- Proximal Tubule: Na/H antiport and Na/Gluc cotransporter --> 67% of Na

- Thick Ascending Limb: NKCC 2 transporter (2Cl, K, and Na influx) --> 25% of Na

- Distal Tubule: Na/Cl cotransporter --> 5% of Na

- Collecting duct: Na influx channel (ENaC) and K efflux channel --> Controlled by Aldosterone --> 3% of Na

- Na usually moves in conjunction with water --> Na moves down gradient and water follows down it's gradient

- ADH incorporates AQP2 into apical membrane

- ADH binds membrane --> cAMP increase which causes vesicles to fuse with apical membrane

- ADH secretion: AII, sympathetic stimulation, hyperosmolarity, hypovolemia, and hypotension

- Secretion and reabsorption of K in the collecting duct

- Secretion stimulated by aldosterone, ADH, increased potassium intake, increased Na delivery to the distal nephron, and alkalosis

- Reabsorption stimulated by potassium loss

- Proximal tubular cell H secretion: Na/H antiport and H ATPase in the apical membrane --> Secretes H into the lumen to bind with filtered HCO3-

- Intercalated cell type A H secretion: H ATPase and H/K antiport in the apical membrane --> Secretes H into the lumen to bind with ammonia to create ammonium

- Proximal tubular cell HCO3- secretion: Cl/HCO3 antiport at the apical membrane

1. Serum osmolality: Lab value

- Normal: 280-300 mOsm/Kg

- 2Na + gluc/18 + BUN/2.8 + (EtOH/4.6)

- Regulated by ADH

2. Urine osmolality: ADH surrogate

- Normal: 50-1200 mOsm/Kg

- Gives information about the kidney's ability to concentrate urine

- UNa and UCl: RAAS and Aldo surrogate

- Net balance is dependant on sodium intake and sodium excretion

- Volume status is dependant on body sodium content

- Plasma sodium concentration is dependant on water content

- Dehydration: Overall water loss

- Hypovolemia: Extracellular fluid volume loss --> Decreased tissue perfusion

- Salt and water loss comes primarily from the extracellular fluid

- Urine Na excretion/Filtered Na load= UNa x UV/(GFRx PNa)

- Part of the extracellular fluid (ECF) in the arterial system perfusing different tissues

- Pressure perfusing the arterial baroreceptors

- Varies directly with the ECF --> Both are dependent on total body sodium

- Controls: Arterial baroreceptors, cardiopulmonary baroreceptors, and intrarenal baroreceptors

- Factors regulating: Na intake, RAAS, sympathetic nervous system, atrial natriruetic peptide vasopressin, prostaglandins, and tubuloglomerular feedback

- Increased BP --> Increased afferent arteriolar pressure

- Increased afferent arteriolar pressure --> Decreased AII and increased glomerular capillary pressure

- Increased glomerular pressure --> Increased GFR and peritubular capillary pressure

- Increased peritubular capillary pressure --> Increased renal interstitial pressure

- Decreased renin and increased renal interstitial pressure --> Decreased fluid reabsorption by the proximal nephron

- Increased GFR and decreased fluid reabsorption --> Increased excretion of salt and water

- This all leads to reduced plasma and ECF volume and blood pressure

1. Decreased tubular fluid and NaCl delivery to the macula densa --> renin and prostaglandin release

- PGE2 --> Vasodilation of afferent and efferent arterioles

- Renin release --> AII and Aldo release systemically

- Renin stimulated by sympathetic neurons, decreased systemic blood pressure, and reduced NaCl delivery to macula densa

- Avoid NSAIDs in acute decompensated heart failure --> Reduces local PGE2 in the kidney and causes vasoconstriction --> Reduced kidney perfusion

2. Increased tubular fluid and NaCl delivery to the macula densa

- Adenosine release --> Vasoconstriction of afferent arteriole

- Stimulated by AII binding to adrenal cells due to decreased blood pressure

- Increased ENaC incorporation into the apical membrane of the distal tubule

- Increased Na reabsorption

- Increased intracellular cGMP

- Reduced vascular tone --> Increased GFR

- Decreased AQP2 in the collecting duct apical membranes

- Decreased ENaC incorporation in distal tubule

- Activated PDE5 cleaves and inactivates cGMP

- Physical Exam: Decreased skin tugor, decreased JVP, hypotension, orthostasis, and dizziness upon standing

- Labs: Increased BUN and Cr, high BUN/Cr ratio, low UNa, and low FeNa

- FeNa could be <1% in CIN, acute GN, and bilateral renal artery stenosis without hypovolemia

- FeNa could be >1% with diuretic induced hypovolemia

- Physical exam: Peripheral edema/ankle swelling, pulmonary edema, and increased JVP

- 2.5-3L of fluid needs to accumulate before it is clinically apparent

- Due to either increased capillary permeability, decreased serum oncotic pressure, or lymph obstruction

- Impaired aldosterone escape in CHF --> Na and H2O retention --> Edema

1. Underfill hypothesis

- Hypoalbuminemia --> Decreased ECV --> Activation of neurohumoral factors --> Increased sodium absorption --> Edema

2. Overfill hypothesis

- Hypoalbuminemia --> Increased renal sodium retention --> Increased ECV --> Increased hydrostatic pressure and decreased oncotic pressure --> Edema

