Renal Flashcards
Pronephros
Early embryologic kidney (Week 4)–> degenerates
Mesonephros
Interim kidney for 1st trimester
- Contributes to male genitalia
Metanephros
Permanent kidney structure; appears in 5th week
- Nephrogenesis until 32-36 weeks gestation
Structures within metanephros:
- Ureteric bud
- Metanephric mesenchyme (mesoderm)
Intermediate mesoderm
Forms urogenital ridge–> nephrogenic cord–> mesonephros:
- Wolffian duct in males
- Gartner’s ducts in females
Ureteric bud
Caudal end of mesonephros; canalized by week 10 Collecting system: - Collecting duct - Major/minor calyxes - Renal pelvis - Ureters
Metanephric mesoderm
Kidney structures:
- Glomerulus
- Bowman’s space
- Proximal tubule
- Loop of Henle
- Distal and collecting tubule
** formed through interaction/induction with ureteric bud
Ureteropelvic junction
Last part of kidney to canalize–> most common site of obstruction (hydronephrosis) in fetus
Potter’s syndrome
Oligohydramnios–> compressed fetus–> limb/facial deformities, pulmonary hypoplasia (death)
can’t Pee–> Potters
Causes:
- ARPKD
- Posterior urethral valves
- Bilateral renal agenesis
Horseshoe kidney
Inferior poles of kidneys fuse
- Ascend–> trapped under inferior mesenteric artery
Normal function
* Associated with Turner’s syndrome (46XO)
Multicystic dysplastic kidney
Abnormal interaction between ureteric bud and metanephros–> nonfunctional kidney (cysts and connective tissue)
- Unilateral= asymptomatic, contralateral kidney hypertrophies to compensate
Prenatal diagnosis with ultrasound
Fluid balance
60% total body water
- 2/3 (40% total) Intracellular (ICF)
- 1/3 (20% total) extracellular (ECF): 1/4 plasma, 3/4 interstitial
Plasma volume= measured by radiolabeled albumin
ECF= measured by inulin (freely filtered, fully cleared)
Glomerular filtration barrier
Vessel: fenestrated capillary endothelium (size barrier)
Glomerulus:
- Basement membrane (fused) with heparin sulfate= negative charge barrier
- Epithelial layer= podocyte foot processes
** charge barrier lost in nephrotic syndrome–> albuminuria, hypoproteinemia, generalized edema, hyperlipidemia
Renal clearance
Clearance (x)= Urine[x]*Urine flow (V)/ Plasma[x]
Cx=UxV/Px
Cx < GFR: reabsorption
Cx > GFR: secretion
Cx = GFR: no net secretion or reabsorption
GFR
Inulin clearance used to calculate GFR= completely cleared
GFR= U[inulin]*V/P[inulin]= C[inulin]
** Creatinine clearance is approximate measurement of GFR (slightly overestimates as renal tubules secrete):
Creatinine= Non-protein waste product of skeletal muscle metabolism
Clearance= 15-25 mg/kg/day= proportional to muscle mass; Serum concentration dependent on:
- Excretion (glomerular filtration)
- Secretion into lumen
Changes in creatinine excretion have hyperbolic relationship with GFR:
- jump from 1 to 2 mg/dL–> 50% loss of nephrons
Effective renal plasma flow
Estimate using PAH clearance: filtered and actively secreted in proximal tubule
- All entering kidney–> excreted
ERPF= U[PAH] * V/P[PAH}
** underestimates by ~10%
Filtration
Filtration fraction= GFR/RPF
- Normal = 20%
- Filtered load= GFR * plasma concentration
- Prostaglandins dilate Afferent arteriole–> increased RPF, GFR–> constant FF)
- Blocked by NSAIDs
- Angiotensin II constricts Efferent arteriole–> decreased RPF, increased GFR–> increased FF
- Blocked by ACE-I
Glucose clearance
Completely reabsorbed in proximal tubule: Na+/glucose cotransport
- 160 mg/dL–> glucosuria
- 350 mg/dL–> transporters fully saturated (Tm)
Pregnancy: decreased reabsorption of glucose, amino acids–> glucosuria, aminoaciduria
Amino acid clearance
Reabsorbed in proximal tubule:
Na+-dependent transporters
Hartnup’s= deficiency of neutral aa (tryptophan) transporter–> pellagra
Urea excretion
Freely filtered at glomerulus
- Passively reabsorbed in proximal tubule, inner medullary collecting duct
- Passively secreted by thin loop of Henle
10-70% excreted depending on urinary flow, concentration
PTH in kidney
Acts on interstitial side of tubules
Proximal tubule: inhibits Na/Phosphate cotransporter–> excrete phosphate
- enhances activity of enzyme (1-alpha-hydroxylase) that converts 25-OH to 1,25-OH2 Vit D
DCT: increases Ca+2/Na+ exchange–> increased Ca+2 reabosorption
Angiotensin II
Maintains blood volume and BP
Within kidney:
- Constricts efferent arteriole
- PCT: stimulates Na+/H+ exchange on luminal side–> increased Na+, H2O, HCO3- reabsorption (compensatory Na+ resorption with water vs ADH)
* Contraction alkalosis (dehydrated–> more ATII–> more bicarb resorption)
Adrenal gland:
- Synthesis of aldosterone
Vasculature:
- AT1 receptors on smooth muscle–> vasoconstriction–> increased BP
Posterior pituitary:
- ADH secretion–> H2O absorption via aquaporin in medullary collecting duct
Hypothalamus:
- Thirst
Cardiac:
- Limits reflex bradycardia that normally accompanies increased BP
Aldosterone
decreased blood volume–> renin–> angiotensin II production–> Aldosterone in adrenal gland
- Also secreted in response to elevated [K+]
Cortical Collecting duct:
- Mineralocorticoid receptor–> insert Na+ channel on luminal side–> increase Na+, water resoprtion
- Na+/K+ pump insertion on interstitial side
- upregulates K+ channels, intercalated H+ channels–> K+ and H+ excreted–> can cause metabolic alkalosis
** Directly blocked from receptor by spironolactone; effects blocked by amiloride, triamterine (K+-sparing diuretics)
ADH
decreased blood volume–> renin–> angiotensin II production–> ADH in posterior pituitary
Regulates osmolarity
Responds to low blood volume (overrides osmolarity)
Collecting tubule
- Acts on V2 receptor
- Inserts aquaporin channel on luminal side
ANP
Released from atria in response to increased blood volume
- “Checks” RAAS
- Relaxes vascular smooth muscle: increased cGMP–> increased GFR–> decreased renin–> Na+ and H2O loss
Juxtaglomerular apparatus
JG cells= smooth muscle cells of afferent arteriole
- Secrete renin when renal BP low
Macula densa= DCT NaCl sensor
- Induce JG cells to secrete renin in response to low NaCl in DCT
Renin converts Angiotensinogen (liver) to angiotensin I–> lungs (ACE)–> angiotensin II
+ Increased sympathetic tone (Beta-1)
** Beta-blockers (Beta-1 selective, like metoprolol) can decrease BP–> inhibiting B1 receptors of JGA–> decreased renin release
EPO
Erythropoietin
- Released by interstitial cells in peritubular capillary bed in response to hypoxia
1,25-OH2 Vitamin D
Converted by PCT cells from 25-OH to 1,25-OH2 (active form)
- PTH enhances activity of enzyme (1-alpha-hydroxylase)
** PTH secreted in response to low plasma [Ca+2] or [vit D] or high plasma [Phosphate]
Potassium shift out of cell
DO Insulin LAB work:
- Digitalis
- hyperOsmolarity
- Insulin deficiency
- Lysis of cells
- Acidosis
- Beta-adrenergic antagonist
Na+ balance
Low serum [Na+]
- Nausea, malaise, stupor, coma
High serum [Na+]
- Irritability, stupor, coma
K+ balance
Low serum [K+]
- ECG: U waves, Flattened T waves
- Arrhythmias, muscle weakness
High serum [K+]
- Wide QRS, peaked T waves
- Arrhythmias, muscle weakness
Ca+2 balance
Low [Ca+2]
- Tetany, seizures
High [Ca+2]
- Stones, bones, groans, moans
Mg+2 balance
Low [Mg+2]
- tetany, arrhythmias
High [Mg+2]
- decreased DTRs, lethargy, bradycardia, hypotension, cardiac arrest, hypocalcemia
