, FF (GFR/RPF) does not change
Effects of efferent arteriole constriction on GFR, RPF, and FF (GFR/RPF)
GFR increases, RPF decreases, FF (GFR/RPF) increases
Effects of an increase in plasma protein concentration on GFR, RPF, and FF (GFR/RPF)
GFR decreases, RPF does not change, FF (GFR/RPF) decreases
Effects of a decrease in plasma protein concentration on GFR, RPF, and FF (GFR/RPF)
GFR increases, RPF does not change, FF (GFR/RPF) increases
Effects of constriction of ureter on GFR, RPF, and FF (GFR/RPF)
GFR decreases, RPF does not change, FF (GFR/RPF) decreases
Calculation of reabsorption and secretion rate
Filtered load=GFR x Plasma concentration. Excretion rate= V x Urine concentration. V = urine flow rate (ml/min or ml/24hr). Reabsorption= filtered- excreted. Secretion= excreted- filtered.
Glucose clearance
Glucose at a normal plasma level is completely reabsorbed in PCT by Na/glucose cotransport. At plasma glucose of around 200 mg/dL, glucosuria begins (threshold is reached). At about 375 mg/dL, all transporters are fully saturated (Tm). Glucosuria is an important clinical clue to diabetes mellitus. Normal pregnancy may decrease ability of PCT to reabsorb glucose and amino acids, leading to glucosuria and aminoaciduria.
Amino acid clearance
Amino acids are reabsorbed in the proximal convoluted tubule via cotransport with Na+.
Hartnup disease
Hartnup disease is a hereditary defect of the intestinal and renal reabsorption of neutral amino acids. Hartnup disease is inherited in an autosomal recessive manner. Patients with Hartnup disease present with the symptoms of pellagra, including the classic triad of: Diarrhea, Dementia (including ataxia and hallucinations), Dermatitis, aka “Casal necklace”. Insufficient reabsorption of tryptophan is responsible for the symptoms of Hartnup disease. Patients with Hartnup disease present with the symptoms of pellagra because there is insufficient tryptophan for conversion to niacin. Patients with Hartnup disease have neutral aminoaciduria. Patients with Hartnup disease are treated with a high-protein diet and supplemental nicotinic acid.
Na+/K+ ATPase
Na+/K+ ATPase in the basolateral membrane extrudes Na+ from renal tubular cells into the interstitium, thereby lowering intracellular Na+ and maintaining a gradient that favors passive Na+ reabsorption from the lumen into the renal tubular cells.
Proximal convoluted tubule (PCT)
The PCT has a distinctive brush border packed with microvilli. The fluid within the PCT is isosmotic, since solutes are reabsorbed isosmotically within this part of the nephron. A sodium-glucose linked transporter (SGLT) in the PCT reabsorbs glucose, while a variety of dedicated Na+ co-transporters reabsorb amino acids. Reabsorption of phosphate is directly linked to a sodium/phosphate cotransporter in the proximal tubule. PTH (parathyroid hormone) induces sodium/phosphate cotransporter endocytosis, leading to decreased reabsorption of phosphate. Reabsorption of filtered HCO3- is directly coupled to renal secretion of H+ via the action of carbonic anhydrase and the Na+/H+ antiporter. For each HCO3- filtered, one H+ is secreted into the renal tubular lumen. 67% of filtered Na+ and H2O reabsorption in the PCT.
The reabsorption of filtered HCO3
The reabsorption of filtered HCO3 in the PCT involves 5 steps: 1. Na+/K+ ATPase on the basolateral membrane extrudes Na+ from renal tubular cells into the interstitium, thereby lowering intracellular Na+. 2. Na+ enters the cell from the renal tubular lumen in exchange for H+ via the Na+/H+ antiporter. 3. This luminal H+ may combine with filtered HCO3- via the action of luminal carbonic anhydrase (located in the brush border of the proximal tubule) to produce water and CO2. 4. This luminal CO2 can then diffuse into the cell, where it is converted by intracellular carbonic anhydrase back into H+ and HCO3-. 5. This intracellular HCO3- is transported through the basolateral membrane into the interstitial fluid and ultimately the bloodstream. Since Angiotensin II stimulates the Na+-H+ antiporter in the proximal tubule, it also stimulates the reabsorption of HCO3- and H2O. Thus, increased reabsorption of HCO3- can cause a metabolic alkalosis in the setting of volume contraction, also known as a contraction alkalosis.
Thin descending limb of the Loop of Henle
The thin descending limb of the Loop of Henle allows passive reabsorption of water, but is impermeable to sodium, which concentrates the tubular fluid, increasing its osmolarity greater than the osmolarity in plasma (TFosm/Posm > 1.0). This makes urine hypertonic.