- Excess Na intake (UNa >100 mEq/day)

- Decreased or delayed intestinal drug absorption

- Decreased drug entry into tubular lumen --> CHF, renal failure, cirrhosis and low albumin

- Increased distal reabsorption

- Decreased loop Na delivery due to low GFR and/or enhanced proximal reabsorption --> Severe CHF and advanced cirrhosis

- CHF

- Cor pulmonale

- Cirrhosis

- Nephrotic syndrome

- History: CAD, HTN, ETOH, drugs that cause cardiac, hepatic or renal disorders

- Edema location: SOB= LVF, SOB+peripheral edema=LVF+RHF and CKD, ascites=cirrhosis, and peripheral edema=CHF, CKD, and CVI

- Intermittent edema=Pre-menstrual

- Serum sodium <135 mEq/L --> <120 mEq/L is danger zone

- Does NOT mean there is a low level of sodium in the blood

- Means there is EXCESS water relative to sodium

- Symptoms: N/V, fatigue, muscle weakness, altered mental status, and seizure/coma

- Can have isoosmolar, hypoosmolar or hyperosmolar hyponatremia

- Normal serum osm of 280-300 mOsm/Kg

- Causes: Pseudohyponatremia, paraproteinemia, and hypertriglyceridemia

- Elevated serum osm: >300 mOsm/Kg

- Causes: Hyperglycemia and hypertonic infusion of glucose or mannitol

- Low serum osm --> <280 mOsm/Kg

- Hypovolemic

- Euvolemic

- Hypervolemic

- Hypoosmotic condition --> <280 mOsm/Kg

- Water excess relative to sodium and decreased total body sodium

- Renal causes: Diuretics (thiazide), salt wasting neuropathy (rare), mineralocorticoid deficiency, and cerebral salt wasting (rare)

- Non-renal causes: Gastrointestinal losses and skin losses

- Physical exam: Hypotension, tachycardia, and dry mucous membranes

- Lab values of extrarenal causes: Urine sodium <20, activation of RAAS due to kidney detection of hypoperfusion, and FeNa <1%

- Lab values of renal causes: Urine sodium < 20

- Treatment: Isotonic IV fluids with normal saline, stop thiazide diuretics, and correct mineralocorticoid deficiency if present

- Rate of sodium correction: <10 mEq/L over first 24 hours and <18 mEq/L over first 48 hours

- Occurs if hypovolemic hyponatremic patients have isotonic fluids infused too quickly

- Rapid correction of hypotonic state --> Quick increase in osmolality leads to demyelination

- Central pontine myelinolysis is the worst response to too rapid correction --> Locked in quadriparesis

- Normally water gain occurs due to hyponatremia --> Swelling of brain cells

- Over time water seeps out to restore normal cell size but hyponatremia persists

- Risk factors: Chronic hyponatremia (48-72 hours), serum sodium concentration < 105, hypokalemia, alcoholism, malnutrition, and liver disease

- Water excess relative to sodium

- Endocrine causes: Hypothyroidism, glucocorticoid deficiency, and syndrome of inappropriate ADH release (SIADH)

- Extreme causes: Psychogenic polydipsia, tea and toast diet, and beer potomania --> Urine Osm <200

- Reset osmostat occurs

- Hyponatremia is the result of increased ADH --> But is it appropriate??

- Causes: Malignancies, pulmonary pathology, CNS pathology, and drugs

- Drug causes: Antidepressants and antipsychotics are the most common

- Diagnosis: Diagnosis of exclusion, urine Osm > Serum Osm (urine Osm >300), urine Na > 20, and hypouricemia

- Treatment: Free water restriction, liberalize dietary sodium, and if Na <120 then treat with hypertonic saline --> Must be monitored in the ICU

- Psychogenic polydipsia: Schizophrenics gulp down water and can't stop --> Drink out of toilet too

- Beer potomania: Prolonged beer drinking --> Essentially just water

- Tea and toast diet: Most common in elderly --> Essentially drinking water too and not taking in sodium

- Treatment: Free water restriction and liberalized dietary sodium --> Add solute to diet

- Water excess relative to sodium and increased total body sodium

- Edematous states: Cirrhosis, decompensated CHF, and nephrotic syndrome

- Also common in acute kidney failure --> Inadequate GFR to deliver tubular fluid to diluting segments of the kidney

- Urine Na <20 --> CHF, cirrhosis, and nephrotic syndrome

- Urine Na >20 --> Advanced kidney disease

- Urine Osm > 350

- Treatment: Sodium and free water restriction, loop diuretics, and ADH antagonists (Tolvaptan)

- Reduced survival in end-stage CHF and liver disease with ADH antagonists

- Na >145 mEq/L

- Always hyperosmolar --> Always a water problem, somtimes a salt problem

- Humans are normally protected from hypernatremia by ADH release and intact thirst mechanism

- Causes: Hypertonic sodium infusion, water loss, and decreased water intake

- Treatment: Increase free water intake, D5W IV fluids, 1/2NS IV fluids, and NS IV fluids if hypovolemic and hemodynamically unstable

- Risk of correcting too fast: Cerebral edema --> Brain cells swell too fast!!

