RENAL ANATOMY

General: Outer cortex with inner medulla containing the pyramids Glomerulus (located in the cortex and contained w/I Bowman's capsule) - site of most filtration Collecting system: drains to calyx >> renal pelvis to ureter Kidney is major site of EPO production Nephron: glomerulus + tubule structure Some glomeruli at the juxtamedullary region

Innervation: sympathetic stimulation >> release of renin from juxtaglomerular cells >>Angiotensin & aldosterone production Blood supply:from main renal artery (branch of aorta) Baroreceptors Afferent arteriole >> glomerular capillaries >> efferent arterioles >> form hairpin loops called vasa recta that extend deep into medulla >> venous circulation Coretx has high blood flow >> greatly diminishes as vasa recta descends into medulla Juxtagomerular apparatus: macula densa (portion of distal convoluted tubule) MD cells sense solute concentration of ultrafiltrate juxtaglomerular cells communicate with MD >> receive sympathetic innervation >> Can make renin & Angiotensin AND cause vasoconstriction of arterioles Corticomedullary osmotic gradients: (300 in cortex >> 1200 in medulla) Established via: 1. Na/K/2 Cl transport into water impermeable TAL then interstitium 2. Reabsorption of urea in CCD in presence of ADH 3. Slow blood flow through medulla >> removal of solutes minimized Proximal Tubule: Nephron segments: Primary function is isoosmotic reabsorption of glomerular ultrafiltrate (2/3rd) Bowmans capsule Reabsorption: Sodium Water Cl Bicarb Calcium PT - Proximal tubule Amino acids, glucose and PO4 can also be cotransported with Na DTL - Descending thin limb 3Na/ 2K+ ATP ase in basolateral membrane sets up ionic gradient ATL - Ascending thin limb Secreted: Ammonia, and H+ TAL - Thick ascending limb MOI: Na+/H+ antiporter - Na reabsorption, H+ secretion DT - Distal tubule Bicarb + H+ CO2 + H20 via carbonic anhydrase (CA inhibited by diretics) Passive water reabsorption CCD - Cortical collecting duct Passive salt reabsorption IMCD Inner Medullary collecting duct Active NaCl and K absorption Impermeable to water >> luminal fluid hypotonic PTH stimulates rate of Calcium reabsorption MOI: Na/K/2 Cl symporter Rom K K+ channel >> K+ secretion >> (+) lumen potential >>Ca+ and Mg+ reabsorption Site of loop diuretics Impermeable to Water Active NaCl reabsorption (symporter) K secretion Ca+ reabsorption Symporter blocked by Thiazides Na, K & H20 channels K+/H+ pump K secretion K secretion further stimulated by Aldosterone H+ secretion & bicarb reabsorption Negative lumen potential due to more Na reabsorbed than K being secreted Acts on CCD and IMCD >> insertion of water channels into principle cells ADH increases reabsorption of urea

DTL: ATL: TAL:

DT:

CCD:

ADH: Vitamin D: Renin:

requires two hydroxylations to become hormone that regulates interstitial calcium reabsorption One of these occurs in proximal tubule Hydroxylation stimulated by PTH and low phosphate From JGA cells >> ultimately to AII >> vasoconstriction, Na reabsorption in PT, Na reabsorption in DT (Aldosterone), h20 reabsorption in CCD (ADH) Stimulus: 1.renal hypoperfusion in afferent arterioles 2. effective circ vol (barorecptors) >>sympathetic stim 3. NaCl sensed in macula densa cells

Vasoactive Substances
Vasoconstrictors: Angiotensin II: constriction in efferent arteriole > afferent arteriole NE/E: Stimulate constriction of afferent arterioles and inhibit filtrate production This stimulates macula densa cells and activates RAAS NE also binds to B receptors on juxtaglomerular cells >> renin secretion >> increase BP via RAAS Endothelium: **Most powerful** vasoconstrictor secreted by vascular endothelium and some tubule cells Vasodilators: Prostaglandins: PGE2 and PGI2 produced in kidneys in response to sympathetic stimulation & A II Nitric Oxide: Produced by vascular endothelium and acts locally Bradykinin: Increases GFR by stimulating release of NO a& prostaglandins Dopamine: secreted by proximal tubules >> increased renal blood flow and inhibiting renin secretion

Balance the in BP induced by NE and A II

Other Adenosine: In systemic system is a vasodilator, though causes renal vasoconstriction Atrial Natriuretic peptide: secreted by heart when BP is high >> vasodilation of afferent & vasoconstriction of efferent Overall effect is to slightly increase GFR Adenosine Triphosphate: ATP may either increase or decrease GFR depending upon conditions Glucocorticoids: As a therapeutic drug >> increases GFR Also produced by adrenal cortex as part of stress response Histamine: Local release increases renal blood flow w/o increasing GFR by resistance in both arterioles

GFR & Renal Plasma Flow

Autoregulation: GFR maintained within a wide range of blood flows (70 - 180 mm Hg) 1. Myogenic reflex (stretch receptors in afferent arteriole) renal perfusion >> stretching of afferent >> afferent constriction to prevent tx of high P to glomerular capillaries Fall in BP >> dilation of afferent and constriction of efferent by systemic rise in A II 2. Tubuloglomerular feedback Changes in NaCl delivery to macula densa control afferent arteriole tone in arterial P >> initial in GFR >> NaCl delivery to MD of DT >> results in constriction of afferent Normal GFR of 120 translates to an ultrafiltrate of 180 L/day 98% of this reabsorbed >> daily urine output of 1.5 - 2 L Afferent Constriction: Efferent Constriction: Results in decreased GFR and RPF Results in increased GFR and decreased RPF Renal Plasma Flow: 600 ml/min GFR: 120 ml/min Filtration Fraction (GFR/RPF) ~ 20%

GFR: Volume of fluid that passes from glomerular capillary space to Bowman's capsule per unit of time Measure of functioning renal mass Clinical Estimation of GFR: Relies on clearance (amount of plasma cleared by a substance For a given substance: Plasma clearance x plasma concentration must = urinary clearance x urinary concentration Ideal substance to measure GFR is one that can reach steady state in plasma (100% filtered - not metabolized, reabsorbed or secreted) Creatinine: produced by metabolism of creatine in skeletal muscle Not ideal b/c it is secreted by renal tubules and therefore overestimates GFR Need to be sure creatine is at a steady state for this to be useful parameter Late marker: Must have a large decrease in GFR before you see an increase in serum creatinine Cockrft - Gault Formula: Creatine Clearance ~ (140-age) x lean body wt (kg) / Plasma Cr (mg.dl) x 72 * Multiply by .85 in females MDRD Formula (Modification of Diet in Renal Dz): More accurate formula and what is used in clinic Based on Plasma Cr, age, gender, ethnicity, Bun & Albumin

Volume Disorders
General: We are 60% salt water - 40% ICF, 20% ECF 40% ICF ECF is primarily what changes 3/4 of ECF is interstitial space, 1/4 is plasma Barrier between ICF and ECF >> largely impermeable to solutes, more permeable to water
K+, Mg 2+ Phosphates (-) Proteins (-) Na+ ClCO3-

Osmolarity: # osmoles/L solute Osmolarity: # osmoles/kg solute Osmole: osmotic force generated/1 mole of solute 1 L H20 = 1 kg >> osmolarity & osmolality are used interchangeably Total Body fluid (TBF) osmolarity is tightly regulated by water intake & excretion ECF volume changes in parallel with total body sodium content & is regulated by renal sodium excretion

65%

35%

Response to water load: Low TBF osmolarity, low serum Na and High TBF volume ADH water excretion, TBF osmolarity and volume restored to nml Response to pure NaCl load: High ECF Osmolarity H20 moves from ICF to ECF High ECF volume/Low ICF volume & High TBF osmolarity ADH (& thirst) TBF osmolarity, serum Na and ICF volume normal High ECF volume/Na content Since TBF osmolarity (~ serum Na): Any alteration in Na content will result in proportional alteration in ECF volume ECF Vol/Na content: Sensed: Effective Vascular Volume or Effective Circulating Volume: art of ECF in the vascular space AND effectively perfusing the tissues P "fullness & pressure in arterial tree" Determined by ECF volume, CO and vascular tone Closely related to BP Sensor: Sensed by stretch receptors - not volume receptors Baroreceptors in carotid sinus, aortic arch and afferent glomerular arterioles Ex: decreased Na in take >> decreased intravascular volume (and effective arteriole volume) >> decreased stretch >> ACTIVATION Effector: Angiotensin II, Aldosterone, SNS & ANF >> in urine an excretion Na restriction >> Angiotensin II and SNS action Mechanisms to increase effective circulating volume: vasoconstriction, CO renal sodium reabsorption (water passively follows) renal water reabsorption (w/o Na) - not as good >> decrease in osmolarity/hyponatremia only happens in severe pathology to maintain ECF volume - ADH is activated non-osmotically SNS - venous & arterial constriction, CO, HR & contractility, renin secretion from kidney, Na reabsorption in PT >> Increased BP, renal blood flow & GFR Clinical dx of ECF: JVP - indicative of venous compartment of intravascular volume Orthostatic BP/HR - index of arterial volume Peripheral/pulmonary edema & ascites - excess of interstitial fluid volume & total ECF volume TBF Osmolarity/H20: Sensed: plasma osmolarity Sensor: osmoreceptors Effector: ADH >> urine osmalrity/H20 output & thirst/H20 intake Clinical dx: serum [Na] Serum an concentration not = Na content Can have Na & be volume depleted