Thick ascending limb (TAL) of the Loop of Henle
The thick ascending limb (TAL) of the Loop of Henle is impermeable to water, but allows reabsorption of: Na+, K+ (or NH4+), Cl-, Ca2+, Mg2+. Reabsorption of ions in the thick ascending limb is facilitated by an active Na-K(NH4)-2Cl co-transporter (NKCC symporter) within the luminal membrane. NH4+ competes with K+ for reabsorption by this transporter. Reabsorption of ions, but not water, results in dilution of the tubular fluid, making the fluid osmolarity decrease to less than the osmolarity in plasma. K+ leak channels allow K+ to leak into the tubular lumen of the ascending limb, thereby generating an electrochemical potential gradient that drives further reabsorption of the following cations: K+, Mg2+, Ca2+. 10-20% of Na is reabsorbed here.
Distal convoluted tubule (DCT)
The distal convoluted tubule (DCT) reabsorbs of NaCl by an NaCl co-transporter, making the tubular fluid here becomes hypotonic. The distal convoluted tubule is lined by simple cuboidal cells with NO brush border. Increased sodium absorption in the late distal convoluted tubule and collecting ducts is mediated by aldosterone. The distal convoluted tubule (DCT) is the site of action for PTH-driven Ca2+ reabsorption in the kidney. In the nephron, PTH acts at the proximal convoluted tubule to decrease phosphate reabsorption and at the distal convoluted tubule to increase calcium reabsorption. 5-10% of Na is reabsorbed here.
Collecting tubules
The collecting tubules are the final branch of the nephron consisting of two cell types: principal cells and intercalated cells.
Principal cells
Principal cells, located in the collecting tubules, reabsorb Na+ and H2O and secrete K+. Principal cells are sites of aldosterone and antidiuretic hormone (ADH) action. Aldosterone increases Na+ reabsorption [via epithelial sodium channel (ENaC)] and K+ secretion [via renal outer medullary potassium channel [ROMK)] in principal cells. Antidiuretic hormone (ADH) acts at the V2 receptor on principal cells to activate the adenylyl cyclase-cAMP pathway, thereby stimulating the insertion of aquaporin-2 (AQP2) channels into the apical plasma membrane. The majority (90%) of cases of hereditary nephrogenic diabetes insipidus are caused by a mutation in the V2 receptor, rendering it unable to stimulate adenylyl cyclase.
Intercalated cell
There are two types of intercalated cell located in the collecting tubules: alpha-intercalated and beta-intercalated. Activity of these cells plays a major role in acid-base homeostasis.
Alpha-intercalated cells
Alpha-intercalated cells, located in the collecting tubules, secrete H+ (and reabsorb K+) via an apical H+/K+-exchanger as well as an H+-ATPase. Alpha-intercalated cells also reabsorb bicarbonate by a basolateral Cl-/HCO3- exchanger. Aldosterone acts at alpha-intercalated cells to increase H+ secretion by stimulating the H+-ATPase. Under conditions of K+ depletion, reabsorption of K+ by alpha-intercalated cells predominates over K+ secretion by principal cells, resulting in net K+ reabsorption. Under conditions of K+ surplus, K+ secretion by principal cells predominates over K+ reabsorption by alpha-intercalated cells, resulting in net K+ secretion.
Beta-intercalated cells
Beta-intercalated cells, located in the collecting tubules, secrete HCO3- (and reabsorb Cl-) via an apical Cl-/HCO3- exchanger. Beta-intercalated cells also reabsorb H+ by a basal H+-ATPase.
Renal tubular defect
The kidneys put out FABulous Glittering LiquidS. FAnconi syndrome is the 1st defect (PCT). Bartter syndrome is next (thick ascending loop of Henle). Gitelman sindrome is after Bartter (DCT). Liddle syndrome is the last (collecting tubule). Syndrome of apparent mineralocorticoid excess (collecting tubules).
Fanconi syndrome
This is a generalized reabsorption defect in the PCT. It is associated with increased excretion of nearly all amino acids, glucose, HCO3, and PO4. It may result in metabolic acidosis (proximal renal tubular acidosis). Causes include hereditary defects (eg Wilson disease, tyrosinemia, glycogen storage disease), ischemia, multiple myeloma, nephrotoxins/ drugs (eg expired tertracyclines, tenofovir), lead poisoning.
Bartter syndrome
Reabsorptive defect in the thick ascending loop of Henle. It is autosomal recessive. It affects Na/K/2Cl cotransporter, resulting in hypokalemia and metabolic alkalosis with hypercalciuria.
Gitelman syndrome
It is a reabsorptive defect of NaCl in the DCT. It is autosomal recessive. It is less severe than Bartter syndrome. It leads to hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria (Bartter leads to hypercalciuria).
