Bennie Berkvens
Renal/Male Repro
ICS 2009
ICS Objectives for Renal and Male Repro-2009-2010
The parts of the syllabus containing the Cases (ICS) we covered in conferences will have the (case # and conference #) in green.
Normal Values of Laboratory Tests & Renal Physiology (pgs 1-2)-Kasinath
Renal Physiology (pgs 3-18)-Kasinath
1)overview of the functions of the kidney
1) Excretion of: waste products, acid, water
2) Reabsorption of: solutes, bicarbonate, water
3) Secretion of substances: Uric acid, Penicillin, Salicylates
4) Endocrine Functions: secretion of EPO and rennin, conversion of 25(OH) vit D3 to 1:25(OH)2 vit D3
2)Process and regulation of glomerular filtration
Ultrafiltration of plasma at the glomerulus-glomerular capillary wall has size-selective and charge selective barrier preventing loss of plasma proteins. (nl protein excretion~150mg/24hrs)
Clearance: UV/P (U=[urinary] V=volume of urine P=[plasma])= volume of plasma from which the substance is totally removed by glomerular filtration. According to the definition then, the amount excreted (UxV)= amount filtered (PxC)
Transcapillary hydrostatic pressure difference: ∆P=Pgc-Pt (gc=glomerular capillary t=tubule)
Transcapillary oncotic Pressure difference: ∆∏=∏gc-∏t
SNGFR= ∆P-∆∏
GFR decreased by: ↓ capillary wall area or permeability (glomerulonephritis), Hypotension (↓Pgc↓ sngfr), Obstructive uropathy (↑Pt↓sngfr), ∆vascular resistance or RPF ∆Pgc∆SNGFR
RPF: 25% of CO per minute. Kept stable by autoregulation,
FF: proportion of RPF that forms the glomerular filtration rate=GFR/RPF x 100 (nl 20-25%)
3)Endocrine functions of the kidney including the renin-angiotensin system
EPO: secreted by tubulointerstitial cells ↑ RBCs
25(OH) vit D3 converted to 1:25 (OH)2 vit D3 by proximal tubules ↑ absorption of Ca and Phosphorous in the gut
RAAS system: juxtaglomerular apparatus includes renin secreting juxtaglomerular cells in the afferent arterioles, extraglomerular mesangial cells, and columnar epithelial cells of distal tubule.
Renin (RAAS): converts (cleaves) angiotensinogen to angiotensin I. ACE removes 2 AA from ATI to form ATII. ATII vasoconstrictor ↑ BP. Also ATII stimulates secretion of aldosterone and direct stimulation of Na transport in the early PT Na Reabsorption followed by H20 reab (so no overall change in [Na]↑BP. ATII causes ↑ADH release, and ↓ GFR causing ↑ Na reab.
Aldosterone:↑ Na and K channels in collecting duct ↑ reab of NaCl and secretion of K (↑ plasma K+ causes aldo release).
4)Physiologic handling of Na by the kidney
Proximal Tubule: Nearly 65-70% of filtered Na and H2o are reabsorbed here. Pay attention to the Na-H+ exchanger-isoform 3 (antiporter).
Loop of Henle:active and passive Na and Cl Reabsorption. ~25% of Na reabsorbed here. Transport via the electroneutral Na+, K+, 2CL- transporter. Descending limb is not permeable to Na so filtrate gets concentrated. The ascending limb less permeable to H2o so filtrate becomes diluted (50-60mOsm) compared to plasma (300mOsm) “major diluting segment” (loop diuretics: furosemide work here)
Distal Convoluted Tubule: 5-8% of Na Reabsorption in electroneutral manner by NaCl co-transporter. Relatively H2o impermeable. (thiazide diuretics acting on the NaCl transporter work here).
Collecting Tubules: 2-5% of Na reab. Final site of Na regulation, Contain principal cells and type A and B intercalated cells. Principal cells are sensitive to mineralocorticoid and aldosterone (1)↑ Na reab via ENaC (principal cells) 2)↑ Na-K ATPase in basolateral membrane (principal cells) 3)↑ K secretion by principal cells by K channel in apical memb (principal cells) 4) ↑ secretion of H+ by ↑ H+ATPase in apical memb (type A intercalated cells) (spironolactone, triamterene, and amiloride interfere w/ Na Reabsorption here)
Urinary [Na] <20mEq indicates need for Na conservation by the kidney. Prerenal azotemia (<20-kidney function is normal) Acute Tubular Necrosis (Na >20)-direct damage to the kidney.
5)Physiologic handling of H2o by the kidney
Kidney is the major water regulator of TBW content.