- Rate of sodium correction: <10 mEq/L over first 24 hours and <18 mEq/L over 48 hours

1. Decreased water intake

- Impaired thirst mechanism (Elderly)

- Imapaired access to water: Dementia, intubated/sedated, newborns, and desert wanderers

2. Water loss --> Urine Osm >300

- GI losses: Urine Osm >300 --> Osmotic diarrhea

- Renal losses --> Osmotic diuresis (gluc + mannitol) and central or nephrogenic diabetes insipidus (Urine Osm <200)

- Insensible losses: Fever, sweating and burns

- Water diuresis

- Diagnosis: Polyuria, very dilute urine (Urine Osm <200)

- Treatment: Replace ADH in central and treat underlying cause or give thiazides with nephrogenic

1. Central DI: Lack of ADH production or release

- Etiology: Congenital, familial, infiltrative disease (sarcoidosis), head trauma, pituitary surgery, tumors, and hypoxic encephalopathy

2. Nephrogenic DI: Lack of renal response to ADH

- Etiology: Inactivating mutation of V2 receptor or AQP2, hypercalemia, severe hypokalemia, lithium, amphotericin B, post renal obstruction, recovery phase of acute tubular necrosis, and pregnancy

- Placenta can produce vasopressinase

- Sodium: 100 mEq/day

- Chloride: 100 mEq/day

- Bicarbonate: 2 mEq/day

- Potassium: 50 mEq/day

- Water: 1.5 L/day

- Sodium: 136-145 mEq/L

- Chloride: 95-105 mEq/L

- Bicarbonate: 22-28 mEq/L

- Potassium: 3.5-5.0 mEq/L

- Calcium: 4.2-5.1 mEq/L

- Magnesium: 1.5-2.0 mEq/L

- Sympathetic activation: Renal efferent arteriolar vasoconstriction and B1 receptor mediated renin release

- Hormonal influence: Angiotensin-II induced aldosterone output

- Reduction in plasma oncotic pressure: Hypoalbuminemia

- Glomerular filtration of drugs not bound to plasma albumin or A1-acid glycoprotein

- Proximal tubular secretion by carriers: Organic anion transporter proteins (OATs and MRPs) and MDR1 gene product

- Reabsorption by diffusion dependent on pKa and lipophilicity

- Filtered but not reabsorbed

- Increase extracellular fluid volume and renal blood flow

- Reduces the tonicity of renal medulla

- Decreases water reabsorption, especially in the desending limb, by increasing osmolarity of tubular fluid

- Prototype: Mannitol

- Uses: Glaucoma, cerebral edema, and previously used to acute renal failure from hypovolemia and nephrotoxins

- Prototype: Acetazolamide

- PT Effects: Blocks bicarbonate reabsorption in the PT, inhibits sodium reabsorption, increases urinary Na and bicarbonate excretion, and causes metabolic acidosis leading to loss of diuretic effect

- Distal Effects: Decreases H availability and increases urinary K secretion

- Uses: Metabolic alkalosis, familial hypokalemic periodic paralysis, open-angle glaucoma, and mountain sickness pre-treatment

- Side effects: Hypokalemia due to increased K secretion, calcium stones due to alkalinization of urine, metabolic acidosis and hypersensitivity reactions

- Prototypes: Hydrochlorothiazide

- Inhibit NaCl symporter in distal tubule

- Increased Na and Cl excretion

- Blocks urinary diluting capacity only

- Variable degree of CA inhibition --> HCO3- excretion occurs --> Metabolic acidosis

- Effects on K and Ca: Increased K secretion due to increased Na delivery to distal tubule and increased Ca reabsorption due to inhibition of Na reabsorption

- Uses: Hypertension, calcium nephrolithiasis, edema, and nephrogenic diabetes insipidus

- Side Effects: Hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hyperlipidemia, and hypersensitivity reactions

- Prototype: Furosemide

- Inhibit Na-K-2Cl symporter (NKCC2) in thick ascending limb

- Blocks urinary diluting AND concentrating ability

- Increases distal Na delivery and therefore K excretion

- Increases Ca and Mg excretion due to reduced reabsorption in ascending limb

- Much more effective than hydrochlorothiazide

- Uses: Acute pulmonary edema, edema from cardiac, hepatic and renal causes, and hypertension refractory to other diuretics

- IV or PO formulations --> 50% bioavailability with high variability for PO

- 95% is bound to albumin in plasma --> Altered albumin states will greatly increase the active concentration in blood

- 50% renal excretion unchanged --> OAT mediated

- Urine concentration correlates with natriuretic effect --> Can be monitored this way

- Short half-life compared to others in the class (1-2 hours)

- Volume depletion

- Hypokalemia

- Excess Ca + Mg excretion

- Hyperuricemia

- Ototoxicity (rare)

- Hypersensitivity reactions

- Tubuloglomerular feedback (TGF) is impaired due to blockade of NaCl uptake via NKCC2 transporter into the macula densa --> Renal blood flow and GFR are maintained but RAAS activated!!

