USMLE (Fach) / Renal (Lektion)

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• Renal clearance Cx = (Ux V)/Px = volume of plasma from which the substance is completely cleared per unit time. Cx = clearance of X (mL/min)Ux = urine concentration of XV = urine flow rate (mL/min)Px = plasma concentration If Cx < GFR: net tubular resorption of X.If Cx > GFR: net tubular secretion of X.
• Fanconi syndrome Generalized reabsorption defect in PCT → ↑ excretion of nearly all amino acids, glucose, HCO3-, and PO43-, and all substances absorbed by the PCT. - May result in metabolic acidosis (proximal RTA), hypophosphatemia, osteopenia. Causes:- Hereditary defects (eg Wilson disease, tyrosinemia, glycogen storage disease, cystinosis)- Ischemia- Multiple myeloma- Nephrotoxins/drugs (eg ifosfamide, cisplatin, tenofovir)- Lead poisoning
• Bartter syndrome Resorptive defect in thick ascending loop of Henle (affects Na+/K+/2Cl- cotransporter). - Autosomal-recessive - Results in metabolic alkalosis, hypokalemia, hypercalciuria.- ↑ renin, ↑ aldosterone, ↑ urine Ca2+ - Presents similarly to chronic loop diuretic use.
• Gitelman syndrome Reabsorption defect of NaCl in DCT.- Autosomal-recessive- Less common than Bartter syndrome - Leads to hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria.- ↑ renin, ↑ aldosterone, ↓ magnesium, ↓ urine Ca2+ - Similar to using life-long thiazide diuretics.
• Liddle syndrome Gain of function mutation → activity of ↑ Na+ channel → ↑ Na+ reabsorption in collecting tubules - Autosomal-dominant - Results in hypertension, hypokalemia, metabolic alkalosis, ↓ renin, ↓ aldosterone - Presents like hyperaldosteronism, but aldosteron is nearly undetectable. Treatment: amiloride
• Syndrome of Apparent Mineralcorticoid Excess In cells containing mineralocorticoid receptors, 11β-hydroxysteroid dehydrogenase converts cortisol (active) to cortisone (inactive).Hereditary deficiency of 11β-hydroxysteroid dehydrogenase → excess cortisol → mineralocorticoid receptor activity- Autosomal recessive- Can acquire disorder from glycyrrhetinic acid (present in licorice), which blocks activity of 11β-hydroxysteroid dehydrogenase. - Hypertension, hypokalemia, metabolic alkalosis.- ↓ serum aldosterone levels Treatment: K+-sparing diuretics (↓ mineralocorticoid effects) or corticosteroids (exogenous corticosteroids ↓ endogenous cortisol production → ↓ mineralocorticoid receptor activation)
• Renin-angiotensin-aldosterone system Renin: Secreted by juxtaglomerular cells in response to ↓ renal arterial pressure, ↑ renal sympathetic discharge (β1 effect), ↓ NaCl delivery to macula densa cells. AT II: Helps maintain blood volume and blood pressure. Affects baroreceptor function; limits reflex bradycardia, which would normally accompany its pressor effects. Acts at AT1 receptors on vascular smooth muscle, constricts efferent arteriole of glomerulus, causes aldosterone and ADH secretion, increases Na+/H+ activity in PCT, stimulates hypothalamus (thirst). ANP, BNP: Releases from atria (ANP) and ventricles (BNP) in response to ↑ volume; may act as "check" on RAAS; relaxes vascular smooth muscle via cGMP → ↑ GFR, ↓ renin. Dilates afferent arteriole, constricts efferent arteriole, promotes natriuresis. ADH: Primarly regulates osmolarity, also responds to low blood volume states. Stimulates reabsorption of water in collecting ducts. Also stimulates reabsorption of urea in collecting ducts to maintain corticopapillary osmotic gradient. Aldosterone: Primarily regulates ECF volume and Na+ content; responds to low blood volume states. Responds to hyperkalemia by ↑ K+ excretion.
• Renal oncocytoma Benign epithelial cell tumor arising from collecting ducts. Macroscopic: Well-circumscribed mass with central scar.Microscopic: Large eosinophilic cells with abundant mitochondria without perinuclear clearing (vs chromophobe renal cell carcinoma). - Presents with painless hematuria, flank pain, abdominal mass. - Often resected to exclude malignancy (eg, renal cell carcinoma).