Urinary dilution requires: 1) Adequate GFR 2) Intact function of the water-impermeable “diluting segment” 3) ADH secreted by the supraoptic and paraventricular nuclei of the hypothalamus. (binds V2 recepror in collecting duct basolateral membrane Camp releaseact PKAphosphorylation of aquaporin 2 fuses w/ apical membraneH20 reabsorption. In absence of ADH the collecting duct is impermeable to H20dilute urine (minimal urine osmolality is 50-60mOsm/kg)
Diabetes Insipidus: lack of ADH action. Central DI: Lack of ADH production. Nephrogenic:resistance of renal tubules.
6)Overview of urinary acidification
RTA type I: inability to generate steep H+ gradient in distal tubuleshypokalemia and ↓ ammonium secretion, and hyperchloremic metabolic acidosis. (Sjogrens, SLE, Ampho-B)
RTA type II abnormal H+ secretion in Proximal tubulesimpaired reab of filtered HCO3maximally acidified urine in academia, hypokalemia, Hyperchloremic metabolic acidosis. (acetazolamide, MM, Wilsons disease)
7)Short review of handling of Ca and K by the kidney
Calcium: either ionized, complexed w/ ions, or protein bound (not filtered). Nearly 70% reab in PT and 20% in TAL. Reab is passive and dependent on Na reab. 5-10% reab in DT by active process tim by PTH and Vit D.
Potassium: freely filtered and 90% reab by PT & ascending loop. Reab not regulatable so excess K gets secreted in CD and is controlled by aldosterone.
Sodium Metabolism (pgs 19-40)-Abboud
1)Body fluid compartments, normal Na end ECV and the concept of effective arterial blood volume (EABV)
Na is the main solute in the ECF (2550meq) while K is the main solute in the ICF (4500meq). These are maintained by Na-K-ATPase. Na is the main osmotically active solute and therefore dictates H2o distribution between ICF and ECF. Electrolyte free water expands both ICF and ECF (2/3 and 1/3 respectively)whereas giving isotonic saline (.9% nacl) will only expand the ECF. Giving .45% saline (.5L isotonic + .5L H20) will result in .67L ECF ↑ (.5 isotonic + .33 of the .5L free h20) and .33L ICF ↑ (.66 of .5L free h20).
Increasing Na content in ECF causes fluid accumulation in: interstitial space (edema), peritoneal space (ascites), and pleural/pericardial spaces (effusions)
EABV: (unmeasurable) part of the ECF that is in the arterial system and actively perfusing tissues. It is a reflection of 1) absolute plasma volume (intravascular volume) 2) CO 3) Arterial BP (systemic vascular resistance) 4) neural and endocrine factors that govern 1-3. It varies directly w/ ECF volume and Na content. In CHF there is a ↓EABV independent of ECF volume because ↓ CO causes Na retention↑ plasma and total ECF volume.
A ↑ in EABV causes Na excretion by the kidney whereas a ↓ in EABV causes Na conservation.
In Cirrhosis there is a ↑ in ECF including plasma volume and CO is often elevated, yet most of the fluid is ascites and is hemodynamically ineffective. Behave as if they are volume depleted.
Urea exists in equal concentration in both ICF and ECF so does not influence water movement.
2)The physiological responses to low and high Na intake, renal handling of Na through glomerular filtration and tubular Reabsorption and the systemic and renal responses to changes in Na intake and/or ECF volume.
Abrupt High Na intake: enhanced Na excretion which lags several days before excretion rises to levels on increased intake so there is retention of some excess Na. This causes a ↑ in ECF volume. Fig 8-p26
Abrupt Low Na intake: the opposite is true. There is a ↓ in Na excretion that requires several days to adjust to levels of intake resulting in Na wasting. This causes a ↓ in ECF volume. Fig 9-p26
Low pressure Sensors: Low pressure/high volume. Cardiac atria, pulmonary vasculature. ↑ intravascular volume↑ atrial natriuretic peptide & ↓ SNS activityenhanced Na excretion.
High Pressure Sensors: arterial side of circulation. Carotid sinus and aortic arch. ↓ arterial pressure↑ renal SNS Na retention.
Juxtaglomerular apparatus: ↓ wall tension in afferent arteriole or ↓ salt delivery in the macula densa renin secretion
Normal daily Na intake ~150mEq and about 140mEq is excreted by the kidney, and 5 mEq by stool and 5 by sweat. About 25000 mEq is filtered per day (so <1% is excreted).