Volume Depletion
Result from alterations in Sodium balance Hx: decreased PO intake increased fluid losses Causes: GI Losses: postural lightheadedness tired, lethargy PE: Decreased JVP Orthostatic hypotension & tachycardia Absent edema, decreased turgor

vomiting, NG suction diarrhea, ostomies, tube drainage bleeding Diuretics adrenal insufficiency NaCl wasting nephropathy

Renal:

Skin/ Insensible Respiratory: Sweat, fever Burns Bleeding 3rd space Sequestration: Abdominal pathology Crush injury Acute pancreatitis Edematous disorders - pathologic misdistribution of ECF volume overall ECF (Na & H20), effective arterial volume, interstitial or venous volume CHF, Cirrhosis & Nephrotic syndrome

Volume overload:
Volume overload:

CHF:

Filling Pressures >> sequestration of blood in venous compartment & mvmt of fluid from vascular to interstitial space (edema) CO >> effective arterial volume >> activation of SNS and RAAS >> renal Na retention Result: overall increase in ECF (volume overload) with a misdistribution of the volume intrahepatic and portal venous pressure >> sequestration of excess blood volume in splanchnic circulation & ascites Vasodilation (NO mediated) in splanchnic & peripheral circulations >> further sequestration and decreased effective arterial volume Hypoalbuminemia contributes to tendency to form peripheral edema ( plasma oncotic pressure) primary renal protein loss >> hypoalbuminemia >> misdistribution of ECF to interstitial space >> effective arterial vol & 2 renal Na retention hypoalbuminemia may also promote PRIMARY renal Na retention Result: Expanded total ECF volume/Na content - edema

Cirrhosis:

Nephrotic syndrome:

Rx:

Treat underlying disorder Na restriction in combo with diuretics

Na+ CO3-

35%

stored to nml

& tachycardia

2 renal Na retention

Acute Renal Failure

General: abrupt deterioration in the ability of the kidney to excrete nitrogenous waste Lab values lag behind the dz and may be unchanged for awhile kidney function/GFR must 30-40% before creatinine rises Small creatinine represents significant kidney injury ARF has high mortality Poor prognostics: age, severe underlying dz, multiple organ failure Leading cause of deaths: infx, underlying dz progression, fluid/electrolyte imbalance Classification: Prerenal azotemia Acute parenchymal RF: ATN (acute tubular necrosis) - most common Glomerular, tubuloinerstitial or Vascular inflammation Thrombotic or Embolic RV occlusion Postrenal azotemia ( a.k.a) Obstructive uropathy Pre & postrenal azotemia almost always treatable by treating underlying cause Urinalysis: Oliguria: < 400 ml/24 hr prerenal ARF Acute parenchymal ARF Urinary tract obstn .5 - 2L /24hr Nephrotic ATN > 2L/24 hr Hyperosmolar stress, diabetes insipidus Catabolic pts receiving high protein load partial urinary tract obstn < 100 ml/24hr urinary tract obstn bilateral renal cortical necrosis (septic miscarriage) Acute glomerulonephritis, vascular occlusion or massive ATN event Prerenal vs. fine hyaline casts SG Urine Osm Urine Na (<20) Creatinine (> 40) Renal/ATN dirty brown coarse casts RTE (renal tubular epithelial cells) Urine Osm Urine Na (> 40) Creatinine (< 20)

Normal: Polyuria:

Anuria:

Acute vs. Chronic? Factors suggesting chronic: Small kidney size hx of kidney dz, HTN or abnormal urinalysis Anemia, metabolic acidosis, hyperkalemia, hyperphosphatemia usually present

Obstructive or Postrenal ARF Causes: Intrinsic obstn: blood clots, stones, sloughed papillae, fungal balls Bladder: Stones, blood clots, prostatic hypertrophy or malignancy, carcinoma Clinical: History

Extrinsic obstn: Urethral:

malignancy, retroperoneal fibrosis, iatrogenic strictures, phimosis

of previous UTO or UTI predisposing to papillary necrosis (DM, sickle cell, analgesic abuse) Pelvic or retroperitoneal dz or surgery Sign & sx: Dysuria, nocturia, frx, hesitation, weakening stream Anuria or wide range in urine output Enlarged prostate Distended bladder Many asymptomatic Flank masses or tenderness Normal urinalysis in setting of progressive renal failure - suggests the problem is in the plumbing Decrease in effective blood volume - volume depletion ECF may be decreased or also may be increased (cardiac failure, cirrhosis), but effective blood volume is decreased Renal hypoperfusion - kidney take their cue exclusively from renal artery P - they assume you are volume depleted and tries to compensate >> RAAS, SNS & ADH >> cortical blood flow >> Na, water & urea reabsorption >> Oliguria, Azotemia & urine osmolarity, Na Osmolarity of urine increases b/c there is < water respectively NSAIDS & ACEI >> cortical blood flow & GFR >> ATN Reduced CO CHF, cardiogenic shock Pericardial tamponade PE Systemic Vasodilation Anaphylaxis Drug OD Sepsis or drugs Systemic or renal Vasoconstn Anesthesia, Surgery Dopamine Alpha agonist Impaired renal autoregulation Hyperviscosity syndrome

Prerenal Azotemia

Causes:

Intravascular Vol Hemorrhage GI, renal, skin losses Sequestration Hx & Sx: Signs:

Clinical:

Hx of fluid loss, use of NSAIDs or ACEI, thirst Fluid deficit, weight loss, oliguria, orthostatic hypotension Flack neck veins when supine

Tachycardia Lack of sweat, dry mucosa and decreased turgor

Renal/ATN: Ischemic or toxic injury to kidney >> imbalance in vasoactive hormones >> persistent intrarenal vasoconstriction >> medullary hypoxia in renal hemodynamics >> in total RBF & redistribution away from outer cortex Death of tubule cells - dieing cells slough off >> block tubules >> may lead to oliguria Cells can recover from insult and regenerate/restore normal function Back-leak of filtered tubular fluid due to damaged tubular epithelium In hospital setting, ATN is most common cause of ARF Clinical Course: Initiating Phase: Maintenance Phase:

Recovery Phase:

Rhabdomyolysis:

b/t onset of renal function & establishment of renal failure usually reversible renal failure not immediately reversible last few hours to 6+ weeks most complications occur during this phase renal function begins to improve recovery w/i 4 weeks and is usually complete some pts have polyuric phase >> serious fluid/electrolyte imbalance muscle breakdown >> muscle pain & dark brown urine w/o RBC are diagnostic clues creatine kinase should be elevated, coupled with myoglobin in the urine

Management of ARF
General: ID & correct all reversible factors Attempt conversion of oligouric >> nonoligouric ATN by administering diuretics Monitor fluid/electrolyte imbalance Biochemical Monitoring: Serum Na - avoid hyponatremia by restricting free water Serum K - rx w/ sodium bicarb, glucose plus insulin or dialysis Serum bicarb - maintain above 15 mEq (for acidosis) Serum phosphate - control hyperphosphatemia w/ phosphate binders (aluminum hydroxide) Serum Ca - Rx only if symptomatic or if IV sodium bicarb used

Complications: Hypervolemia Hyperkalemia - can lead to asystole High anion gap metabolic acidosis Hyponatremia >> CNS dysfunction Uremia >> neuro dysfunction, GI bleed or platelet dysfunction Infx (sepsis, pneumonia & UTI) leading cause of mortality Fluids & Diet: Fluids: Diet:

Restrict fluids to match measured + insensible losses Electrolytes - restrict to match measured losses Protein - restrict Carbs - provided at least 100 g/day Weight - allow for loss of .5 lb/day due to catabolism Pneumonic AEIOU A - acidemia E - electrolyte (K+) I - ingestion O - Overload (volume) U - Uremia

Dialysis:

Early dialysis simplifies management and nutritional support Indications for dialysis in Oliguric patients: 1. Severe hyperkalemia (monitoring EKG better guide than K) 2. Volume overload resulting in CHF or HTN 3. Sever metabolic acidosis (pH < 7.2) 4. Symptomatic uremia (encephalopathy, hemorrhagic gastritis) 5. BUN > 100 mg/dl 6. Uremic pericarditis

s, iatrogenic

smolarity, Na

roxide)

Acid Base Disorders

Endogenous acid production: catabolism of glucose & fatty acids >> CO2 and H20 >> pulmonary excretion metabolism of sulfur containing amino acids, phospholipids & phosphoproteins >>kidney metabolism CO2 CO2 + H20 H2CO3 H+ + HCO3Acidemia: Arterial pH < 7.37 Acidosis: Normal values: pH H+ pCO2 HCO3Process that results in acidemia if left unopposed Arterial 7.37-7.43 37-43 36-44 22-26 Alkalemia: Arterial pH > 7.43 Venous 7.32-7.38 42-48 42-50 23-27 Alkalosis: process that results in alkalemia if left unopposed Metabolic: From primary alteration in [H+] or [HCO3-] Respiratory: From primary alteration in pCO2 due to in CO2 elimination Buffering: Immediate defense of pH In acute setting, hemoglobin, albumin, plasma proteins & intracellular phosphates can all accept protons (H+) In chronic setting, bone can release base into the blood (>>ultimately results in brittle bones) Renal Handling of Acid Load: Requires base/bicarb reclamation & net acid secretion Bicarb: Kidneys are stingy with bicarb - < 1% secreted in urine (if tubular abnormalities exist >> spilling of bicarb in urine0 75% of bicarb reclamation occurs in proximal convoluted tubule Stimulatory factors for bicarb absorption: Volume depletion Intracellular acidosis Hypokalemia Chloride depletion IntracellularpCO2 Acid: Secretion occurs primarily in distal nephron Must have secretion of H+ into tubule and trapping of the protons by ammonia (NH3 formed in proximal tubule) to form ammonium (NH4) Stimulatory factors for acid secretion: Na delivery & transport (CCT) K+ deficiency Aldosterone Increased pCO2 Ammoniagenesis: Enhanced in proximal tubule by chronic acidosis and hypokalemia Secretion in distal tubule enhanced by chronic acidosis and aldosterone Clinical Approach: Questions to ask: What is primary event (ex. loss of acid via vomiting) What is the response (from lungs or kidneys)? Is it appropriate? How to correct quickly? Respiratory Alkalosis: Respiratory Acidosis: Metabolic Alkalosis: Metabolic Acidosis: 1in pCO2 1in pCO2 1in HCO3 1in HCO3