- Antagonism by NSAIDs --> PGs contribute to the diuretic effect --> COX2 upregulation in macula densa and TAL

- Antagonism by inhibitors of OATp tubular secretion --> Probenecid, penicillins, and anionic metabolites

- Chronic renal insufficiency: Decreased renal blood flow and increased anionic metabolites reduce diuretic renal excretion rate

- Nephrotic syndrome: Hypoalbuminemia increases Vd of diuretic and decreases renal excretion rate --> Increased effective dose and half-life

- Inhibit sodium reabsorption by principal cells of late distal tubules and collecting ducts

- Decreased potassium excretion --> Less of a risk of hypokalemia

- Mechanism of Action: Directly inhibiting epithelial Na channel (ENaC) or indirectly by antagonism of aldosterone at the mineralocorticoid receptor (MR)

- Prototype: Amiloride

- Uses: In combination with thiazides or loop diuretics, Liddle's disease, and in combination with lithium

- Liddle's Disease: Reduces excess Na uptake by mutated constituitively active ENaC

- Combination with Lithium: Blocks Li uptake into principal cells and inhibits Li-induced diabetes insipidus

- Prototype: Spironolactone

- Mechanism: Competitive antagonism of aldosterone with mineralocorticoid receptor (MR)

- Effects: Blocks MR-induced ENaC expression in apical membrane, expression of sgk (ENaC activator), and Na/K ATPase expression

- Uses: Hyperaldosteronism, combination with thiazides or loop diuretics to decrease hypokalemia, and combination with loop diuretics and ACE inhibitors in CHF

- Increases survival in CHF patients

- Side Effects: Hyperkalemia, gynecomastia and impotence (endocrine abnormalities)

- Alternative to spironolactone

- More selective antagonist of the mineralocorticoid receptor

- Used in combination with other meds for heart failure in post-MI patients --> Improved morbidity and mortality with no change in endocrine side effects

- "Braking phenomenon"

- Decrease in diuretic and natriuretic potency

1. Decreased renal clearance of drug due to reduced renal blood flow and tubular transport

2. Hyponatremia --> Stimulates reabsorption on it's own

3. Sodium retention due to RAAS, AII, catecholamines, and aldosterone level increases

4. Increased ENaC and distal sodium reabsorption

- Increase dose of diuretic

- Use loop and thiazide diuretics together

- Restrict fluid and salt intake

- Block AII effect

- Add aldosterone antagonist (spironolactone)

- Avoid vasodilator that impairs renal perfusion

- pH=pKa + log (A)/(HA)

- Balance due to physiological buffers --> Phosphate and carbonic anhydrase buffer systems are the most important

1. Respiratory acidosis: Hypoventilation and increased pCO2 --> Renal compensation through bicarbonate production and reabsorption

2. Respiratory alkalosis: Hyperventilation and decreased pCO2 --> Renal compensation through bicarbonate excretion

3. Metabolic acidosis: Decreased HCO3- concentration --> Leads to hyperventilation to decrease pCO2

4. Metabolic alkalosis: Increased HCO3- concentration --> Leads to hypoventilation to increase pCO2

- Combustion of hydrocarbon based fuel (food) that contains surfur and phosphorous residues

- Volatile acids: 20,000 mEq/day of CO2

- Non-volatile acids: 1-2 mEq/day/Kg BW due to kidney excretion

- Acid excretion: Controlled by chemosensors in the brain, carotid and aortic bodies, and atrial baroreceptors

- Brain detects pCO2 levels

- Carotid and aortic bodies detect high pressures --> Increased firing with rise in pressure

- Aortic bodies detect low pressure --> Increased firing with drop in pressure

- Regulated reabsorption of filtered HCO3-: ~ 4,800 mEq/day --> 80% in PT, 10% in loop, and 10% in collecting duct

- Excretion of net acid: 1-2 mEq/Kg BW/day --> 60-120 mEq/day --> 10% PT and 90% collecting duct

- Reabsorption capacity can be exceeded! (Tm)

- Tm can be altered by various conditions

- pH of urine can get as low as 4 but there is ALOT of acid in solution!! --> Bound to NH3 and phosphorous buffers to keep free H+ concentration down and allow for additional H+ excretion

- NH3 from glutamate metabolism via glutaminase

- Excretion of NH3 rises dramatically in acidosis!!!

- Primary overproduction of acid or loss of HCO3-

- Normal or increased anion gap acidosis

- Normal: Increased Cl- with decreased HCO3- concentrations (Hyperchloremic)

- Increased: Decreased HCO3- with normal Cl- (normochloremic) --> Production of organic acids (ketoacids or lactic acid)

1. Acute Metabolic Acidosis

- Respiration --> Can increase up to 8x normal but decreases with pH <6.8

- CNS --> Lethargy, disorientation, stupor/coma

- Cardio --> Decreased CO when pH <7.0 and hypotension due to vessel dilation

- Endocrine --> Insulin resistance --> Can cause or perpetuate ketocidosis!! 