Atrial Natriuretic Peptide: released from atria in response to stretch from volume expansion. It’s a vasodilator lowering systemic BP, and it ↑ urinary Na and H20 excretion suppresses release of renin and Aldosterone from the adrenals.
(Case 1, Conference 1)
3)Hypovolemic and Hypervolemic disorders
Assessment of total body Na content or volume status is based on clinical criteria and Cannot be estimated from plasma [Na].
“effective” arterial Hypovolemia: ECF volume overload causing edema as seen w/ CHF and Cirrhosis. Expansion of interstitial space w/ an intravascular volume depletion (capillary leak syndrome or severe hypoalbuminemia).
Na depletion: prerenal azotemia (BUN/creatinine ratio >20:1) and hyperuricemia. When renal losses are not the cause we see oliguria, low urine Na, and concentrated urine).
ECF volume Overload:Edema. Signs of LV overload (↑ JVP and distension), S3 gallop and pulmonary edema.
1) CHF(Case 2, Conference 1) (↑ Na reab to ↑ ECF volume↑CO) 2) Nephrotic Syndrome (inability to excrete NaTX w/ Na restriction) 3) Hepatic cirrhosis (↑ intrahepatic pressure stimulates Na reab directly or by causing vasodilation) 4) Renal Failure ( ↓ functioning nephrons ↓GFR↓ Na excretion).
ECF volume overload w/ intravascular volume depletion: 1) Capillary leak syndrome (edema w/ findings of IV volume depletion due to toxic insults or damage to capillary endothelium) 2) Severe Hypoalbuminemia (↓ oncotic pressure causes fluid shift from Intravascular to interstitial space).
ECF volume depletion: tachycardia, postural hypotension, dry mucous membranes, skin tenting. 1) renal Na losses (urine Na >20 w/ signs of ECF contraction)-most commonly caused by diuretics or diuresis caused by hyperglycemia. 2) Extrarenal Na losses-vomiting or diarrhea, burns, exercise, hot climates. Volume depletion may also be caused by hemorrhage.
Water Metabolism I-Hyponatremia-(pgs 41-50)-Nolan
1)Understand the fundamental difference total body Na and TBW
Serum Na provides no information on absolute amounts of Na or water in body fluids.
TBNa: determines volume status (ECF volume). ECF depletion means deficient TBNa, and fluid overload excess TBNa.
TBH2o: determines osmolality ([Na] dissolved in ECF). Hyponatremia (Na <135)=excess H2O relative to Na, Hypernatremia (Na>145)=deficient H2o. Since Na is the main cation in ECF, serum [Na] is an indirect measure of the osmolality of all body fluid compartments.
2)Understand that pure excess of TBW does not cause fluid overload
Excess of TBW leads to hyponatremia but no fluid overload.
2/3 of TBW is ICF and 1/3 is ECF. Of the 1/3 ECF, ¾ is interstitial fluid and ¼ is Intravascular fluid. So only 1/12 of TBW is in the vascular space. This means that only 1/12 of every liter of free water put into the body increases the intravascular volume.
So basically, the distribution of TBW explains why TBW content determines osmolality of body fluids but does not determine volume status.
3)Etiologies and mechanisms of impaired free water clearance in 3 categories of hyponatremia.
Hyponatremia means the ECF osmolality is ↓ (more water content compared to Na). this causes water movement and shift from ECF to ICF cellular swelling. (GI-nausea, vomiting, anorexia. CNS-altered mental status, seizures, coma)
First step in hyponatremia is determining volume status.
Hypovolemic Hyponatremia: ↓↓TBNa/↓TBH2o. TX volume repletion w/ normal saline decreases stimulus for ADHcan now excrete excess water to correct hyponatremia. (hypovolemia is the underlying stimulus for ADH secretion in this category)
Extrarenal:Una or Ucl <10mEq/L. vomiting, nasogastric suction (Una high b/c dumping of NaHCO3 as result of met alkalosis), blood loss, diarrhea, blood loss, sweating, burns. Bowel obstruction, Rhabdomyolysis, pancreatitis (all 3 cause sequestration)
Renal: Una and Ucl >20mEq/L. Diuretic use, Addison’s disease (impaired mineralocorticoid -aldo release) (case 2 conference 2), acute/chronic interstitial nephritis (renal NaCl wasting).
Euvolemic Hyponatremia: NL TBNa/↑↑TBH2o. urine [Na] >20. TX w/ fluid restriction to a level less then pts insensible water loss. (giving extra salt will only cause the Na to be excreted b/c the [Na] is already normal.