Evaluation: Hx & PE Obtain simultaneous chemistries and ABGs >> determine primary disorder & appropriate response Calculate serum anion gap Common causes: Respiratory Alkalosis: Respiratory acidosis: Metabolic Alkalosis: Metabolic Acidosis:

PE, cirrhosis, sepsis, pregnancy COPD Vomiting, diuretic use (excrete NaCl and tubules hold onto bicarb) Hypotension (perfusion), severe diarrhea (lose bicarb from fluids), renal failure & sepsis

Compensation
Primary Disorder Respiratory Acidosis Respiratory Alkalosis Metabolic Acidosis Metabolic Alkalosis Primary Defect hypoventilation PCO2 Hyperventilation PCO2 Loss of bicarb or gain of H+ Gain of bicarb or loss of H+ Effect on pH Compensatory Response HCO3 generation HCO3 consumption Increase in ventilation PCO2 Decrease in ventilation PCO2 Expected Compensation [HC03] = 1-4 mEq/L for each 10 mm Hg in PCO2 [HCO3] = 2-5 mEq/L for each 10 mm Hg in PCO2 PCO2 = 1.5 [HCO3-] + 8 (+/- 2) Winter's formula PCO2 = .6 * in HCO3 Compensatory Limits [HC03] = 45 mEq/L [HCO3] = 12-15 mEq/L PCO2 = 12-14 mm Hg PCO2 = 55 mm Hg

Metabolic Acidosis
General: Decreased arterial pH, decreased serum bicarb, decreased arterial pCO2 Respiratory response calculated via winter's formula Expected PCO2 = 1.5 [HCO3-] + 8 (+/- 2) Anion Gap: When organic acids (ex. lactic) added to ECF, bicarb falls as acid is buffered Anion gap increases as organic base is accumulated Represents the unmeasured anions in serum [Na] - [Cl + HCO3] Normal is 8-12 If AG is high >> there is an anion not usually present in pt Ex. salicylate (ASA) or ketones (DKA or starvation) Normal AG = hyperchloremic High AG = normochloremic Rx: Should be aimed at underlying cause In pt w/ nml lung function, PCO2 should decrease in attempt to normalize pH Parenteral Sodium bicarb if pH < 7.1 & pt hemodynamically unstable Oral bicarb if loss is due to GI loss or RTA (renal tubule acidosis) Increased arterial pH, increased serum bicarb, increased arterial pCO2 Often accompanied by hypochloremia or hypokalemia Generation Stage: Maintenance Stage: loss of acid, gain of bicarb, 1 aldosteronism (oversecretion of aldosterone by adrenal medulla) Kidney loses ability to excrete bicarb efficiently Cl- deficiency Decreased GFR =/- increased PT bicarb reabsorption Hypermineralocorticoidism and hypokalemia DDx Anion Gap MUDPILES M - Methanol U - Uremia (RF) D - DKA P - Paraldehyde I - Intoxication (Alcoholic KA) L - Lactic acidosis E - Ethylene glycol (suicide) S - Salycylate (ASA) or Starvation

Metabolic Alkalosis
General:

Stages:

Assess/Rx: What is the source of alkali gain or acid loss? What is preventing renal excretion of HCO3Commonly GI HCl loss, diuretics, endogenous or exogenous mineral corticoid excess Volume depletion >> aldosterone secretion >> stimulates DT K+ and H+ secretion Hypokalemia >> maintenance of metabolic alkalosis >> must correct K+ deficiency to correct alkalosis Monitor K and Cl depletion Rx often involves administration of K+ and Volume If urinary [Cl-] , pt will be responsive to saline If urinary [Cl-], pt will be unresponsive to saline

Simple vs. Mixed

Simple: Mixed:

One primary disorder with appropriate compensatory response If compensation inappropriate, must consider more than one primary disorder Normal pH in combo with abnormal PCO2 and serum bicarb also suggest mixed

ACID-BASE BALANCE AND THE KIDNEYS

Stages of Acid Base Balance: Acid Synthesis >> Buffering >> Excretion most metabolic processes occurring in the body result in the production of acid Endogenous Acid Production: mostly f/ catabolism of glc and FA to CO2 and H2O (cellular respiration) volatile acids excreted by lungs metabolism of sulfur containing aa, phospholipids/proteins nonvolatile acids excreted by kidneys Bicarbonate buffering system: Normal Acid Base Values: Arterial Venous Arterial pH < 7.37 = acidemia Buffering CO2 + H2O H2CO3 H+ + HCO3pH [H+] pCO2 7.37-7.43 37-43 36-44 7.32-7.38 42-48 42-50 Arterial pH > 7.43 = alkalemia [HCO3] 22-26 23-27

immediate defense of pH; acute - Hgb, albumin, plasma protein, intracellular phosphates; chronic - bone but, ultimately, the acid produced must be excreted

Renal Handling of Acid Load: Bicarb:

base (bicarb) reclamation and net acid secretion 1 mEq/kg H+ (nonvolatile) produced daily proximal tubule reabsorption due to presence of carbonic anhydrase stimulated by volume depletion chloride depletion intracellular acidosis increased intracellular pCO2 hypokalemia

Acid:

Distal nephron secretion Eliminates hydrogen equivalent to nonvolatile acid prod. Inorganic bases of nonvolatile acids filtered at glomerulus, poorly reabsorbed; these bases and ammonia f/ PT cells trap secreted H+ for elimination in urine stimulated by increased Na delivery and transport aldosterone K deficiency increased pCO2

Ammoniagenesis: Ammonia secretion:

in proximal tubule cell enhanced by chronic acidosis and hypokalemia in distal tubule enhanced by chronic acidosis and aldosterone

CLINICAL APPROACH TO ACID BASE DISORDERS

Assessment of Acid Base Status: 1st: ABG and serum electrolytes Obtain a minimum diagnosis/primary disorder look at pH for acidemia v. alkalemia match w/ pCO2/HCO3 for metabolic v. respiratory Determine appropriate compensation/response if compensation is inappropriate, consider mixed disorder Calculate anion gaps (serum, urine, delta, osmolar) high v. nml is used to aid in the ddx of metabolic acidosis

Terminology: Acidemia - blood pH < 7.35 Alkalemia - blood pH < 7.45 Acidosis - process that results in acidemia if left unopposed Alkalosis - process that results in alkalosis if left unopposed Metabolic - disorder that results f/ primary alteration in [H] or [HCO3] Respiratory - disorder that results f/ primary alteration in pCO2

Anion Gap:

represents unmeasured anions in serum conventional calculation: [Na] - [Cl + HCO3] high: indicates loss of bicarb w/o subsequent increase in Cl-; electroneutrality maintained by production of anions like ketones, lactate, SO4 and PO4 (not part of calculation); so, there is an anion in this pt that is not normally present normal: (8-12) hyperchloremic metabolic acidosis; drop in bicarb is compensated for by in Cl-

Respiratory Alkalosis ( in pCO2) pulmonary embolism, cirrhosis, sepsis, pregnancy Respiratory Acidosis ( in pCO2) chronic obstructive pulmonary disease Metabolic Alkalosis ( in HCO3) vomiting, diuretic use Metabolic Acidosis ( in HCO3) hypotension, severe diarrhea, renal failure, sepsis Simple disorder: one primary disorder (including appropriate reponse) Mixed: 2,3,4 primary disorders Varieties of Acid Base Disorders: METABOLIC ACIDOSIS Manifested by: arterial pH serum bicarb conc arterial pCO2

Assessment of low serum bicarb:

Check ABG to exclude chronic resp alkalosis Calculate serum anion gap

Classification of Metabolic Acidosis: Renal Origin Uremic Acidosis (GFR usu. <15-20 mL/min) High Anion Gap Normal Extrarenal Origin Lactic Acidosis Ketoacidosis (diabetic, alcoholic, starvation) Poisoning (ethanol, salicylates)

Renal Origin Proximal RTA (Type II) Hypokalemic distal RTA (Type I) Hyperkalemic distal RTA (Type IV) *aka hypoaldosteronism RTA of renal insufficiency (GFR usu. > 15 mL/min)

Extrarenal Origin Diarrhea Gastrointestinal ureteral connections Extrarenal loss of biliary/pancreatic secretions

*w/ normal anion gap, calculate urine anion gap..positive indicates renal origin, negative indicates extrarenal origin