Liddle syndrome
It is a gain of function mutation that increases Na reabsorption in the collecting tubules (by increasing the activity of epithelial Na channel). It is autosomal dominant. It results in hypertension, hypokalemia, metabolic alkalosis, and a decrease in aldosterone. Treatment is amiloride.
Syndrome of apparent mineralocorticoid excess
This is a hereditary deficiency of 11 beta-hydroxysteroid dehydrogenase, which normally converts cortisol into cortisone in mineralocorticoid receptor-containing cells before cortisol can act on the mineralocorticoid receptors. Excess cortisol in these cells from enzyme deficiency, causes an increase in mineralocorticoid receptor activity, leading to hypertension, hypokalemia, metabolic alkalosis. There are low serum aldosterone levels. This disorder can be acquired from glycyrrhetic acid (present in licorice), which blocks activity of 11 beta hydroxysteroid dehydrogenase.
Relative concentrations along proximal convoluted tubules
TF/P= Tubular fluid/ Plasma. When TF/P is greater than 1, solute reabsorption is slower than water, causing net secretion (PAH and cretinine fall in this category). When creatinine. When TF/P=1, solute and water reabsorption is at the same rate (insulin falls in this category). When TF/P is less than 1, solute is reabsorbed more quickly than water, leading to net reabsorption (amino acids, electrolytes and urea fall in this category). Tubular insulin increases in concentration (but not in amount) along the PCT as a result of water reabsorption. Cl reabsorption occurs at a slower rate than Na in early PCT and then matches the rate of Na reabsorption more distally. This, its relative concentration increase before it plateaus.
Macula densa
Macula densa provide signal for the juxtaglomerular apparatus (JGA) smooth muscle cells to secrete renin.
Renin
Renin (also known as angiotensinogenase) circulates in blood to cleave a plasma alpha globulin, angiotensinogen (made in the liver) to angiotensin I.
Angiotensin I
Angiotensin I is cleaved by angiotensin-converting enzyme (ACE) to Angiotensin II. ACE is primarily secreted by lung and kidney vascular endothelium.
Angiotensin II (AT II)
Actions of angiotensin II (AT II): 1. Potent vasoconstriction (via angiotensin II receptor, type 1 (AT1) on vascular smooth muscle) causing an increase blood pressure. 2. IncreasedNa+/H+ exchange and HCO3- reabsorption in proximal tubule. This is the mechanism of contraction alkalosis. 3. Increased release of aldosterone causing increased intravascular volume. 4. Increased release of ADH causes increased intravascular volume. 5. Stimulates hypothalamus to increased thirst sensation. 6. Increases the filtration fraction (FF) by constricting the efferent arteriole of the glomerulus, thereby increasing the GFR and decreasing RPF. This protects the kidney in states of volume depletion. 7. Modulates baroreceptor function to limit reflex bradycardia, which is a normal response to AT II-induced vasoconstriction.
Juxtaglomerular apparatus (JGA)
The stimulus for renin release is the juxtaglomerular apparatus (JGA) perception of: Decreased renal blood pressure, Decreased NaCl delivery to distal tubule sensed by the macula densa, Increased sympathetic tone. Technically, only the delivery of Cl- is sensed by the macula densa. However, Na+ and Cl- usually travel together, so Cl- delivery can be considered a proxy of Na+ delivery to the distal convoluted tubule. Renin is produced by juxtaglomerular cells of the juxtaglomerular apparatus. Juxtaglomerular cells are modified smooth muscle cells found in walls of the afferent arterioles.
ANP
ANP is a potent vasodilator, which relaxes vascular smooth muscle by increasing intracellular cGMP. ANP dilates the afferent glomerular arteriole while constricting the efferent glomerular arteriole, thereby increasing GFR. ANP inhibits the reabsorption of NaCl via cGMP-dependent inhibition of Na+ reabsorption in the inner medullary collecting duct and Cl- in the cortical collecting duct. ANP reduces renin and aldosterone secretion.
BNP
It is also a potent vasodilator with the same mechanism as ANP but it is released by the ventricle. Nesiritide is a recombinant form of BNP used for the treatment of heart failure.
ADH
Primarily regulates osmolarity. It also responds to low blood volume states. It is secreted in response to increased plasma osmolarity and decreased blood. volume. It binds to receptors on principle cells, causing an increased in number of aquaporins and increased H2O reabsorption.
Aldosterone
Primarily regulates ECF volume and Na content. It responds to low blood volume states (via AT II) and increase plasma concentration. It causes an increase in Na reabsorption, increases K secretion, and increases H secretion.
Erythropoietin
It is released by interstitial cells in the peritubular capillary bed of the kidney in response to hypoxia
1 alpha-hydroxylase
Located in the PCT cells and converts 25-OH vitamin D to 1, 25-(OH)2 vitamin D (active form). It is activated by PTH.