Causes: drugs that impair free water clearance by causing non-osmotic release of ADH ,or directly making tubules more permeable to water. Also, SIADH caused by CNS tumors, Lung disorders/tumors (oat cell)(case 1-conference 2), post-op pain, hypothyroid, glucocorticoid deficiency, psychosis.
Hypervolemic Hyponatremia:↑TBNa/↑↑TBH2o. inability of kidney to excrete salt and free water. TX: salt restriction and diuresis to ↓ excess TBna/ fluid restriction to fix excess TBwater.
Exra-Renal:(case 2, conference 1)CHF, Nephrotic syndrome, decompensated Cirrhosis. (in all cases there is ↓ EABV (by different mechanisms causing non osmotic ADH releaseimpaired free water clearance).
Renal: ARF, CRF. (Loss of functional renal mass).
In all 3 cases there is no sign of fluid overload because although there is ↑ in free TBH2o, only 1/12th of it is intravascular.
4)Know causes of hyponatremia with normal plasma osmolarity.
Hyperglycemia: measured serum [Na] is low b/c ECF glucose cannot get into the cell water shifts out of the cell and dilutes ECF Nahyponatremia. For every 100mg/dl that serum glucose is above nl the serum [Na] should drop by 1.6mEq/L. however, pOsm is either normal or high.
Mannitol: (similar mechanism as hyperglycemia). Large amounts of IV contrast. Hyperlipidemia and hyperproteinemia.
5)Know how to use osmolar gap in the DX of methanol, ethylene glycol, and isopropyl alcohol intoxication.
pOsm=2[Na] + Glucose/18 + BUN/2.8 + EtOH/4.6
osmolar gap=difference of measured and calculated pOsm of >10.
Osmolar gap not elevated in salicylate, or sedative-hypnotic overdose (large MW compounds).
Disorders of Urinary Concentration—Polyuria and Hypernatremia (pgs 51-58)-Nolan
1)Understand the urinary concentrating mechanism (countercurrent multiplication) and the role of AVP and aquaporin-2 in urinary concentration.
Reabsorption of NaCl in the TAL of the loop of Henle generates a hypertonic interstitial osmotic gradient where there is 200mOsm difference b/t the intra-tubular and interstitial fluid.
When there is water deprivation there is a release of ADH which causes tubular fluid to become more concentrated.
AVP: produced by supraoptic and paraventricular nuclei in hypothalamus. Regulated by plasma osmolality and intravascular volume and EABV. Releaseact on V2 receptor on basolateral membraneinsertion of AQP2 into apical membrane of collecting ductwater enters the cell and is able to cross the basolateral membrane through the AQP3 and AQP4 water channels water Reabsorption.
2)Learn the etiologies and underlying pathophysiology of central and nephrogenic DI
Central DI: is a disorder of urinary concentration causes by inadequate production of ADH (↓) by the hypothalamic-pituitary axis—AQP2 in collecting ducts is ↓ impaired urinary concentration and ↑ polyuria with polydipsia to compensate for excessive urinary loss of water. (massive polyuria >12-15L w/ Uosm ~50). Causes: AD central DI, traumatic, idiopathic, iatrogenic, neoplasms, sarcoidosis, eosinophilic granuloma.
Nephrogenic DI: appropriate ADH release in response to ↑ pOsm, but failure of collecting ducts to respond. Causes: congenital (Xlinked recessive-mutation in V2 receptor.)(Autosomal recessive-mutation in AQP2)- Uosm~50mOsm-unresponsive to exogenous AVP.
3)Know how to use classical osmolar clearance and free water clearance formulae to determine whether polyuria is due to osmotic diuresis, water diuresis, or both.
Osmotic diuresis: (case 4 conferencce 2)↑ in obligatory water loss secondary to ↑ urinary solute excretion. DM most common-(glycosuriawater excretion), non-resorbable solutes (mannitol, urea, radiocontrast agents).
DX: if significant polyuria is present (urine output >3L/day) and the Uosm is above 300. Urinary Na is usually >50-70mEq and the Fractional excretion of Na (FEna=(Una/Pna)/(Ucreat/Pcreat) x 100 is >1% (in nl individuals and those w/ DI it is usually <1%). Also, solute excretion rate will be well in excess of the normal 600mOsm/day.
Osmolar clearance: >3ml/min in osmotic diuresis, whereas normal is 1.4ml/min (Cosm=Uosm x urine vol/ Posm x collection time)
4)Be able to use electrolyte-free free water clearance to calculate free water loss.