RENAL TUBULAR ACIDOSIS SYNDROMES group of disorders in which there is a failure of the kidney to either resorb bicarb or excrete hydrogen ions which is unrelated to advancing renal failure Proximal RTA (Type II) Distal RTA (Type I) bicarb threshold is reduced from 25 to 18-20; occurs w/ systemic illness or molec defects most common type; disease of the intercalated cell of distal nephron usually due to inherited defect in H+ ATPase always hyperchloremic acidosis accompanied, b/c of Na loss, by 2ndary hyperaldosteronism, leading to K depletion hyporeninemic hypoaldosteronism disorder of the prinicpal cells, usually in interstitial renal dz destruction of macula densa >> renin productionimpaired angiotensin production tendency to develop hyperkalemia

Distal RTA (Type IV)

METABOLIC ALKALOSIS Manifested by: Accompanied by: Generation Stage Maintenance Stage arterial pH hypochloremia loss of acid serum bicarb conc hypokalemia gain of bicarb arterial pCO2

primary aldosteronism

kidney loses ability to excrete bicarb efficiently Cl- deficiency (extracellular volume contraction) GFR and/or proximal tubule HCO3 reabsorption hypermineralocorticoidism and hypokalemia Saline Unresponsive ( urinary Cl-) Hypertensive Primary aldosteronism Cushing syndrome Renal artery stenosis Normotensive Mg++ deficiency Severe K+ deficiency Bartter syndrome Gitelman syndrome Treat the underlying cause

Diagnostic Categories: Saline Responsive ( urinary Cl-) Normotensive Vomiting/nasogastric suction Diuretics Posthypercapnia K+ depletion Volume expansion = mainstay of therapy

Volume depletion associated w/ vomiting, mechanical drainage, diuretic use leads to enhanced bicarb reabsorption and aldosterone secretion, which stimulates distal tubular hydrogen and potassium secretion. Mineralocorticoid excess is another imp cause of alkalosis. In all of these, concomitant hypokalemia promotes maintenance of metabolic alkalosis. Renal compensation for sustained hypercapnia >> incr in serum bicarb; if ventilatory rate acutely increases, pCO2 falls rapidly,but bicarb remains transiently elevated.

Potassium Disorders
Resting membrane potential: Intracellular K+ far exceeds etracellular K+ Only 2% of total body stores are in ECF 1 mEq decrease in serum K+ is proportional to 200 mEq deficit in total body K+ Membrane more permeabile to K+ than Na >> readily moves down CG to set up RMP Small change in K on either side of membrane >> significant change in RMP Acid/base status another determinant of serum K (bc of H+/K+ pump in nephron)

K+ metabolism: Primarily from diet Renal excretion is slow >> most K is rapidly redistributed from extracellular to intracellular compartment Insulin: activates ATPase by recruiting more pumps to cell membrane B2 agonists: breaks down ATP >> cAMP >> stimulates ATPase Renal response: bulk of K reabsorption occurs in PT; further reabsorption occurs in TAL Aldosterone >> K+ secretion in CCD and IMCD via principal cells w/o Aldosterone - prone to hyperkalemia (asystole & death) H+/K+ pump in IMCD last gate to reabsorb K in presence of low K+ intake TAL: Na/2 Cl/K channel moves these ions from lumen back into the cell An additional K channel (ROM K) allows for K diffusion back to the lumen >> positive electrical potential in the lumen >> enhances mvmt of Ca+ and Mg+ back to blood >> enhances absorption of NaCl (because cotransported with K from lumen) Furosemide (Lasix) blocks Na/2 Cl/K channel K+ secretion enhanced by: 1. Rate of DT flow 3. Presence of poorly reabsorbable anions in tubular fluid 2. Distal delivery of Na 4. Stimulation by aldosterone (NaCl reabsorbed - K secreted)

Hyperkalemia
General: Increased extracellular K >> CM partially depolarizes>> AP Na permeabilty decreases Lethal condition & medical emergency! Chronic renal insufficiency does not cause hyperkalemia unless advanced Sx: EKG: muscle weakness & paralysis Accelerates repolarization Peaked T waves decreased or absent P waves Late stage - inactivation of Na channel >> wide QRS complex

Rx: ER or need for rapid - give Ca gluconate (Ca+ antagonizes effects of hyperkalemia - protects conduction system) Dextrose/Insulin to shift K+ intracellularly (buys time for the kidneys excretory function to kick in) K exchange resin (Kayexalate) - enhances K+ secretion from GI tract

Hypokalemia
Etiology: Low serum potassium - may not accurately reflect total body stores Caused by either inadequate intake, excess secretion or transcellular shift Transcellular shift: Alkalemia (drop in K+ b/c body hanging on to H+ via pump) Insulin B agonists/stress (esp in conjuction with MI, alcohol withdrawl or asthma attack) Renal loss: Too much K+ leaking into lumen >> Urinary K+ > 20 mEq Extrarenal loss: Urinary K+ <20 mEq May be due to either metabolic acidosis (lower GI problem) or metabolic alkalosis (upper GI problem)

Bartter's syndrome:

Rare defect of primary renal tubular NaCl reabsorption Diagnosed in infancy Na/2 Cl/K pump is blocked (as in the case of Furosemide) >> increased NaCl & K excretion >> volume depletion Body's compensatory response is to Renin/Aldosterone Accompanied by hypercalciuria (w/o pump >> no positive electriacal gradient to reabsorb Ca+) Gitelman's Syndrome: Similar to Bartter's syndrome, though only a defect in NaCl transporter (K+ not involved) Body's compensatory response is to Renin/Aldosterone Accompanied by hypocalciuria Liddle's syndrome: Hyperabsorption of NaCl (due to faulty channel) >> favors K+ dumping & volume expansion >> renin & aldosterone Sx: Rhabdomyolysis, muscle weakness & paralysis Ab pn, bloating & constipation (adynamic ileus) THIRSTY Palpitations

EKG:

Increased ventricular excitabilty (extra systoles) Delayed repolarization >> flattening of T waves and development of U waves Late development - inactivation of Na channel >> prolonged QRS Determine serum Mg >> if hypomagnesemia, Mg must be administered to correct hypokalemia Oral potassium IV potassium if severe arrythmias or dig toxicity

Rx:

Water Disorders
Osmolality: ratio of solute to water in all compartments in ECF osmolality >> reciprocal in ICF ECF osmolality estimated by calculating serum osmolality = 2 [Na] +[glucose]/18 + [BUN]/2.8 Serum osmolality ~ 290 or 2[Na] Tubular Fluid - upon arriving at distal tubule = 50 to 100 mOsm/kg Concentration of Urine: In response to plasma Osm/ECV >> thirst & ADH Water retention primarily due to ADH acting on CD ADH docks on receptor >> Aquaporin 2 >> from cytoplasm to luminal membrane to form water channels Water then free to move down isomotic gradient for reabsorption ADH typically regulated osmotically Non-osmatic regulation of ADH (in pathologic setting of volume disorder) can >> extreme stimulatory effect on ADH in plasma Na almost always reflects in H20 balance PE findings refelect patient's volume status

Hypoooooonatremia
General: Path: WATER INTOXICATION!!!!!!! Can occur in context of hypovolemia, euvolemia and hypervolemia Either due to an increase in PT reabsorption of H20 or inability to excrete H20 H2O excretion impaired due to GFR, NaCl reabsorption in diluting segments of DT, or failure to suppress ADH secretion Kidneys CANNOT excrete water when they have a volume disorder (hyper or hypovolemia)

Causes of hyposomolar hyponatremia

Hypovolemia: ECF volume, ECV Hypervolemia: total ECF volume ECV - Una > 20 ECV - Una < 20 Pseudohyponatremia: (hyperosmolality) hyperglycemia hypertonic mannitol

Management of Noneuvolemic Hyponatremia Hypovolemic hyponatremia Hypovolemic hyponatremia volume restoration with isotonic saline identify and correct cause of H2O and Na loss Na and H2O restriction Loop diuretics Treat underlying condition no saline

Syndrome of Inappropriate ADH Secretion (SIADH) prototype of primary release of ADH usually pathologic processes of central nervous system or pulmonary system ADH >> excessive H2O reabsorption >> GFR >> kidney (hey now) Na >> reestablish euvolemia (but, now hyponatremia) Diagnosis: Essential osmolarity (<270) inappropriate urinary concentration (> 100) clinical euvolemia U Na conc w/ nml Na/H2O intake no adrenal, thyroid, pituitary, diuretic use, renal insufficiency Supplemental plasma ADH level inappropriately relative to plasma osmolarity no correction of plasma Na w/ vol expansion, but improvement after H2O resriction

Causes:

hypothalamic production of ADH (neuropsych disorders, drugs, pulmonary dz, post op, severe nausea) ectopic production of ADH (carcinoma - oat cell, bronchogenic) potentiation of ADH effect (drugs, including NSAIDs) exogenous administration of ADH Symptomatic SIADH acute hyponatremia (< 48 hrs): chronic hyponatremia (> 48 hrs): Administer Na slowly because rapid infusion can shrink the brain

Tx:

serum Na at rate up to 2 mEq/hr until sxs resolve don't exceed 1-1.5 mEq/hr measure serum and urine electrolytes every 2 hrs perform frequent neurologic evaluations