• Squamous cell carcinoma of the bladder Chronic irritation of urinary bladder → squamous metaplasia → dysplasia and squamous cell carcinoma. Risk factors:- Schistosoma haematobium (Middle East)- Chronic cystitis- Smoking- Chronic nephrolithiasis - Presents with painless hematuria
• Urinary incontinence Stress incontinence: Outlet incompetence (urethral hypermobility or intrinsic sphincteric deficiency) → leak with ↑ intraabdominal pressure (eg, sneezing, lifting).- ↑ risk with obesity, vaginal delivery, prostate surgery.- ⊕ bladder stress test (directly observed leakage upon coughing of Valsalva maneuver).Treatment: pelvic floor muscle strengthening (Kegel) exercises, weight loss, pessaries. Urgency incontinence: Overactive bladder (detrusor instability) → leak with urge to void immediately. - Associated with UTI.- Treatment: Kegel exercises, bladder training (timed voiding, distraction or relaxation techniques), antimuscarinics (eg, oxybutynin). Mixed incontinence: Features of both stress and urgency incontinence. Overflow incontinence: Incomplete emptying (detrusor underactivity or outlet obstruction) → leak with overfilling. - Associated with polyuria (eg, diabetes), bladder outlet obstruction (eg, BPH), neurogenic bladder (eg, MS).- ↑ postvoid residual (urinary retention) on catheterization or ultrasound.Treatment: catheterization, relieve obstruction (eg, α-blockers for BPH).
• Urinary tract infection (acute bacterial cystitis) Inflammation of urinary bladder.  - Presents as suprapubic pain, dysuria, urinary frequency, urgency.- Systemic signs (eg, high fever, chills) are usually absent. Risk factors: female gender (short urethra), sexual intercourse ("honeymoon cystitis"), indwelling catheter, diabetes mellitus, impaired bladder emptying. Causes:- E coli (most common)- Staphylococcus saprophyticus – seen in sexually active women (E coli is still more common in this group)- Klebsiella- Proteus mirabilis – urine has ammonia scent Lab findings: - ⊕ leucocyte esterase- ⊕ nitrates (indicate gram ⊝ organisms)- Sterile pyuria and ⊝ urine cultures suggest urethritis by Neisseria gonorrhoeae or Chlamydia trachomatis
• Acute tubular necrosis Most common cause (~85%) of intrinsic acute kidney injuries in hospitalized patients. Spontaneously resolves in many cases. Can be fatal, especially during initial oliguric phase. ↑ FENa. Key finding: granular ("muddy brown") casts. 3 stages:1. Inciting event2. Maintenance phase – oligouric; lasts 1-3 weeks; risk of hyperkalemia, metabolic acidosis, uremia. LM shows tubular epithelial necrosis, denudation of the tubular basement membrane, casts.3. Recovery phase – polyuric; BUN and serum creatinine fall; risk of hypokalemia and renal wasting of other electrolytes and minerals. Characteriized by re-epithelization of tubules. Causes:- Ischemic – 2° to ↓ renal blood flow (eg, hypotension, shock, sepsis, hemorrhage, HF). Results in death of tubular cells that may slough into tubular lumen (PCT and thick ascending limb are highly susceptible to injury).- Nephrotoxic – 2° to injury resulting from toxic substances (eg, aminoglycosides, radiocontrast agents, lead, cisplatin, ethylene glycol), crush injury (myoglobinuria), hemoglobinuria. Proximal tubules are particularly susceptible to injury. 
• Nephron physiology Early PCT – contains brush border.- Reabsorbs all glucose and amino acids and most HCO3-, Na+, Cl-, PO43-, K+, H2O and uric acid. Isotonic absorption. Generates and secretes NH3, which enables kidney to secrete more H+.- PTH – inhibits Na+/PO43- cotransport → PO43- excretion.- AT II – stimulates Na+/H+ exchange → ↑ Na+, H2O, and HCO3- reabsorption (permitting contraction alkalosis). Thin descending loop of Henle – passively reabsorbs H2O via medullary hypertonicity (impermeable to Na+). Concentrating segment. Makes urine hypertonic. Thick ascending loop of Henle – reabsorbs Na+, K+, and Cl-. Indirectly induces paracellular reabsorption of Mg2+ and Ca2+ through ⊕ lumen potential generated by K+ backleak. Impermeable to H2O. Makes urine less concentrated as it ascends. Early DCT – reabsorbs Na+, Cl-. Makes urine fully dilute (hypotonic).- PTH – ↑ Ca2+/Na+ exchange → Ca2+ reabsorption. Collecting tubule – reabsorbs Na+ in exchange for K+ and H+ (regulated by aldosterone).- Aldosterone – acts on mineralocorticoid receptor → mRNA → protein synthesis. ↑ apical K+ conductance, ↑ Na+/K+ pump, ↑ epithelial Na+ channel (ENaC) activity → lumen negativity → K+ secretion. In α-intercalated cells: lumen negativity → ↑ H+ ATPase activity → ↑ H+ secretion → ↑ HCO3-/Cl- exchanger activity.- ADH – acts at V2 receptor → insertion of aquaporin H2O channels on apical side. 