2. Chronic Metabolic Acidosis

- GI tract --> Smooth muscle relaxation, anorexia and nausea

- Bone --> Demineralization of bone due to H+ --> Leeches Ca out of bone over time

- Cause of metabolic acidosis

- Increased anion gap --> Increased production of organic acids without an increase in Cl-

- Results from insulin resistance or insulin deficiency --> Diabetes

- Effects: Increased gluconeogenesis, increased ketogenesis, increased lipolysis, and decreased glucose utilization in skeletal muscle

- Ultimately leads to ketonemia, hyperglycemia, and increased protein breakdown

- Increased anion gap acidosis

- Decreased oxygen availability in tissues --> Cannot breakdown glucose via Kreb's cycle --> Must produce lactic acid instead

- Main sites of lactate production: Muscle, brain, skin and RBCs

- Lactate --> Utilized by the kidney and liver

- Increased gluconeogenesis in the liver --> Further perpetuates lactate production

- Can result from either overproduction of lactic acid or underutilization by liver and kidney

- Causes: Tissue hypoxia, drugs/toxins, liver failure, neoplastic disease, diabetes mellitus, congenital and idiopathic

- Associated with end-stage renal disease

- Net acid excretion is less than net acid production

- Decreased renal ammoniogenesis --> Inability to keep pH high enough to continue adding H+ into solution

- Decreased filtration and excretion of phosphates --> Other source of buffer for H+ secreted into tubular fluid

1. Associated with hypokalemia

- Gastrointestinal loss of HCO3- --> Diarrhea and entero-fistula/Pancreatic fistula

- Renal loss of HCO3- --> Renal tubular acidosis, urterosigmoidostomy or ileostomy, and carbonic anhydrase inhibitors

2. Associated with hyperkalemia

- Hypoaldosteronism

- Failure of tubular response to aldosterone

- Metabolism of cations (lysine, arganine or NH4+)

- Treat underlying cause (DKA, diarrhea, LA, etc)

- Alkali therapy for severe acidemia (pH <7.2)

- Benefits of alkali therapy: Prevents or reverses acidemia, reinstates cardiovacular responsiveness to catecholamines, buys time to figure out cause, and provides a measure of safety against other acidifying agents

- Alkali therapy is dangerous though --> Can cause hypernatremia/hyperosmolality, volume overload, overshoot alkalosis, hypokalemia, decreased plasma ionized calcium, organic acid production, and hypercapnea

- Primary loss of H+, shift of H+ into cells, or gain of HCO3-

- Volume/Chloride Sensitive causes: Vomiting, gastric drainage, diuretics, and excessive hypercapnia --> Volume depleted

- Volume/Chloride Resistant causes: Cushing's syndrome, primary aldosteronism, Barter's syndrome, steroid therapy, and severe K+ depletion --> Volume overload so doesn't respond to fluids

- All due to volume depletion and HCl loss (vomiting)

- Loss of HCl --> Generation of metabolic alkalosis directly

- Loss of KCl --> Hypokalemia --> Increased distal secretion of H+ in the kidney and increased NH3 synthesis leading to further excretion of H+

- NaCl/H2O loss --> Hypovolemia --> Increased aldosterone secretion and Na/HCO3- reabsorption in PT

- Increased aldosterone leads to increased H+ secretion in DT

- Further perpetuates metabolic alkalosis due to decreased Cl delivery to the CD (absorbed in PT, etc) --> Decreased activity of HCO3/Cl- antiport --> Low pH urine and H+ excretion

- Completely reversed with NS fluid resuscitation

- Increased HCO3- reabsorption

- Increased NH4+ synthesis and entry into the lumen

- No mineralocorticoid excess --> No change in GFR

- Results in K+ depletion

- Causes Cl resistant metabolic alkalosis, hypokalemia, and hypercalciuremia

1. Type 1

- NKCC2 mutant channel (15q15-q21 mutation)

- Affects TAL reabsorption of Na, K, and 2 Cl

2. Type 2

- ROMK mutation (11q24 mutation) 

- Alters K+ secretion in both the TAL and collecting duct

- Autosomal recessive disorder

- TSC channel mutation (16q13 mutation)

- Inactivating mutation of the Na/Cl symport in the distal convoluted tubule

- Leads to metabolic alkalosis, hypokalemia, and hypocalciuria

- Increases the amount of NaCl delivered to the collecting duct --> Increased Na reabsorption and increased K+ secretion --> Hypokalemia

- Alkali gain --> Discontinue administration of bicarbonate or its precursors

- H+ loss --> Administer antiemetics for gastric causes or discontinue loop and distal diuretics for renal causes --> Substitute with amiloride or spironalactone

- H+ shift in cells --> Potassium repletion

- Decreasing GFR --> ECF volume repletion and renal replacement therapy

- Cl- responsive --> Administer NaCl and KCl

- Cl- resistant --> Adrenalectomy or other surgery, potassium repletion, administration of amiloride or spironolactone

- Alveolar hyperventilation with reduction in pCO2

- Causes: Psychogenic hyperventilation, hypoxia, high altitude, salicylate intoxication, CNS disturbances, hypermetabolic states (fever), ventilator, G- sepsis, exercise, chronic liver disease, and intrathoracic processes

- Kidney compensates by excreting HCO3- 

- pH <7.55 --> Manage underlying disorder but no specific measures indictated

- pH >7.55 without hemodynamic instability, altered mental status, or cardiac arrhythmias --> Have patient rebreathe into closed system to increase pCO2 and manage underlying disorder

- pH >7.55 with hemodynamic instability, altered mental status, or cardiac arrhythmias --> Reduce HCO3- with acetazolamide, ultrafiltration, normal saline replacement and hemodialysis and increase PaCO2 by rebreathing into closed system or controlled hypoventilation by ventilator