Respiratory compensation for metabolic acidosis
Winter’s formula:
PCO2= 1.5 (HCO3-) + 8 +/-2
Anion Gap
Check with metabolic acidosis:
Na+ - (Cl- + HCO3-)
Increased: MUDPILES - Methanol - Uremia - Diabetic ketoacidosis - Propylene glycol - Iron tablets/INH - Lactic acidosis - Ethylene glycol - Salicylates
Normal: HARDASS - Hyperalimentation - Addison's disease - Renal tubular acidosis - Diarrhea - Acetazolamide - Spironolactone - Saline infusion
Distal Renal tubular acidosis
Type 1 Renal Tubular Acidosis:
Failure of distal alpha intercalated cells to excrete H+
Leads to:
- Elevated blood H+
- Inability to acidify urine (pH > 5.3)–> increased risk of calcium phosphate stones
- Elevated Chloride
- Hypokalemia
- Bone reabsorption (Rickets in kids, osteomalacia in adults)
Hyperchloremic non-anion gap acidosis
Proximal renal tubular acidosis
Type 2 Renal Tubular Acidosis
Failure of proximal tubular cells to reabsorb bicarb
Leads to:
- Elevated blood H+
- CAN acidify urine (excrete H+)- ph < 5.3
- Hypokalemia
- Increased rick for hyposphatemic rickets
Seen in Fanconi’s anemia
Hyperkalemic renal tubular acidosis
Type 4 RTA
Collecting tubule not responsive to aldosterone or hypoaldeosteronism
–> HYPERkalamia–> impaired ammoniagensis in PCT
- Decreased buffering, decreased urine pH
Alport syndrome
Type IV collagen defect
- type IV collagen= basement membrane, basal lamina of kidneys, ears, eyes
X-linked recessive (boys)
Symptoms:
- Progressive nephritis
- Deafness
- Ocular disturbances
Calcium stones
Calcium oxalate= due to hypercalciuria
- Acidic urine (low pH)
- Calcium oxalate stones are hard and dark
- Presentation: hypercalciuria and normocalcemia
- Urinalysis: calcium oxalate crystals are colorless tetrahedra (envelope shape), oval or dumbbell shapes; polarizable
- seen in ethylene glycol poisoning (antifreeze), Vitamin C overuse, Crohn’s disease (low calcium reabsorption–> oxalate crystal formation)
Calcium phosphate: due to hypercalciuria
- increased pH causes precipitation
Prevention: thiazides, citrate
Struvite stones
Magnesium ammonium phosphate (15% of stones)
- Due to urea-splitting bacteria (Proteus, Staphylococcus, Providencia)
- Alkaline urine (high pH)
- Triple phosphate crystals in urinalysis are colorless, rectangles or coffin lids shaped
- Staghorn calculi (nidus for UTIs)
Uric acid stones
Due to hyperuricemia (6% of stones)
- precipitate in collecting duct @ low pH
- RadiolUcent: can see on CT, ultrasound
- Acidic urine (low pH)
- Rhomboid crystals
Hyperuricemia also seen in high cell turnover states (leukemia)
Tx: alkalinize urine
Cystine stones
Due to genetic defects in cystine transport
- Autosomal recessive
- Yellow-brown radiopaque stones
- acidic urine (low pH)
- Hexagonal crystals
** Sodium nitroprusside testing–> urine turns purple after 2-10 minutes
Tx: alkalinize urine
Renal papillary necrosis
Sloughing renal papillae:
- Presentation: gross hematuria, acute, colicky flank pain (ureteral obstruction from sloughed papillae), proteinuria; recent infection/immune stimulus
- Associated with: DM, acute pyelonephritis, chronic phenacetin use (acetaminophen), NSAID use, sickle cell anemia/trait
Histo: coagulative infarct necrosis with preserved tubule outline
- Scars develop on cortical surface (fibrous depressions replace inflammatory foci)
Prerenal azotemia
Elevated nitrogen levels in blood NOT due to kidney damage
- Renal blood flow decreased–> decreased GFR–> decreased clearance of metabolites
- Kidney is intact and cells are not damaged
- Kidney avidly reabsorbs salt and water to try and preserve intravascular blood volume and renal blood flow.