• Ethylene glycol poisoning Toxic alcohol that is metabolized to glycolate, which is cytotoxic to the renal tubules and causes acute tubular necrosis.Glycolate is further metabolized to oxalate, which contributes to oliguric renal failure by precipitating in the kidneys and causing tubular obstruction. - Symptoms of ethanol intoxicationTriad:1. Flank pain2. Gross hematuria3. Oliguria- High anion gap acidosis- Elevated osmolar gap - Urine microscopy shows envelope- or dumbbell-shaped calcium oxalate crystals that are positively birefringent on polarization.
• Kidney embryology Pronephros – week 4; then degenerates. Mesonephros – functions as interim kidney for 1st trimester; later contributes to male genital system. Metanephros – permanent; first appears in 5th week of gestation; nephrogenesis continues through weeks 32-36 of gestation.- Ureteric bud – derived from caudal end of mesonephric duct; gives rise to ureter, pelvises, calyces, collecting ducts; fully canalized by 10th week- Metanephric mesenchyme (ie, metanephric blastema) – ureteric bud interacts with this tissue; interaction induces differentiation and formation of glomerulus through to distal convoluted tubule (DCT)- Aberrant interaction between these 2 tissues may result in several congenital malformations of the kidney (eg, renal agenesis, multicystic dysplastic kidney) Ureteropelvic junction – last to canalize → most common site of obstruction (can be detected on prenatal ultrasound as hydronephrosis)
• Congenital solitary functioning kidney Condition of being born with only one functioning kidney. Majority asymptomatic with compensatory hypertrophy of contralateral kidney, but anomalies in contralateral kidney are common. - Often diagnosed prenatally via ultrasound. Unilateral renal agenesis – Ureteric bud fails to develop and induce differentiation of metanephric mesenchyme → complete absence of kidney and ureter. Multicystic dysplastic kidney – Ureteric bud fails to induce differentiation of metanephric mesenchyme → nonfunctional kidney consisting of cysts and connective tissue. Predominantly nonhereditary and usually unilateral; bilateral leads to Potter sequence.
• Duplex collecting system Bifurcation of ureteric bud before it enters the metanephric blastema creates a Y-shaped bifid ureter.  Duplex collecting system can alternatively occur through two ureteric buds reaching and interacting with metanephric blastema. Strongly associated with vesicoureteral reflux and/or ureteral obstruction, ↑ risk for UTIs.
• Posterior urethral valves Membrane remnant in the posterior urethra in males; its persistence can lead to urethral obstruction. Can be diagnosed prenatally by hydronephrosis and dilated or thick-walled bladder on ultrasound.  Most common cause of bladder outlet obstruction in male infants.
• Kidney anatomy and glomerular structure - Left kidney is taken during donor transplantation because it has a longer renal vein. Renal blood flow: renal artery → segmental artery → interlobar artery → arcuate artery → interlobular artery → afferent arteriole → glomerulus → efferent arteriole → vasa recta/peritubular capillaries → venous outflow.
• Fluid compartments 60-40-20 rule (% of body weight for average person)- 60% total body water- 40% ICF, mainly composed of K+, Mg2+, organic phosphates (eg, ATP)- 20% ECF, mainly composed of Na+, Cl-, HCO3-, albumin Plasma volume can be measured by radiolabeling albumin. Extracellular volume can be measured by inulin or mannitol. Osmolality = 285-295 mOsm/kg H2O.