- Hypoventilation with increased pCO2

- Most commonly caused by COPD or other chronic lung injury

- Causes: Drugs, neuromusclar disorders, CNS lesions, large airway obstructions, extreme obesity, sleep apnea, and CHF

- Kidney compensates by increasing H+ excretion, NH3 synthesis and increased acid excretion in the urine

- Kidney also increases HCO3- reabsorption and production

- PaO2>60 mmHg without severe symptoms --> Observe

- PaO2<60 mmHg --> Administer O2 to improve PaO2 and correct underlying cause with bronchodilators, antibiotics or corticosteroids

- PaO2 <60 mmHg with severe hypercapnic encephalopathy or hemodynamic instability --> Intubation, ventilation and correct underlying cause with above methods

- Combination of up to three of the previous acid-base imbalances

- Determined when pH, pCO2, and HCO3- levels do not follow common pattern

- Hard to truly diagnose so must use patient history!!

- ECF: 1-2% --> 65 mEq --> Only compartment that can be sampled

- RBC: 7% --> 250 mEq

- Liver: 7% --> 250 mEq

- Bone: 8.5% --> 300 mEq

- Muscle: 75% --> 2,635 mEq

- Total body K= 3,500 mEq for 70 Kg person

- 1 mEq difference in ECF translates to about 100 mEq in total body K

- Consequences of pyramid: ECF under-estimates K deficit, can use re-distribution mechanisms to relieve hyperkalemia, and release of cellular K increases serum K via RBC hemolysis, transfusion or muscle cell death

- Dietary potassium is rapidly hidden within cells

- Cellular uptake is rapid and effective

- Cellular uptake via insulin and catecholamines

- Urinary excretion is too slow to maintain levels with dietary intake --> 33% within 2 hours and 80% within 8 hours

- Not true hyperkalemia but hyperkalemia is present in test tube

- Occurs during leukocytosis, thrombocytosis, and hemolysis due to venupuncture

- Can also occur due to local skeletal muscle release of K if patient contracts muscles around vein right before extraction of sample

- Never causes ECG changes

- ICF: 120-130 mEq/L of K and 10 mEq/L of Na

- ECF: 140 mEq/L of Na and 4 mEq/L of K

- Maintained by Na/K ATPase activity

- Hypokalemia --> Hyperpolarization of cells

- Hyperkalemia --> Hypopolarization of cells

1. Endocrine Regulators

- Catecholamines (B2 agonists) --> K influx 

- Insulin with glucose --> K influx

- Aldosterone --> Increased K secretion by DT

2. Non-endocrine Regulators

- Acid-Base balance --> K efflux during acidosis

- Plasma osmolality

- Physical activity --> Increased K efflux during exercise

- Renal function

- Sudden hypo or hyper-kalemia --> Sudden muscle weakness caused by K shifts --> Flaccid paralysis

- Familial autosomal dominant disorder --> Rare mutation of skeletal muscle voltage gated Ca-channel

- Hypokalemia alters membrane potentials --> Ca channel opens and Ca exits cell

- Clinical presentation: Sudden onset of muscle weakness, alcohol exposure, and carbohydrate ingestion

- Treatment: Acetazolamide --> Activates sarcolemma Ca-activated K channel and shifts K out of cells to restore serum K

- K >5 mEq/L --> Can cause serious cardiac arrhythmias and ECG changes

- ECG changes: Peaked T waves, prolonged PR interval, widened QRS complex, flat/absent p waves and sine waves late

- Causes: Increased intake, impaired renal excretion, and re-distribution of cell K into serum

- Perpetuated by hyporenin-hypoaldo states, ACEI use, spironolactone use, digoxin impairs K shift into cells, KCl salt substitute increases K intake, and reduced GFR decreases excretion ability

- Changing K concentration causes regional electrical variations in cardiac myocytes

- Channel heterogeneity promotes depolarization

- Ventricular tachycardia and fibrillation results

- K <3.5 mEq/L --> ~100 mEq K deficit

- Can be worsened by administering insulin --> Insulin stimulates K influx into cells --> Induces fatal arrhythmias

- Hypokalemia can cause insulin resistance and induce DKA in diabetic patients (~25%)

- Insulin resistance in turn produces hyperkalemia

- Hypokalemia inhibits K channel activity --> Reduces glucose uptake causing hyperglycemia

1. Decreased urinary intake: Nausea due to DKA causes lack of appetitie

2. Increased urinary losses: K must be excreted to bind negatively charged ketoacids

3. Hypokalemia can cause secondary hyper-aldosteronism due to volume depletion --> Further perpetuates hypokalemia

- Conduction changes, arrhythmias and necrosis of cardiac muscle

- Weakness and rhabdomyolysis of skeletal muscle

- Ileus and postural hypotension due to smooth muscle abnormalities

- Poor urinary concentration and chronic kidney disease

- Hyperglycemia, metabolic alkalosis, and hepatic encephalopathy due to glucose, acid and ammonia retention