Chronic Asymptomatic SIADH fluid restriction solute intake (furosemide + 2-3 g NaCl daily pharmacologic inhibition of ADH via demeclocycline or V2-receptor antagonist Signs and Symptoms of Hyponatremia CNS: Mild - apathy, HA, lethargy Moderate - agitation, ataxia, confusion, disorientation, psychosis Severe - stupor, coma, Cheyne-Stokes respirations anorexia, N/V cramps, diminished DTR most sxs related to brain swelling: hypoosmolar ECF >> water shift >> brain water content

GI: MSK:

Hyperrrrrrrnatremia
WATER DEPLETION, DEHYDRATION!!!!!!!!!!! General: Path: can be hypervolemic, euvolemic, hypovolemic most cases - excess H2O loss, not Na gain usually, primary defect is in urinary concentrating ability + insufficient admin of free H2O

Causes of hypernatremia: Osmotic Diuresis lg amt of osmotically active solutes in filtrate >> H2O loss in urine in excess of electrolytes

Diabetes Insipidus Central Causes Nephrogenic Causes

collecting tubule is impermeable to H2O central defect in release of ADH vs. nephrogenic defect w/ responsiveness Congenital Acquired: post-traumatic, tumor, aneurysm, meningitis/encephalitis, Guillain-Barre Congenital Acquired: renal dz, hypercalcemia, hypokalemia, drugs (lithium, demeclocycline)

Signs and Symptoms of Hypernatremia CNS: mild - restlessness, lethargy, altered mental status, irritability moderate - disorientation, confusion severe - stupor, coma, seizures, death Respiratory: labored respirations GI: intense thirst, N/V MSK: muscle twitching, spasticity, hypereflexia Tx: hypernatremia w/ hypovolemia implies Na deficit in addition to H2O deficit >> isotonic saline infusion other pts >> hypotonic IV solutions (D5W, 1/2 NS, 1/4 NS); administer soln that is hypotonic relative to urine chronic hypernatremia (> 36-48 hrs) brain makes compounds to raise intracellular osmolarity to minimize shrinkage rapid correction >> H2O shift to relatively hypertonic intracellular compartment >> brain edema general rule = correct over 48 hrs not exceeding 0.5 mEq/L/hr, or 12 mEq/L/day

Rate is important!

Urinalysis Dip Stick: start with clean catch, note color

measures: SG: pH, SG, glucose, proteins, ketones, bilirubin, blood, urobilinogen, nitrite Normal range 1.003-1.035 SG of 1.010 approximates plasma (osmolality of 300 in plasma) = isothenuria Correlates with osmolality ([urine]) < 1.010 is dilute > 1.010 is concentrated (Water is 1.0) Specific gravity may be different than osmolality in cases of proteinuria, glycosuria, radiocontrast dyes or increased urea in urine Normally 4.5 - 6.0 (Physiologic range 4.5 - 8.0)

pH:

(grade correlates with concentration) Detects negatively charged proteins well (albumin) Won't detect: microalbuminuria (+) like Ig in monoclonal gammopathy (ie Bence Jones) tubular proteins (Tamm - Horsfall proteins) Large amounts of albumin suggest glomerular dz (normally filtration in glomerulus is restricted by size and charge) Normal: < 300 mg/day Consisting of Tamm Horsfall proteins = glycoprotein coating renal tubular cells in DT Dipstick refelects concentration of protein not quantity Characterizing Proteinuria: Evaluation of Proteinuria Quantity: > 3.5 g/day = Nephrotic <3.5 g/day = Non-nephrotic 24 hr urine collection or Quality: Glomerular: mostly albumin Random sample - U protein:U creatinine ratio Tubular: low molecular weight proteins Tubular interstitial or glomerular dz Reflects g protein excreted/day Overflow: Bence Jones proteins Multiple myeloma Protein Electrophoresis (Myeloma) Transient: Orthostatic, exertional, UTI, fever, infalmm dz, CHF or HTN

Proteinuria: Graded on scale from Negative to trace to 1+, 2+, 3+, 4+

Hematuria: Graded on scale from negative to trace, 1+, 2+, 3+, 4+

Positive results due to RBCs, hemoglobin or myoglobin - Hb and Mg due to hemolysis 80-90% of hematuria is from lower tract of collecting system (not kidneys) May be intra-renal or extra-renal: Intrarenal hematuria with proteinuria suggests glomerulonephritis Evaluation of Hematuria: Dysmorphic RBC suggests glomerular dz Renal ultrasound Casts conrfirm nephrotic origin CT scan

Etiology: UTI Nephrolithiasis Cancer BPH Glomerular dz Trauma

Glycosuria: Glucose in blood ranges from 60 - 100 >> is freely filteres but later reabsorbed
Glucose > 500 exceeds reabsorptive capabilities Damage to PT (even w/ nml glucose) >>low reabsorptive capability

Microscopic Findings: Cells, casts, crystals & bacteria

Hyaline casts: Normal finding - are a cast of DT itself, made of Tamm-Horsfall proteins and seen on microscopy as transluscent Granular casts: Have cellular debris within - suggestive of renal parenchymal damage (may be coarse or fine) Coarse (dirty brown) suggestive of ATN Oval fat bodies: Lipid laden macrophages or renal tubule cells - seen in nephrotic syndrome (glomerulonephritis, pyelonephritis or ATN) RBC casts: pathognomonic for glomerularnephritis WBC casts: Hypersensitivity & interstitial nephritis Waxy casts: Indicative of more advanced failure or chronic dz Broad casts: Due to tubular enlargement w/ time - chronic dz Crystals: Calcium oxylate: (seen in more acidic urine) nml in absnce of other sx, may be seen w/ stones or polyethelene glycol poisoning Triphosphate: (seen in more alkaline urine)

n:U creatinine ratio otein excreted/day yeloma)

hrolithiasis

merular dz

ronic dz

Glomerular Diseases
Glomerular Anatomy: Fed & drained by afferent and efferent arteriole 4 cell types: Visceral epithelial cell (podocyte) - supports glomerular basement membrane (GBM) Foot processes interdigitate, line exterior of GBM >> barrier Endothelial cell - fenestrated to keep out larger objects>> supports GBM Mesangial cell - skeletal framework for capillary network Parietal epithelial cell - cover interior of Bowman's capsule

Nephrotic Syndrome "bland urine" Proteinuria >3.5 gm.day Hypoalbuminemia Hyperlipidemia, lipiduria Edema Aniscara

Nephritic Syndrome RPGN (Rapidly Progressive) "active urine" Acute nephritis Hematuria w/ dysmorphic RBCs ARF >> ESRD in weeks to months Variable proteinuria (<1.5 gm/day) Hematuria with RBC casts or dysmorphic cells RBC casts (pathognomic for GN), granular casts, pyuria Edema (not as lg scale), HTN (salt retention), renal insufficiency, oliguria BUN and Creatinine 1. Circulating Ab directed against GBM Histological: 2. Immune complex formation (get stuck) & complement activation glomerular enlrgmnt & hypercellularity 3. Circulating Ab against cytoplasmic Ag >> neutrophil activation & injury leukocytes SLE IgA Nephropathy deposits of IgG, IgM, C3 on GBM sub-endothelial hump-like deposit

Nephritic Syndrome:
Path: Some immune system defect -

Causes: PSGN:

PSGN

Vasculitis

Children > adults M>F prototype Group A streptococci - pharynx is primary site of infx 95% resolve spontaneously - adults poorer prognosis Due to circulating immune complexes - PSGN usually 1-4 weeks after infx >> proliferation of glomerular cells w/ influx of leukocytes Clinical: Edema, hematuria, proteinuria (non-nephrotic levels), oliguria, HTN, casts Labs: Depressed complement (C3) and elevated stept Ab

IgA nephropathy: Path: usually mesangial proliferation most common worldwide cause of glomerulonephritis M>F IgA deposits in mesangium - diagnostic 15-40% progress to ESRD, but slowly (80-90% 10 yr survival) Tx: no therapy presents w/ hematuria +/- proteinuria usu dx by asymptomatic hematuria mostly nephritic (but can be nephrotic) Henoch-Schlonein Purpura: sm vessel systemic vasculitis w/ IgA immune complexes; purpura, nephritis, abd pn, arthralgia

Nephrotic Syndrome
Path: 1. Minimal Change Dz & FSGS due to injury to glomerular epithelial cells 2. Membranous Neuropathy due to immune-complex formation & complement activation in subepithelial space 3. Deposition Dz - diabetic neuropathy , SLE, amyloidosis - affect GBM 4. Membranoproliferative 5. Ig A Nephropathy

Process: Clinical:

loss of interdigitation & foot process effacement >> "swiss cheese" blanket over glomerulus = gaping holes for protein to leak through Proteinuria > 3.5, hyperlipidemia (oval fat bodies), Hypoalbumemia >>edema (Na retention), hyperlipoproteinemia, platelet hyperaggregability Hyperlipidemia may be both choleterol and/or triglycerides Renal Tubular Injury Negative nitrogen balance & malnutition Loss of Ig >> depressed cellular immunity Rx edema w/ restricted NaCl & diuresis ACE I - reduces proteinuria by 50% Complications: Thromboembolic Loss of carrier/binding proteins >> Mineral, calcium & Vit D deficiencies in drug metabolism and diuretic resistance MCD - Corticosteroids Cyclosporine FSGS - Corticosteroids & Immunosppression Membranous - Steroids & Alkylating agents

Rx:

Dietary protein restriction NSAIDs - in high doses protein (severe only)

Membranous Glomerulonephritis (MGM): Most common cause of Nephrotic syndrome in adults Path: Microscopic hematuria w/o RBC casts Thickening of capillaries with BM "spike formation"