Features:
- History of volume depletion
- Exam consistent with volume depletion
- Fractional Excretion of Na (FENa) < 1 %
- Urine Na < 20 mEq/L (low if kidney is Na avid, tubules intact)
- Urine Osm > 500 mOsm/L
- Increased BUN/Creatinine Ratio
- Bland urinalysis
- Ultimate Test: Give Fluid
- If immediate improvement, then it’s pre-renal
Intrinsic renal failure
Causes:
- Acute tubular necrosis
- Ischemia/toxins
- Acute glomerulonephritis (RPGN); rarer
Pathogenesis:
- Patchy necrosis–> debris obstructs tubule
- fluid backflow–> decreased GFR
Urine sediment:
- epithelial/granular casts on urinalysis
- Casts= mucoprotein secreted by renal tubule cells
- -> decreased GFR–> increased accumulation of casts
Urine lytes:
- Na > 40 mEq/L or FENa > 2%
- Serum BUN/Cr < 15
Postrenal azotemia
In patients with two functioning kidneys, both need to be effected to produce significant renal failure Causes: - Urethral obstruction – most common - Obstruction of a solitary kidney - Bilateral ureteral obstruction
Causes:
- Urethral obstruction
- Bladder neck obstruction (prostatic hypertrophy, bladder carcinoma, bladder infecion)
- Bilateral ureter obstruction:
1. Intraureteral: - Sulfonamide, uric acid crystals, blood clots/stones
2. Extraureteral: - tumor (cervix, prostate, endometriosis)
- Retroperitoneal fibrosis
- Ureteral ligation/edema due to pelvic operation
Features:
- low urine osmolality
- high urine Na+
- FENa > 2%
- Serum BUN/creatinine > 15
Renal Failure consequences
Can’t make urine (oliguria) or excrete nitrogenous waste
Acute loss of kidney function
- Typically connotes acute drop in GFR
Multiple definitions of this, typically based on changes in:
- Serum Creatinine
- Oliguria: <50cc UOP/day
- Azotemia: elevated blood urea nitrogen (BUN ) without symptoms of uremia
- Uremia: buildup of toxins that are cleared by the kidney. Most of these toxins are unknown. (Nausea, anorexia, pericarditis, asterixis, encephalopathy, platelet dysfunction)
- An elevated Urea level alone is NOT sufficient to diagnose uremia
- Na/H2O retention (CHF, pulmonary edema, HTN)
- Hyperkalemia
- Metabolic acidosis
- Anemia (failure of interstitial cells to synthesize EPO)
- Renal osteodystrophy
- Dyslipidemia (increased TG)
- Growth retardation, developmental delay in children
Renal osteodystrophy
- High PTH due to: hypocalcemia, hyperphosphetemia, low calcitriol level,
- Low calcium due to low calcitriol level
- High phosphate due to decreased GFR
- Result of increased PTH: too rapid bone turnover, abnormal bone (woven vs. trabecular)
Mannitol
Osmotic diuretic
Not reabsorbed, causing water to be retained initially, then diuresis
Site of action:
- Proximal tubule: decreased Na reabsorption by osmotic gradient–> increased urine volume
- Descending loop of Henle: increased medullary blood flow, inhibit reabsorption of water
- Collecting duct: opposes action of ADH
Clinical:
- Prevents acute renal failure after severe trauma, complicated surgical procedures (hemolysis, rhabdomyolysis)
- Drug overdose: Toxin excretion
- Reduces intracranial, intraocular pressure–> fluid (not Na) leaves cells
- Does not increase Na excretion (only water)
- Must be given IV (only effects colon if given orally)
AEs:
- PULMONARY EDEMA (contraindicated in anuria, CHF)
- Rapidly distributes to ECF–> extracts water from cells
- Causes acute increase in ECF/hyponatremia (can’t use in CHF, pulmonary edema)
- N/V, headache
- Severe dehydration, hypernatremia
- Hyperkalemia
Acetazolamide
Carbonic anhydrase inhibitor