- Check ECG for U waves to determine cardiac arrhythmia susceptibility

- Administer IV fluids before insulin administered

- Administer KCl or KPhos supplementation before insulin administration

- Causes: Adrenal carcinoma, Cushing's disease/syndrome, or adrenal hyperplasia

- Results in excess ACTH, aldosterone or androgens

- Presentation: Hypokalemia, metabolic alkalosis in absence of vomiting or volume depletion, and hirsuitisim (increased sex hormones)

- Prevalence: 0.5-12% of hypertensive patients

- Ages: 30-50 most common

- Women 2x > Men

- 50-75% develop spontaneous hypokalemia

- <5% have adrenal carcinoma

- 50-70% have a solitary adenoma

- 20-30% have bilateral adrenal hyperplasia

- 69% cure rate with tumor excision of solitary adenoma --> Laparoscopy or laparotomy

1. Membrane antagonism: Stabilize myocardial cells

- Calcium gluconate

- Sodium bicarbonate

2. Enhanced transfer into cells

- Beta-agonists --> Albuterol

- Glucose/insulin

- Sodium bicarbonate

3. Enhanced removal from body

- Diuretics --> Loop diuretics

- Cation exchange resin: Kayexalate (polystyrene)

- Dialysis

- Activator of cellular enzymes --> Helps hydrolyze and transfer phosphate groups

- Stimulates Na/K ATPase activity

- Helps maintain Ca and K homeostasis --> PTH secretion and response are impaired by Mg deficiency --> Hypocalcemia and hypokalemia resistant to K repletion

- Causes: GI and kidney Mg loss and chronic alcoholism

- Alcohol: Induces Mg diuresis, tends to lead to poor nutrition, and causes secondary hyperaldosteronism --> All lead to Mg losses

- Diuretic induced Mg deficiency --> Common in the elderly on diuretics and with low intake (especially CHF patients on loop diuretics)

- Malnourished, patients with severe diarrhea, and patients with diseases of the ileum are a high risk of developing Mg deficiency

- Lethargy

- Neuromuscular weakness, hyper-reflexia, tremor and fasiculations

- Seizures, altered mental status, irritiability, tetany, and trousseau spasm

- Cardiac arrhythmia

- Hypokalemia refractory to K supplementation

- Hypernatremia

- Hypertension

- Confirm normal renal function before continuing on!!

- Administer MgSO4 IV over 1-2 min then more over hours for cardiac emergency

- Elemental Mg IV slowly

- Smaller amounts of elemental Mg can be given daily IV or IM for maintenance

- Monitor vitals, ECG, and serum Mg levels

- Causes: Adrenal insufficiency, hypothyroidism, and excessive use of magnesium-containing antacids

- Mg > 4 mEq/L but symptoms may not occur until >6 mEq/L

- CNS symptoms: Depressed deep tendon reflexes, paralysis of voluntary muscles, decreased respiratory rate/respiratory failure, and stupor/coma

- Cardio symptoms: Peripheral vasodilation and hypotension

- ECG changes: Prolonged P-R interval --> Complete heart block --> Cardiac arrest

- Intravenous calcium salt

- Dialysis

- Non-oliguric: >400 mL/day --> Normal is 1-2 L/day

- Oliguric: <400 mL/day

- Anuric: <50 mL/day

- The body requires at least 400 mL of urine per day to properly excrete all toxins

- Even if you're non-oliguric, doesn't mean that your kidneys aren't severely impaired --> Urine volume does NOT equal kidney function!!

- In both cases, serum BUN and Cr are rising

- Poor predictors of prognosis unless anuric

- A significant fall in GFR detected over a few days

- With a change in urine output

- Even a small rise in Cr leads to a pretty dramatic drop in GFR --> 2x Cr --> 50% GFR

- 50% GFR loss --> 6.5x increase in death --> $7500 additional hospital costs

- Normal GFR: 100-120 mL/min

- Must evaluate volume status, history and physical exam

- Renal blood flow and glomerular perfusion are decreased

- Causes: Volume depletion and CHF or hepatic failure

- Volume depletion causes: GI fluid losses, renal losses (diuretics), adrenal insufficiency, and burns

- CHF/Hepatic failure: Leads to 3rd space fluid and decreased effective RBF --> Signs of fluid overload

- Presentation: Signs of volume depletion, increased thirst, and oliguria

- If volume depleted patients aren't given enough fluid or given fluid fast enough --> ATN

- Diagnosis: SG >1.010, UNa <20, BUN/CR >20/1, FeNa <1% --> Implies properly functioning tubules

- Acute tubular necrosis

- Bilateral cortical necrosis

- Tubulointerstitial diseases

- Renovascular and glomerular diseases

- Can result from undertreated pre-renal AKI

- 70% recovery rate

- Types: Ischemic, toxic and pigment-induced

- Mechanisms: Afferent arteriole vasoconstriction, loss of viable and non-viable tubular cells, backleak of filtrate across tubular epithelium, and intratubular obstruction

- Vascular endothelial injury due to increased inflammation and microvscular congestion also contributes

- Diagnosis: Dark pigmented/muddy brown casts, history, physical, CBC and UA, BUN/CR <10:1, low urine SG, high UNa, and FeNa >1% --> Signs that tubules aren't functioning properly

- Decreased renal perfusion --> Volume depletion, hemorrhage, etc.