• Glomerular filtration barrier Responsible for filtration of plasma according to size and charge selectivity. Composed of:- Fenestrated capillary endothelium- Basement membrane with type IV collagen chains and heparan sulfate- Epithelial layer consisting of podocyte foot processes Charge barrier – all 3 layers contain Θ charged glycoproteins that prevent entry of Θ charged molecules (eg, albumin)Size barrier – fenestrated capillary endothelium (prevent entry of >100 nm molecules/blood cells); podocyte foot processes interpose with basement membrane; slit diaphragm (prevent entry of molecules >50-60 nm).
• Glomerular filtration Inulin clearance can be used to calculate GFR because it is freely filtered and is neither reabsorbed nor secreted. GFR = Uinulin X V/Pinulin = Cinulin Normal GFR ~100 mL/min Creatinine clearance is an approximate measure of GFR. Slightly overestimates GFR because creatinine is moderately secreted by renal tubules. Incremental reductions in GFR dfine the stages of chronic kidney disease.
• Effective renal plasma flow Effective renal plasma flow (eRPF) can be estimated using para-aminohippuric acid (PAH) clearance. Between filtration and secretion, there is nearly 100% excretion of all PAH that enters the kidney. eRPF = UPAH x V/PPAH = CPAH Renal blood flow (RBF) = RPF/(1-Hct). Usually 20-25% of cardiac output. Plasma volume = TBV x (1-Hct) eRPF underestimates true renal plasma flow (RPF) slightly.
• Filtration Filtration fraction (FF) = GFR/RPF Normal FF = 20% Filtered load (mg/min) = GFR (mL/min) x plasma concentration (mg/mL) GFR can be estimated with creatinine clearance.RPF is best estimated with PAH clearance. Prostaglandins dilate afferent arteriole.→ NSAIDs: ↑ RPF, ↑ GFR, so no ∆FF)Angiotensin II constricts efferent arteriole.→ ACE inhibitors: ↓ RPF, ↑ GFR, so ↑ FF)
• Calculation of reabsorption and secretion rate Filtered load = GFR x PxExcretion rate = V x UxReabsorption rate = filtered - excretedSecretion rate = excreted - filteredFeNa = fractional excretion of sodium
• Glucose clearance Glucose at normal plasma level (range 60-120 mg/dL) is completely reabsorbed in proximal convoluted tubule (PCT) by Na+/glucose cotransport. In adults, at plasma glucose of ~200 mg/dL, glucosuria begins (threshold). At rate of ~375 mg/min, all transporters are fully saturated (Tm).Splay phenomenon – Tm for glucose is reached gradually rather than sharply due to the heterogeneity of nephrons (ie, different Tm points); represented by the portion of the titration curve between threshold and Tm. Normal pregnancy is associated with ↑ GFR. With ↑ filtration of all substances, including glucose, the glucose threshold occurs at lower plasma glucose concentrations → glucosuria at normal plasma glucose levels. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (eg, -flozin drugs) result in glucosuria at plasma concentrations <200 mg/dL.
• Relative concentrations along proximal convoluted tubules [TF/P] > 1 when solute is reabsorbed less quickly than water or when solute is secreted.- PAH > Creatinine > Inulin (= GFR) > Urea > Cl- > K+ [TF/P] = 1 when solute and water are reabsorbed at the same rate- Na+ [TF/P] < 1 when solute is reabsorbed more quickly than water- Glucose > Amino acids > HCO3- Tubular inulin ↑ in concentration (but not amount) along the PCT as a result of water reabsorption.Cl- reabsorption occurs at a slower rate than Na+ in early PCT and then matches the rate of Na+ reabsorption more distally. Thus, its relative concentration ↑ before it plateaus.
• Juxtaglomerular apparatus Consists of mesangial cells, JG cells (modified smooth muscle of afferent arteriole) and the macula densa (NaCl sensor, located at the distal end of loop of Henle). - JG cells secrete renin in response to ↓ renal blood pressure and ↑ sympathetic tone (β1). - Macula densa cells sense ↓ NaCl delivery to DCT → ↑ renin release → efferent arteriole vasoconstriction → ↑ GFR. - JGA maintains GFR via RAAS.- In addition to vasodilatory properties, β-blockers can decrease BP by inhibiting β1-receptors of the JGA → ↓ renin release.