May be primary or secondary (2ndary to drugs, infx, hepatitis, maliganancy) No inflammatory cells Granular deposits og IgG and complement

Minimal Change Nephrotic Syndrome (MCNS): "Lipoid Nephrosis" 85-95 % of all kids (2-8) w/ nephrotic syndrome have MCD M:F 2:1 Affects visceral epithelial cells (podocytes) >> proteinuria No Ig or complement deposition to be seen by microscopy or immunoflouresence Effacement of foot processes only seen on electron microscopy Bland urine typical of nephrotic syndrome, but good renal function & no HTN Rx:

15-20% of adults

Responds dramatically to corticosteroids Not considered steroid resistant until fail to respond to 16 wks rx Relapses common and treated similary to initial episodes Cyclosporine may be valuable in steroid-resistant pts Good prognosis - 3/4 dz free in 10 years, rarely progresses to kidney failure

Focal Segmental Glomerulosclerosis (FSGS): Characterized by segemntal sclerosis of only a small % of glomeruli May be primary or secondary (HIV, Heroin, Sickle cell, obesity) 10% of kids, 15% of adults Same disease process as MCNS, though you do also get HTN and decreased renal function LM: sclerosis IF: IgM & C3 deposition in mesangium EM: foot process effacement Rx: Poorer response to corticosteroids Kids have better prognosis 20% adults >> rapid renal failure w/i 2 years Recurrence in transplant pts 40-50% of time

Rapidly Progressive Glomerulonephritis (RPGN)

Syndrome with many causes Clinically rapid and progressive loss of renal function and oliguria Severe glomerular injury >> formation of crescents Untreated leads to death w/i weeks to months Classification: Path: Anti-GBM dz (Goodpasture's) Immune complex (SLE, post-infx, Henoch-Schloen, idiopathic)

w/ any underlying cause, imp feature is disruption of GBM allows leakage of fibrin and blood into Bowman's space forms crescents of fibrin, epithelial cells, and infl cells proliferative GN w/ crescents possible focal necrosis of glomerulus Anti-IgM dz - linear deposition of IgG along entire GBM Immune Complex - granular deposits, Ig depending on cause anti-GBM disease autoimmune disease w/ Ab against collagen type IV more common in the young and M > F cross reacts with alveolar basement membranes clinical pres may include RPGN w/ pulmonary hemorrhage/hemoptysis and dyspnea high dose oral prednisone, cytotoxic agents, plasmapheresis

LM: IF:

Goodpasture's:

Rx:

Renal Biopsy:

Can be used for dx of glomerular, tubular & interstitial dzs; following progression of dz In atypical presentation to rule out other causes Usually percutaneous guided by ultrasound - via jugular 3 cores >> 1. Light microscopy 2. Immunofluoresence 3. Electron microscopy Rarely specific and dx b/c many syndromes have similar pathology

Secondary Glomerulonephritis
Lupus primarily a dz of young women presents as any of the glomerular dz syndromes from minimal change to crescentic most common = nephrotic w/ active sediment diagnosis via serologic evidence of antinuclear antibody production in the presence of inflammation of multiple organs nephritis = most common cause of death in SLE biopsy to determine stage of disease class I and II = no tx class III = lowest possible does of corticosteroids class IV = possible addition of cytotoxic drugs characterized by persistent albuminuria, relentless decline in GFR, HTN microalbuminuria (>30 nd <300 mg/day) predicts nephropathy >> almost inevitable proteinuria (>350mg/day) w/i next 5 years >> 50% have ESRD w/i 7 to 10 yrs thickening of GBM Kimmelstiel-Wilson nodular glomerulosclerosis = classic diabetic lesion nodular in hyaline matl >> massively expands mesangial areas surrounded by dilated/thickened capillary loops Diffuse glomerulosclerosis = more common, uniform increase in mesangial matrix Arterioles - accelerated hyaline arteriosclerosis; effects afferent and efferent; accelerated fibroplasia control glc, tx HTN, restrict dietary proteins many different causes of renal disease infection (postinfectious, membranous, membranoproliferative), tubular dz, FSGS

Tx:

Diabetes

Lesions:

Tx: HIV:

rcellularity

Nonglomerular Disorders
Tubulointerstitial Nephropathy disorders that principally affect the renal tubules and interstitium w/ relative sparing of glomeruli and renal vasculature Acute interstitial Nephritis (AIN): sudden onset days to wks acute inflammatory infiltrate Etiology: drugs, systemic infx, immune Clinical: dev of acute renal insuff; often systemic hypersensitivity Diagnosis: U/A may be 1st clue - hematuria, sterile pyuria, leukocyte casts, mild - mod proteinuria Also, hyperkalemia, RTA, sodium wasting Definitive - only by biopsy Tx: discontinue offending drug; possibly short course of hi dose steroids Chronic Interstitial Nephropathy: gradual progression yrs predominantly interstitial scarring and fibrosis Etiology: urinary tract obstruction; drugs (analgesics, usu w/ ASA); cytotoxic/immunosuppressives; hypertensive nephrosclerosis; radiation nephritis (w/ lg doses); heavy metals; metabolic abn; malignancy (multiple myeloma); immune disorders Clinical: slow dev of renal insuff; functional tubular defects; interstitial fibrosis w/ atrophy and loss of tubules interstitial mononuclear cell infiltrate; little or no evidence of active renal infl Diagnosis: underlying cause Cystic Diseases Simple Cysts:

increase with age (esp > 50)

most asymptomatic; usu incidental finding

ultrasound + CT to differentiate benign f/ malignant

Polycystic Kidney Dz: Autosomal Dominant PKD = adult PKD (ADPKD) ADPKD

Autosomal Recessive PKD = infantile (ARPKD)

most common hereditary renal dz in US clinical manifestations rarely before age 20-25 Clinical: usu acute abd flank pn and back pain w/ hematuria; also, nonspecific, dull lumbar pn (when kidneys are lg enough to feel) sharp, localized pn from cyst rupture or infx; initial sign - often microhematuria Other - HTN, nocturia, impaired salt conservation Complications - UTI, pyelo, cyst infx, hepatic cysts, cerebral aneurysm ESRF in almost 50% of pts by age 60 Diagnosis: radiographic evidence of multiple cysts; renal enlargement, cortical thickness US shows characteristic bilateral involvement; CT shows degree of cystic involvement Tx: prevent complications and preserve renal function ESRF - transplant or dialysis Acquired Cystic Kidney Dz: dev of cysts in pt w/ chronic renal failure or ESRD who are on dialysis; dx w/ CT Medullary Cystic Disorders: Urinary Tract Obstruction Unilateral ureteral obstruction - usu no detectable change in urinary flow or renal fxn; azotemia or renal failure only if drainage of both compromised Clinical: Presenting sign - usu chng in urinary habit True anuria = complete obstruction Polyuria = common inpartial Total anuria or widely varying output suggest urinary tract destruction Diagnosis: renal sonography; ID hydronephrosis Tx: ID site and cause; relief of obstruction, usu surgery (may >> post obstructive diuresis rare inherited dz; small medullary cysts not easily seen; ESRF in adolescence; eye deformities, anemia, prolonged eneuresis

Urinary Tract Infection Pyelonephritis: bacterial infx of kidney; collecting system + renal parenchyma Ascending - spread f/ urethra, usus w/ sex, catheter, post op; more common

Cystitis: bacterial infx of bladder either can be acute or chronic Hematogenous - spread f/ blood, usu after septicemia

Acute Pyelonephritis - suppurative infx; may see foci of pus/abscesses; pus may permeate entire kidney and fill renal pelvis (pyonephrosis) mostly females; fever, back pain, dysuria; high WBC, pyuria, positive urine culture kidneys enlarged and edematous; erythematous, possibly dilated renal pelvis; may have papillary necrosis inflammatory infiltrate in tubules and interstitium (neutrophils, lymphocytes, plasma cells); yellow streaks in cortex Chronic Pyelonephritis destruction of renal parenchyma and broad parenchymal scar formation; ultimately, small and irregularly scarred kidney usually asymmetric involvement commonly caused by vesicoureteral reflux and renal pelvic reflux chronic interstitial inflammation; tubular atrophy; interstitial fibrosis; glomerulosclerosis; hydronephrosis; cortical scarring

Acute Cystitis Chronic Cystitis -

grossly visible congestion; mucosal hemorrhages; seen on cystoscopy; severe - mucosa covered w/ pus or ulcerated; bx = acute inflammation foci of hemorrhage, ulceration, thickening; thick bladder wall UTIs: tx w/ antibiotics +/- sulfa drugs

Nephrolithiasis Urinary stones/calculi - common in ages 20-45; M > F; more in developed countries b/c high protein, low fiber diet; most pts, 1st episode >> 2nd w/in 2-3 yrs Clinical: hematuria and sudden onset of colicky pain in flank w/ radiation to groin on same side some polyuria, dysuria, vomiting, ileus Screening: past hx of stones/ infx, fam hx, diet U/A - pH, hematuria, r/o infx, ID type of stone electrolytes, creatinine, serum Ca, PO4, uric acid Mngment: requires identification of type of stone b/c of recurrence, all pt should consume 3 L of fluid/day, maintain 2L of urinary vol/day, protein & salt most pass spontaneously; obstr/fever/pn = surgery; extracorporeal shock wave lithotripsy for pt w/ pelvic/upper ureteral stones; US lithotripsy for lower Types: Calcium Struvite 75% of all stones; calcium oxalate > calcium phosphate (which require alkaline pH) hyperexcretion of Ca in pts w/ abn metabolism (hyperabsorptive hypercalciuria) restrict salt; consider thiazide magnesium ammonia phosphate or sulfate triple phosphate stones radiopaque "staghorn" = lg and irregular typically a complication of UTIs (>> formation of ammonia f/ urea in urine >> alkaline urine >> precipitation of struvite) may grow progressively and fill entire renal pelvis 50% of pts have gout or hyperuricemia precipitated by acidic urine, dehydration need to increase vol and alkalinize urine >> oral sodium bicarb very rare hexagonal in shape maintain high urine output and alkalinize urine