Daily urine output: Volume needed to excrete normal daily amounts of Na (150mEq) + electrolyte free water (in excess of normal)
Clearance of electrolytes (CLelect)= (2[Una+Uk] x urine volume)/(pOsm x collection time)
Free water clearance (Ch2o)=urine volume-CLelect
5)Understand the 3 categories of Hypernatremia.
↑ ECF [Na] water moves from ICF to ECFcell shrinkage (CNS restlessness, irritability, lethargy, mental status changes, seizure, coma. Correct slowly!! (rapid correction can cause cerebral edema)
Hypovolemic Hypernatremia: ↓TBna/↓↓TBh2o TX saline for volume depletion, Water for hyper Na.
Extrarenal:Una or Ucl <10mEq/L. vomiting, nasogastric suction (Una high b/c dumping of NaHCO3 as result of met alkalosis), blood loss, diarrhea, sweating, burns. Bowel obstruction, Rhabdomyolysis, pancreatitis (all 3 cause sequestration)
Renal: Una and Ucl >20mEq/L. Diuretic use, Addison’s disease, acute/chronic interstitial nephritis (renal NaCl wasting).
Euvolemic Hypernatremia:NL TBna/↓↓ TBh2o TX water replacement to slowly correct hypernatremia.
Causes: Renal losses (Central/Nephrogenic DI(Case 3 conference 2)) Extra-renal: unreplaced respiratory and dermal insensible losses of free water.
Hypervolemic Hypernatremia: ↑↑TBna/↓TBh2o TX diuretics and Salt restriction for fluid overload, water for Hypernatremia.
Causes: inadequate replacement of resp and dermal losses of hypotonic fluid, hypertonic dialysate, hypertonic NaHCO3 admin, NaCl tablets.
Potassium Physiology and Disturbances (pgs 59-70)-Fanti
1)Understand the mechanisms by which K shifts in and out of cells to include hormonal and pH changes.
Of the total body K (3500mEq) 90% is IC, 8% is in bone/cartilage, 2% EC.
Insulin and B2-adrenergic agonists (albuterol) increase cellular uptake of K by stimulating Na/K ATPase.
Metabolic acidosis causes H+ to shift from EC space into cells in exchange for K+ (hyperkalemia). Metabolic alkalosis causes the reverse.
K+ is 90% reab in PT. 5-10% reaches DT & CD. In the ladder, Principal cells are responsible for K secretion and intercalated cells are responsible for K Reabsorption. Secretion is regulated by (1) aldosterone (stim Na/K ATPase on basolateral memb and ENaC on apical membrane) (2) High dietary intake (stim ROMK and BK channels on principal cells, and on intercalated cells inhibits apical entry and stimulated apical secretion-p-60) (3) Urine Flow (4) Na delivery to distal segments (5) ECF pH (6) Serum K levels (7) concentration of impermeable anions (HPO4- and SO4- (making lumen more electronegative favoring K secretion).
2)Describe how K moves along the nephron. Understand how urinary flow, urine pH, electrical neutrality, Na delivery to distal tubule, dietary K intake, and different hormonal mechanisms play a role in K Reabsorption and excretion.
3)Understand nephrogenic effects of different drugs on K Reabsorption or excretion
4)Understand the mechanisms which can cause hypokalemia-specifically K loss through the nephron.
Serum K <3.5 mEq/L
In Hypokalemia we see ↓ amplitude of T wavesand prominent U waves (these may be followed by cardiac arrythmias and death).
Redistribution: from EC to IC space. Due to alkalemia, selective B2 agonists (epinephrine, albuterol), or insulin (p.59)
Total Body Depletion:
Extra-Renal:24hr specimen. K<30mEq/day in presence of >50mEq/day of Na. (diarrhea, burns, poor intake)
Renal: K>30mEq/day then renal cause is suspected. (excessive Aldosterone, diuretics-HCTZ (case 3 conference 1), renal tubular acidosis, excess anions (penicillin), aminoglycoside antibiotics (gentamicin, tobramycin), High urine flow rates (primary polydipsia), Liddles syndrome( enhanced tubular absorption of Na in CCTK secretion), Bartter’s syndrome (defect in Na/K/2CL in TALwasting and activation of aldosterone secretion).
TX. Ideally slow replacement per os. Since distribution goes to ECF first followed by ICF, a high dose could cause fatal cardiac arhythmias.
5)Understand mechanisms which may result in hyperkalemia.
Serum [K] >5.5mEq/L levels >6 are medical emergencies. Early cardiac changes (peaking of T waves, prolongation of PR interval). Very high K level (widening of QRS complex, loss of P wave, onset of Sine wave pattern and chaotic wave pattern (v fib).