• Kidney endocrine functions Erythropoietin: Released by interstitial cells in peritubular capillary bed in response to hypoxia. Calciferol (vitamin D): PCT cells convert 25-OH vitamin D3 to 1,25-(OH)2 vitamin D3 (calcitriol, active form). Prostaglandins: Paracrine secretion vasodilates the afferent arterioles to ↑ RBF.- NSAIDS block renal-protective prostaglandin synthesis → constriction of afferent arteriole and ↓ GFR: This may result in acute renal failure in low renal blood flow states. Dopamine: Secreted by PCT cells, promotes natriuresis. At low doses, dilates interlobular arteries, afferent arterioles, efferent arterioles → ↑ RBF, little or no change in GFR. At higher doses, acts as vasoconstrictor.
• Winters formula PCO2 = 1.5 [HCO3-] + 8 ± 2 Predicted respiratory compensation for a simple metabolic acidosis can be calculated using the Winters formula.  If PCO2 < predicted PCO2 → concomitant respiratory acidosisIf PCO2 > predicted PCO2 → concomitant respiratory alkalosis
• Respiratory acidosis pH <7.35; PCO2 >44 mmHgHypoventilation - Airway obstruction- Acute lung disease- Chronic lung disease- Opioids, sedatives- Weakening of respiratory muscles
• Metabolic acidosis pH <7.35; HCO3- <20 mEq/LCheck anion gap = Na+ - (Cl- + HCO3-) ↑ Anion gap (>12 mEq/L): MUDPILES- Methanol (formic acid)- Uremia- Diabetic ketoacidosis- Propylene glycol- Iron tablets - Lactic acidosis- Ethanol glycol (oxalic acid)- Salicylates (late) Normal anion gap (8-12 mEq/L): HARDASS- Hyperalimentation- Addison disease- Renal tubular acidosis- Diarrhea- Acetazolamide- Spironolactone- Saline infusion
• Respiratory alkalosis pH > 7.45; PCO2 <36 mmHg Hyperventilation- Anxiety/panic attack- Hypoxemia (eg, high altitude)- Salicylates (early)- Tumor- Pulmonary embolism
• Metabolic alkalosis pH >7.45; HCO3- >28 mEq/LWorkup: Volume status, urine chloride H+ loss/HCO3- excess:- Loop diuretics- Vomiting- Antacid use- Hyperaldosteronism Low urine chloride → Vomiting/nasogastric aspirationHigh urine chloride, hypo-/euvolemic → Diuretic use; Barter & Gitelman syndromeHigh urine chloride, hypervolemic → Excess mineralocorticoid activity (eg, primary hyperaldosteronism, Cushing disease, ectopic ACTH production)
• Nephritic syndrome When glomeruli are involved, leads to hematuria and RBC casts in urine. Associated with azotemia, oliguria, hypertension (due to salt retention), proteinuria, hypercellular/inflamed glomeruli on biopsy. - Acute poststreptococcal glomerulonephritis- Rapidly progressive glomerulonephritis- Diffuse proliferative glomerulonephritis- IgA nephropathy (Berger disease)- Alport syndrome- Membranoproliferative glomerulonephritis
• Hydronephrosis Distention/dilation of renal pelvis and calyces. Usually caused by urinary tract obstruction (eg, renal stones, severe BPH, congenital obstructions, cervical cancer, injury to ureter); other causes include retroperitoneal fibrosis, vesicoureteral reflux. Dilation occurs proximal to site of pathology. Serum creatinine becomes elevated if obstruction is bilateral or if patient has an obstructed solitary kidney. Leads to compression and possible atrophy of renal cortex and medulla.
• Renal papillary necrosis Coagulative necrosis of the renal medullary pyramids and sloughing of necrotic renal papillae → gross hematuria and proteinuria. - May be triggered by recent infection of immune stimulus Associated with:- Sickle cell disease or trait- Acute pyelonephritis- Diabetes mellitus- NSAIDs Clinical features:- Patients with chronic course are usually asymptomatic- Flank pain, colicky pain- Hematuria (micro- or macroscopic)- Fever, chills
• Simple vs complex renal cysts Simple cysts are filled with ultrafiltrate (anechoic on ultrasound). Very common and account for majority of all renal masses. Found incidentally and typically asymptomatic. Complex cysts, including those that are septated, enhanced, or have solid components on imaging require follow-up or removal due to risk of renal cell carcinoma.
• Crystal-induced acute kidney injury Etiology:- Acyclovir- Indinavir (protease inhibitor)- Methotrexate- Ciprofloxacin Drugs with low urine solubility precipitate within the renal tubules→ tubular obstruction & toxicity to tubules. Symptoms:- Patients are usually asymptomatic- Renal colic Therapy: IV fluids

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