Uric Acid Cystine

Developmental Disorders Renal Agenesis: Horseshoe Kidney: Cystic Dysplasia: failure of kidney to develop; M > F; usually unilateral; asymptomatic (hypertrophy of remaining kidney) bilateral = incompatible w/ life

solitary kidney caused by fusion of lower poles in the midline; usually asymptomatic; M > F; may cause ureteral obstruction ( risk of infx) disordered dev of kidney; may be sm or lg; cystic and distorted; differentiate f/ ADPKD b/c usually unilateral

Chronic Kidney Disease (CKD)

Kidney dz: AKA - Azotemia, renal failure or insufficiency, uremia End stage renal failure (ESRD) - pt is receiving dialysis & is eligible for Medicare Staging: 1 Damage w/ nml or GFR 2 Damage w/ mild GFR 3 Moderate GFR 4 Severe GFR 5 Kidney Failure GFR > 90 60-89 30- 59 15 - 29 < 15

CKD defined: 1. KD > 3 months - structural or functional abnormalities, w/ or w/o GFR, manifested by: a. pathologic abnormalities OR b. markers of kidney damage - abnl blood or urine composition or imaging tests 2. GFR < 60 ml/min for > 3 months, w/ or w/o kidney damage Etiology:

Most die of Stage 3 due to CV problems or infx (before progressing to 4 r 5) Stage 3 mandates dialysis Diabetes & HTN are 2 most common causes (2/3rds of population), followed by glomerulonephritis, PCKD &interstitial nephrits Underlying dz - HTN, diabetes, dyslipidemia Family hx of KD Aging Lifestyle - tobacco, inactivity, obesity Male Ethnic - AA (FSGS), native american (diabetes), latin american (diabetic), asian american & pacific islanders (IgA nephropathy) Prenatal - maternal DM, low birth weight, small for gestational age (born w/ < nephrons) Exposure to nephrotoxic agemnts - NSAIDs, contrst dye Srceen: Basic metanolic panel (BMP): Na, Cl, K, CO2, BUN, Creatinine Urinalysis Often can dx conditions via: H&PDiabetic nephropathy & HTN nephrosclerosis Urinalysis- Interstitial nephritis, glomerular dz Ulrasound - Polycystic dz, obstructive nephropathy Indications for renal biopsy: RF of unknown etiology or nephrotic or nephritic syndrome Dipstick Microscopic Electrolytes (Na, K, Cl, Creatinine) >> Protein/Creatinine ratio 1. Fractional Excretion of Na (FENA) 2. Anion Gap (to determine acidosis) Imaging

Risk factors:

Diagnosis:
General:

Spot urine:

FENA = Cl Na/ Cl Cr * 100 = ( U Na * V)/ (P Na * time) /(U Cr * V)/ (P Cr * time) =[( U Na/ P Na) / (U Cr/ P Cr) ] * 100

In steady state FENA usually 1% If Pt is hypernatremic or volume overloaded (b/c they can't dump Na) >> FE NA will be < 1 % 24 hr urine: Kidney functional has diurnal variation - this can help Creatine Clearance Protein (Both can be obtained to some degree via spot urine - therfore not an indication for 24 hr sample) Urine urea nitrogen - protein intake = (6.25 * UNN in g) + (.031 * Kg of body wt) Urine electrolytes Indication of renal function - can be estimated by Creatinine clearance Cl Cr = U Cr * V/ P Cr * time Can be estimated using Cockroft Gault formula (DON"T DO IT) or MDRD =Modification of Diet in Renal dz (DO IT - GO ONLINE) Ultrasound: (nml is 10-12 cm) can be done w/ doppler exam of vasculature or post void bladder volume ( nml is < 100 mL left) Abdominal CT MRI & angiuography nIrtavenous pyelogram (IVP) - not done anymore Renal artery angiography ( inject contrast to see vasculature) Functional stidies: Renal scan w/ ACE to evaluate stenosuis Renal vein sampling - renin & aldosterone

GFR:

Imaging:

CKD Management
Factors renal function: Hyperfiltration (by surviving nephrons) Increased intraglomerular P Anemia Hypervolemia Hypocalcemia Hyperkalemia Proteinuria Hypotension Hypertension Toxics (NSAIDs, contrast) Signs/sx of Uremia: NV, anorexia, dysguesia (mtl taste) Diarrhea, constipation Memory loss, D/N sleep pattern Asterixes, restless leg Pericarditis Uremic frost. Pruritis (sweating urea) Vol (edem, rales, S$, ascites) BUN/Creatinine Hyperkalemia, Acidosis Hypocalcemia, hyperphosphatemia Anemia

Clinical:

HTN Acidosis > 140/90

Hyperphosphatemia Secondary Hyperthyoidism

HTN:

Due to Volume overload/sodium retention Increased afferent input from injured K (sympathetic activation) Damaged vascular endothelium Excessive renin secretion PTH/Calcium ???? Rx: Restrict dietary Na to 2 gm/day (monitor with 24 hour urine) Loop diuretic if GFR < 30 cc/min Use anti- HTN to control BP - ACEI/ARB (Will GFR & creatinine - 30% ok, > should discontinue) Result of shortened RBC half-life in uremic env'e and EPO Normochromic, normocytic Uremia >> Increased tendancy to bleed (prolonged bleeding time) Rx: Recombinant human EPO Repalce iron Avoid tx (Ag exposure for future tx, tx infx dz) creen for blood in stool Folate, B12 repletion if needed

Anemia:

Osteodystrophy: Secondary Hyperparathyroidism Due to decreased Vit D production (requires a couple of hydroxylations - one of which occurs in kidnay) Vit D >> Ca absorption in gut >> Serum Ca & [phosphate] >> PTH >> osteoclast activity & Ca release Rx: Maintain target PTH: Stage 1 2 3 4 5 PTH 35-70 70-110 150-300 Lower serum phosphate via dietary restriction or phosphate binders (Al hydroxide, Mg, Ca carbonate, Ca acetate) Raise srum Ca - correct serun [phosphate], Ca supplement, replace Vit D Ca+ can >> metastaitic Calcification in heart & arteries

Acidosis:

Bicarb < 24 & pH 7.35) Inability to excrete daily acid load (1 mEq/kg) >> metabolic acidosis & anion gap >> Osteopenia (H+ into bone for Ca out) Rx: Repalace with bicarb - Sodium bicarn, sodium citrate, calcium carbonate, calcium acetete Restrict dietary protein inatke (< .6 - .8 g/Kg body wt/day) Tubular urinary flow ( >> CG to allow K to diffuse into the lumen) Aldosterone or impaired response DT intracellular K due to acidosis (H+/K+ pump) Na delivery to DT (Na exhanged for K 1:1) lumen cations (+) >> unfavorable electrochemical gradient Rx: Restrict dietary K (60 mEq/day or 2 gm/d) Use K-losing diuretics Oral Na/K exchange resins Correct acidosis and hyperglycemia (serum Osm >> H20 leaks out of cell, K follows)

Hyperkalemia: Due to K+ secretion:

Slowing Progression:

Rx underlying condition Control BP Reduce proteinuria (low carb diet, ACEI, ARBs) Reduce hyperfiltration/glomerular HTN (inhibit RAAS) Correct CV risk factors GFR decline is predicatble - plot 1/Serum Cr vs. Time to determine years to ESKD(can also extract from /yr) CKD Stage 5: Options - Hemodialysis (access via fistula, graft or central line), peritoneal dialysis Average rx is 4 hr session 3 days/wk Initiate dialysis if GFR < 15 (< 10 for diabetic pt) Renal tx: Requires same blood tytpe, HLA match (6/6) Immunosuppressive rx to prevent rejection (steroid &)

cal gradient

Hypertension
General: HTN increases CV Mortality Joint Nat'l Committee on prevention, Detection, Evaluation & Rx of HTN = JNC VII >> set guidelines Highlights: For pts > 50 yo Systolic BP > 140 is more important CVD risk factor than diastolic Starting at 115/75, CVD risk doubles for each increment of 20/10 Normotensive pt at age 55 have a 90% lifetime risk of developing HTN Pts w/ preHTN require health-promoting lifestyle modifications African Americans have increased prevalence in both M & W Normal PreHTN HTN I HTN II Systolic < 120 120-139 140-159 >160

CVD risk factors: HTN Smoking Obesity (BMI > 30) DM Microalbuminemia or estimated GFR < 60 Inactivity Dyslipidemia Age (>55M, > 65W) Family Hx of premature CVD (M<55, W <65)

Target Organ Damage (TOD) Heart - LV hypertrophy, angina or prior MI, prior coronary revascularization Brain - stroke or TIA Chronic Kidney dz Peripheral artery dz Retinopathy