Renin
It is secreted by JG cells in response to decreases renal arterial pressure and increased renal sympathetic discharge (beta 1 effect).
Prostaglandins
Paracrine secretion from vasodilates the afferent arterioles to increase RBF. NSAIDs block renal-protective prostaglandin synthesis causes constriction of afferent arteriole and a decrease in GFR. This may result in acute renal failure.
Parathyroid hormone (PTH)
It is secreted in response to decreased plasma Ca concentration, increased plasma PO2 concentration, or decreased plasma 1, 25 (OH)2 D3 production (increasing Ca and PO4 absorption from gut via vitamin D).
Hyponatremia
Causes nausea and malaise, stupor, coma, seizures
Hypernatremia
Causes irritability, stupor, coma.
Hypokalemia
Causes U waves on ECG, flattened T waves, arrhythmias, and muscle spasm.
Hyperkalemia
Wide QRS and peaked T waves on ECG, arrhythmias, and muscle weakness.
Hypocalcemia
Causes tetany, seizures, GT prolongation
Hypercalcemia
Causes stones (renal), bones (pain), groans (abdominal pain), thrones (increases urinary frequency), psychiatric overtones (anxiety, altered mental status), but not necessarily calcuria.
Hypomagnesia
Causes tetany, torsades de pointes, hypokalemia.
Hypermagnesia
Causes decreased deep tendon reflex, lethargy, bradycardia, hypotension, cardiac arrest, hypocalcemia
Hypophosphatemia
Causes bone loss, osteomalacia (adults), rickets (children)
Hyperphosphatemia
Causes renal stones, metastatic calcifications, hypocalcemia.
Causes of potassium shifts out of the cell (causing hyperkalemia)
Digitalis (blocks Na/K ATPase), hyperOsmolarity, Lysis of cells (eg crush injury, rhabdomyolysis, cancer), Acidosis, Beta blocker, high blood Sugar (insulin deficiency). Patients with hyperkalemia? DO LABS.
Causes of potassium shifts into the cell (causing hyperkalemia)
Hypo-osmolarity, alkalosis, beta-adrenergic agonist (increased Na/K ATPase), insulin (increased Na/K ATPase). INsulin shifts K INto cells.
Metabolic acidosis
Metabolic acidosis is defined as an acidotic pH (over 7.37) with a decrease in HCO3- levels. Causes of metabolic acidosis are separated into two categories: increased anion gap and normal anion gap. In metabolic acidosis, pH is decreased, PO2 is decreased, HCO3 is decreased. Compensatory response is hyperventilation (immediate), causing PCO2 to be less than 40 mmHg. Metabolic acidosis can be broken down into anion gap (AG) and non-anion gap acidosis.
Increased anion gap metabolic acidosis
Anion gap calculation: AG (mEq/L) = [Na] – ([Cl] + [HCO3]). Normal = 10-15 mEq/L. Causes of anion gap metabolic acidosis include: Ketoacidosis (starvation, DKA, alcohol use), Exogenous toxins (methanol, ethylene glycol, salicylates), Lactic acidosis (ischemia, shock), Renal failure (decreased NH4+ excretion), Significant uremia, Drugs: paraldehyde, INH. Useful Mnemonic: MUDPILES (Methanol, Uremia, DKA, Paraldehyde, INH, Lactic acidosis, Ethylene glycol, Salicylates)
Normal anion gap metabolic acidosis
Normal anion gap is 8-12 mEq/L causes include (HARD-ASS): Hyperalimentation, Addison disease, Renal tubular acidosis, Diarrhea, Acetazolamide, Spironolactone, Saline infusion.
Winters formula
Winters formula is used to evaluate respiratory compensation in the presence of a metabolic acidosis. If the patients Pco2 differs significantly from the Pco2 predicted by the formula, a mixed acid-base disorder is present: Pco2 = 1.5 [HCO3-] + 8 ± 2
Metabolic alkalosis
Metabolic alkalosis is defined as a serum pH over 7.43 with an increase in serum HCO3- levels. PCO2 is increased, HCO3 is increased. The compensatory response is hypoventilation, leading to a PCO2 over 40 mmHg. Causes include loop/thiazide diuretics, vomiting, antacid use, and hyperaldosteronism.
Henderson-Hasselbalch equation
The Henderson-Hasselbalch equation is used to calculate pH: pH = pK + log {[A-] / [HA]}. Where: [A-] = base form of buffer (mM)/H+ acceptor; [HA] = acid form of buffer (mM)/H+ donor. pH = pK when the concentrations of A- and HA are equal. Using the Henderson-Hasselbalch equation, plasma pH can be determined: pH = 6.1 + log [HCO3-]/[0.03xPCO2]. Where: 6.1 is the pKa for carbonic acid 0.03 is the factor that relates PCO2 to the amount of CO2 dissolved in plasma