Site of action: proximal tubule
MOA:
- Inhibits carbonic anhydrase
- Decreases sodium bicarbonate reabsorption
- Cause bicarbonate diuresis (up to 85%) that may lead to metabolic acidosis
- Over time (several days), effectiveness decreases–> soon increase Na reabsorption (thus reversing diuresis)
Use: metabolic alkalosis (alkalinizes urine)
- Induces hyperchloremic metabolic acidosis after excessive use of other diuretics
- Prophylax acute mountain sickness (decreases CSF formation, pH–> increase minute ventilation–> decrease symptoms)
- Glaucoma (decreases rate of aqueous humor formation–> decreased IOP)
- Pseudotumor cerebri
AEs:
- Metabolic acidosis (decreased bicarb reabsorption)
- Phosphaturia, hypercalciuria (can cause calcium stone formation)
- Potassium wasting
- Toxicity: drowsiness/fatigue (CNS carbonic anhydrase inhibition), parasthesis, avoid in liver disease (increases ammonia–> hepatic encephalopathy)
Loop diuretics
Furosemide, Bumetanide, Ethacrynic acid
Site of action: cortical and medullary TAL of loop of Henle
MOA: inhibits Na+-K+-2Cl- transporter
Clinical:
- Rapid onset of action (first line in pulmonary edema)
- Stimulates prostaglandin synthesis in lung, kidneys (NSAIDs–> decreased prostaglandins–> decreased diuresis)
- CHF (decrease ECF volume)
- Excretion of: K+, Mg+2 and Ca+2 (Ca reabsorbed later in DCT, but can be used in hypercalcemia)
- Nephrotic syndrome
Side effects:
- OTOTOXICITY (esp, with aminoglycosides, salicylates, cisplatin)
- hypokalemia, hypomagnesemia
- hyperuricemia (gouty attack)
- decreased paracellular Ca+2 reabsorption–> hypocalcemia (+ calciuria)
- hypochloremic metabolic alkalosis:
1. increased excretion of H+ in low K+ state in Cortical collecting tubule
2. Volume contraction–> ATII increase–> Na/H exchange in PCT–> increased bicarb reabsorption (contraction alkalosis) - Cross-reactivity with sulfonamide allergy
- Dehydration
- Increased LDL, triglycerides, decreased HDL
Hydrochlorothiazide
Thiazide diuretics
Site of action: early distal convoluted tubule
MOA: inhibits luminal co-transport of Na, Cl
- Contraction of ECF volume–> decrease in CO–> decrease peripheral vascular resistance
Clinical use:
- Use in HTN, mild CHF
- Idiopathic hypercalciuria
- Nephrogenic DI
- Renal stones (decreases Ca+ excretion)
AEs:
- Avoid in low GFR
- “Ceiling diuretics”: increasing dose does not promote further diuresis
- hypokalemic metabolic alkalosis
- hyponatremia
- hypomagnesemia
- Hypercalcemia
- Hyperuricemia (gouty attack)
- Sulfa allergy interaction: photosensitivity, generalized dermatitis (rare)
- Hyperglycemia (impair pancreatic insulin release, tissue utilization of glucose)
- Hyperlipidemia
- Volume depletion
Spironolactone, Eplerenone
Potassium-sparing diuretic
MOA: competitive antagonist of aldosterone receptors on collecting tubule (Na-H exchanger)
SIte of action:
- Cortical collecting tubule
Clinical:
- Most effective in primary/secondary hyperaldosteronism (Conn syndrome) - prevents binding of aldosterone to its receptor
- Secondary hyperaldosteronism seen in: CHF, hepatic cirrhosis, nephrotic syndrome
- Ascites
- HTN
- Loop/thiazide-induced hypokalemia
AEs:
- Hyperkalemia (if not on another diuretic)–> can lead to acidosis (body cells exchange K+ for H+)
- Hyperchloremic metabolic acidosis= blocks collecting duct Na-H exchange (aldosterone receptor)–> can’t excrete H+
- Endocrine abnormalities: gynecomastia, hirsutism, impotence, benign prostatic hyperplasia, menstrual irregularities
Triamterene, amiloride