Primary vs. Secondary: Primary (90% of cases), secondary (10%) Secondary Causes: Endocrine: Renal: Other: Cushing Renal vascular dz Aortic coarctation Primary Aldosteronism Renal Parenchymal dz Drug induced Pheochromocytoma CKD highest incidence Sleep apnea Hyper or hypothyroidism Other Secondary causes: Alcohol, oral contraceptives, symphatomimetics, tricyclic antidepressants NSAIDs, exogenous steroids, EPO, Immunosuppressants or street drugs Workups to ID secondary causes: Chronic renal dz Renovascular dz Aortic coarctation Primary Aldosteronism: Cushing's: Pheochromocytoma: ID secondary causes Duration & levels of BP elevation Use of pressors Sx of TOD - cerebral, cardiac & renal BP Height, wt, BMI Neck - thyroid, veins, carotid bruits Hb & Hct Hx: PE: Urinalysis Abrupt onset HTN (>30 or >60 yo) Sx of atherosclerosis Bruits or high grade retinopathy Renal sonography, isotopic renogram Captopril renogram (looks at renal blood floe before and after giving ACEI), MRI or CT Echocardiogram, aortogram Plasma renin/aldosterone ratio, Plasma or urinary aldosterone after saline load, Adrenal CT Dexamethasone suppression test - to see if cortisol suppressible, adrenal scan Plasma or spot urine for metanephrine, Urinary or plasma catecholamines, adrenal CT Assess lifestyle changes & ID CV risk factors Assess CVD &TOD Recent/past HTN rx Family hx CVD or HTN HTN sx Diet - salt, alcohol, saturated fats Smoking, diabetes or dyslipidemia Psych Fundoscopy - Keith Waggener - Barker grading for retinopathy UE & LE - pulses & edema Blood glucose, creatinine & electrolytes Lipid panel Neuro exam

Clinical Evaluation: Hx:

PE:

Labs: Clues for Renal HTN:

EKG

Severe or resistant HTN Azotemia w/ ACEI Smoker Recurrent pulmonary edema Lab: Hypokalemia, proteinuria, high plasma renin

Pheochromocytoma: Sx Screen:

Tumor producing catecholamines 10% extradrenal, 10% bilateral, 10% malignant Can localize the tumor with CT, MRI or I-MIBG scan Headache, sweating, palpitations, wt loss, pallor, orthostatic HTN, fundoscopic changes 6 Ps: Paroxysmal - Pressure (HTN), Pain (HA, abd pn), perspiration, palpitation, pallor Plasma metanephrines (breakdown product of catecholamines) or catecholamines Spot urine for metaanephrine Decreased incidence of stroke, MI and heart failure With everyone you should encourage lifestyle modification No drug therapy indicated unless compelling indications Thiazide type diuretic for most May consider ACEI, ARB, BB, CCB or combo 2 drug combo (thiazide type for most + ACEI, ARB, BB or CCB BP < 140/90 Greatest benefit with diastolic 80-85 DBP < 80 for blacks BP < 130/80 for diabetics and those with chronic kidney dz SBP of 140-145 for elderly with ISH Thiazide type diuretics should be initial therapy of choice for most Certain High risk conditions warrant other Most pts will require 2 or more drugs to achieve BP goal If BP is > 20/10 mm above goal, initiate therapy with 2 drugs (one of which should be thiazide - unless contraindicated) Patients should have monitoring & follow-up until goal reached - more frx visits for stage II After goal reached, FU at 3-6 month intervals - more frx for comorbid conditions Lifestyle modification: Wt loss 5-20 mmHg/10 Kg loss DASH diet 8-14 mm Limit NaCl 2-8 mm Activity 4-9 mm Alcohol 2-4 mm

HTN Management:
General: PreHTN: Stage I: Stage II: GOALS:

Themes:

Compelling Indications for Certain Drug Classes: Heart Failure: Thiazide, BB, ACEI, ARB, Aldosterone antagonist High CAD risk: Thiazide, BB, ACEI, CCB Post MI: BB, ACEI, Aldosterone antagonist Diabetes: Thiazide, BB, ACEI, ARB, CCB Stroke prevention: Thiazide, ACEI CKD: ACEI, ARB Favorable effects: Unfavorable effects: Thiazide slow dimineralization in osteoporosis Thiazides - used cautiously in gout or hx of hyponatremia BB useful in rx of atrial arrhythmias, migraines, thyrotoxosis BB - avoid in pts w/ asthma, reactive airway dz, 2 or 3rd degree heart block CCBs useful in Reynaud's & certain arrhythmias ACEI & ARBS - contraindicated in pregnant (or soon to be) Alpha blockers useful in prostatism Aldosterone antagonists & K sparing diuretics can >> Hyperkalemia

HTN Urgencies & Emergencies:

HTN Urgency: Accelerated malignant HTN (BP > 200 in asymptomatic pt) Severe HTN in kidney transplant pt Severe HTN (DBP> 120 w/ no impending complications) Severe epistaxis HTN Emergency - Malignant HTN Sudden rise in BP w/ HA, change in mental status & neuro sx Path: cerebral edema, petechial hemorrhages & micro infarcts Eyes: hemorrhages, exudate & papilledema Renal: oliguria, azotemia CNS: HA, confusion, somnolence, stupor GI: N/V Cardio: LV hypertrophy/dysfunction, ischemia DBP > 140 Heme: Microangiopathic hemolytic anemia Drugs: Vasodilators, Adrenergic inhibitors

Rx of Emergencies:

IV Blood & urine Continuous BP monitoring - reduce BP to 160/100 or MAP by 25% Start Oral maintenance drugs ASAP

Diastolic < 80 80-89 89-99 >100

euro exam

20 mmHg/10 Kg loss

Renal Cell Carcinoma General hypernephroma (b/c gross appearance of tumor resembles adrenal tissue b/c of high lipid content) M>F highly vascular; extension into renal veins and even IVC not uncommon; metastasis spread chiefly through vascular routes often undergo cystic internal degeneration; calcification due to internal necrosis = significant radiological indicator of malignancy 5 year survival of 40 % (although stage dependent) Clear Cell most common type of RCC (80%) nodular, variegated masses may extend beyond capsule propensity for venous invasion cells w/ a clear cytoplasm filled w/ glycogen and lipids the rest are papillary (or rare variants such as chromophobe or colleecting duct) Path originate from proximal tubular elements; usually 3 cell types - clear, granular, spindle cells gross exam - nodules/masses sharply demarcated f/ remaining parenchyma cross section - yellow and encapsulated Genetics von Hippel-Lindau syndrome (VHL) - characterized by appearance of cerebellar hemangioblastomas and retinal angiomas associated w/ loss of VHL tumor suppressor gene; 40% of these pts develop RCC and almost all RCCs show loss of this gene Clinical classic triad of hematuria, flank pain, palpable flank mass (seen in ~10% of pts) most commmon clinical finding - microscopic hematuria large number of systemic, extrarenal manifestations - fever, wt loss, ESR, anemia, polycythemia 50% found accidentally in CT ectopic hormone production - hypercalcemia, Cushing's; but paraneoplastic syndromes rare Treatment surgical excision (usually via radical nephrectomy) respond poorly to radiation and chemo Other Kidney and Pelvis Tumors Transitional Cell Carcinoma of the Renal Pelvis papillary neoplasms that resemble transitional carcinoma of the urinary bladder clinical, gross, and microscopic appearance similar to the rest of the urinary tract most present w/ early sxs of hematuria, urinary obstruction and colic, hydronephrosis = early detection surgical removal >> good results; 5 yr survival of 70% for Grade I and II Wilm's Tumor (nephroblastoma) General most common tumor affecting infants and young children; usually present at birth, but not clinically apparent until 2-4 y/o; 5 % bilateral Genetics WT-1: role in nml dev of kidney and other organs; loss >> tumorigenesis WAGR syndrome: Wilms tumor, aniridia (no iris), genitourinary abn, retardation Denys-Drash syndrome: Wilm's tumor + intersexual disorders + glomerular dz WT-2: tumor suppressor gene Beckwith-Widemann syndrome: Wilms tumor + hemihypertrophy of body + visceromegaly + macroglossia Path well-circumscribed fleshy masses; solitary or multinodular; may have hemorrhage or necrosis; made of immature cells similar to fetal kidney form structures resembling fetal tubules and glomeruli or arranged into bundles of spindle cells w/o differentiation resembling renal blastema Clinical abdominal mass +/- hematuria highly malignant improved therapy of surgery + chemo >> 85% cured Bladder Carcinoma General most are transitional cell carcinomas less invasive than RCC; 70% are Grade I exophytic tumors w/ excellent prognosis respond better to combo of surg and chemo Path Papillary - wartlike protrusions most common exophytic - attached to mucosa by stalk usu noninvasive Flat - mucosal plaques or thickening in situ carcinoma - thickening and dysplasia of surface epithelium often multifocal; so, most grossly visible tumors associated w/ additional flat lesions that appear as carcinoma in situ on histological exam invasive = penetration of basement membrane Clinical present w/ sxs early; intravesical growth causes urinary irritation, hematuria hematuria, dysuria, lower abd pain Dx cystoscopy >> confirm w/ biopsy cytological exam of urinary sediment useful w/ early lesions Tx surgical resection of tumor and chemo if multifocal, require radical surgery - removal of entire bladder immunotherapy: intravesical instillations of immunopotentiators, i.e. BCG stim. granuloma formation and delayed hypersensitivity >> destrc't of local tumors