Postassium-sparing diuretic
MOA: interferes with Na+ influx thru epithelial Na ion channels in luminal membrane (Na-H exchanger in collecting duct)
- K+ secretion coupled with Na+ entry (therefore spare K+ secretion by blocking Na entry)
Clinical use:
- HTN
- Loop/thiazide-induced hypokalemia
AEs:
- Hyperkalemia (if not on another diuretic)–> can lead to acidosis
- Hyperchloremic metabolic acidosis= blocks collecting duct Na-H exchange (aldosterone receptor)–> can’t excrete H+
ACE-I
Captopril, enalapril, lisinopril
MOA: inhibits ACE–> decreased angiotensin II–> decreased GFR (prevent constriction of efferent arterioles)
- Increased bradykinin= vasodilator
- Renin increased due to lack of feeback inhibition
- ARBs work similarly but do not increase bradykinin
Use:
- HTN
- CHF
- Proteinuria, diabetic renal disease
- Prevents heart remodeling due to chronic HTN
Tox:
- Cough
- Angioedema
- Teratogen (fetal renal malformations)
- Creatinine kinase (deceased GFR)
- Hyperkalemia
- Hypotension
- avoid in bilateral renal artery stenosis–> further deceased GFR–> renal failure
- Stop thiazides before initiating ACE-I due to 1st dose hypotension (avoid non-selective beta-blocker with ACE-I–> increased K+)
ARB
-sartans
MOA:
- Bind AT-1 receptors (site of angiotensin II binding)–> decreased aldosterone
- Increased renin, angiotensin I and II (no negative feeback)
Use:
- HTN
- CHF
- Proteinuria, diabetic renal disease
- Prevents heart remodeling due to chronic HTN
Tox:
- Teratogen (fetal renal malformations)
- Creatinine kinase (deceased GFR)
- Hyperkalemia
- Hypotension
- avoid in bilateral renal artery stenosis–> further deceased GFR–> renal failure
- Stop thiazides before initiating ARB due to 1st dose hypotension (avoid non-selective beta-blocker with ARB–> increased K+)
Diabetic nephropathy
- Microalbuminuria = 30-300 mg albumin daily
- Overt nephropathy > 300mg/day
- nephrotic syndrome approximately 3,000 mg/day (3g/day)
- Routine urinalysis can’t detect microalbuminuria
- Microalbunuria portends nephropathy
Chronic interstitial nepritis
Prolonged analgesic use (NSAIDs)
- Patchy interstitial inflammation–> fibrosis, necrosis, scarring of papillae, distorted calices architecture, tubular atrophy
Workup of metabolic alkalosis
- Loss of H+ ions from body: vomiting, NG suction–> decreased serum Cl- –> decreased urinary Cl-
- Thiazide/loop diuretics–> Na+ loss–> Cl- follows Na+–> contraction alkalosis (Cl- responsive)
- Corrected by saline administration - Hyperaldosteronism (Conn Syndrome): Increases Na+ reabsorption–> K, Cl, H+ losses–> increased HCO3- (metabolic alkalosis)
- Increased urine Cl-
- Adinistration of saline does NOT correct condition
Casts in urine
RBC: glomerulonephritis, ischemia, malignant HTN
WBC: Tubulointerstitial inflammation, acute pyelonephritis, transplant rejection
Fatty casts (oval fat bodies): nephrotic syndrome
- Microalbuminuria= < 300 mg/day
- Overt nephropathy= > 300 mg/day
- Nephrotic syndrome= 3+ g/day
- Nephrotic syndrome= hyperlipidemia, fatty casts, edema; associated with thromboembolism d/t ATIII loss in urine, infections d/t Ig loss
Granular casts (muddy brown)= acute tubular necrosis
Eosinophils in urine= acute interstitial nephritis (due to meds)
Waxy casts= advanced renal disease/chronic renal failure
Hyaline casts= normal, may be seen in low flow rates d/t Tamm-Horsfall glycoprotein accumulation
Cholesterol crystals in arterioles (not urine)= atherosclerotic embolization (following angioplasty)–> renal arterial damage