- Restoration of perfusion should completely correct damage --> Lingering damage if ischemia is prolonged

- Common in post-operative patients after cardiac, aortic, and GI surgery

- Obstructive jaundice with hyperbilirubinemia --> Increased risk of ischemic ATN

-Causes: Severe burns, severe acute necrotizing pancreatitis, and hypotension

- Diagnosis: History, physical, and UA

- Causative agents: antibiotics (aminoglycosides), intravenous/intraarterial contrast dyes, NSAIDs, heavy metals, organic solvents, and glycols

1. Aminoglycoside induced: 10% of all in-hospital ATN cases, filtered and reabsorbed --> Local toxic effects near PT --> Direct mitochondrial and ER toxicity --> >5 days after exposure

2. Contrast induced: More common in patiens with pre-existing CKD and volume depletion

- IV normal saline before and after injection can help prevent

- N-acetylcysteine administration is thought to prevent

3. Pigment induced: Hemaglobinuria and myoglobinuria due to rhabdomyolysis, crush injury, or severe hemolysis

- 30% of rhabdomyolysis patients

- Diagnosis: Positive dipstick for protein with absence of RBCs in urine sediment --> Also high CPK levels

1. Onset phase: Serum BUN and Cr rise with or without oliguria --> Reversible in 75% of cases

- Uremic symptoms may develop

2. Maintenance phase: Serum BUN and Cr plateau

- Lasts about 1-2 weeks --> Doesn't usually last longer than 4-6 weeks

- Uremic symptoms may develop at this point

3. Recovery phase: Serum BUN and Cr decrease, GFR increases, and increase urine volume

- Increase of 200-300 mL/day --> May be up to 5L/day

- Post-injury diuresis --> Volume overload, osmotic diuresis (urea), and lack of tubular response to ADH

- Without further insult, recovery in 7-10 days

1. Changes in blood chemistries: BUN up 10-20 mg/dL per/day and Cr up by 0.5-1 mg/dL/day

- Must monitor fluid and electrolyte intake carefully

- High sodium and water intake --> Fluid overload

- Free water intake --> Hyponatremia

- Potassium intake --> Hyperkalemia --> Up 0.5 mEq/L/day in uncomplicated ATN

- Serum H+ rises about 1 mEq/Kg/day and serum HCO3- falls 1-2 mEq/L/day

2. Uremia Symptoms: Anorexia, N/V, dysgeusia (metalic taste), pruritis, memory loss, fatigue, day/night reversal, myoclonic twitching, asterixis, confusion, and pericarditis

- Needs urgent dialysis!! 

- Uremic symptoms also increase the likelihood of infection

- Rapid rise in serum creatinine --> >2 mg/L/day

- Creatinine rise out of proportion from BUN

- Severe hyperkalemia

- Severe hyperphosphatemia >8-10 mg/dL

- Hypocalcemia

- Hyperuricemia

- All of these indicate muscle breakdown --> Rhabodmyolysis 

- Mechanisms of injury: Direct Fe toxicity, free radical injury, toxic myoglobin by-product (ferrihematin), intra-tubular obstruction, and concomitant volume depletion

- Overall mortality 50-60% --> 80% before dialysis

- Continually high mortality --> Increased prevalance in the elderly with underlying co-morbidities

- Systemic manifestations that can not be addressed simply with dialysis --> We don't really know what these are so we really can't treat them!!

- Systemic response: Hypoxemia, low cardiac output, abnormal LFTs, and renal injury

- Prognosis really depends on the causative agent for ATN

- Highest mortality in ATN caused by surgery or trauma

- Lowest mortality in young and otherwise healthy patients

- Lower mortality in non-oliguric AKI

- Correct pre-renal causes that may lead to ATN

- Remove any nephrotoxic agents --> Antibiotics, etc

- Administer isotonic fluids --> Volume expansion may  prevent pre-renally caused ATN and also may prevent high risk patients from developing other complications

1. Diuretics (loop)

- Will not improve GFR or reverse ATN but can help convert a patient from an oliguric to non-oliguric form

- May help wash out any tubular obstructions

- Used as a test to see if patient will response in the future

- Repeated large doses --> Ototoxic by blocking NKCC2 channel in the inner ear

2. Conservative treatment: Alter medications, IV fluids, monitor Is and Os, and manage any electrolyte imbalances

3. Renal replacement therapy: Dialysis if patient shows signs of uremia --> Severe N/V, protein or calorie malnutrition, altered mental status, pericarditis, and uncontrolled bleeding

- Can be crucial for managing fluid overload, hyperkalemia, and metabolic acidosis as well!!

- Due to some sort of obstruction --> Bilateral if ureter

- Causes fluid backflow behind obstruction

- Causes in women: Neurogenic bladder, foley catheter, and cervical cancer

- Causes in men: BPH, urethral stricture, neurogenic bladder, and foley

- Increased pressure in the calyces and the tubules

- Leads to distal tubular and collecting duct damage --> Lack of proper ADH response

- Symptoms: Hesitancy, urgency, frequency, decreased stream force, and nocturia (conc. defect)

- Signs: Benign history, unremarkable exam, and bland UA results

- Diagnosis: Renal ultrasound is crucial

- Post-obstruction diuresis: Excessive peeing after obstruction is removed due to tubule damage and lack of proper response to ADH --> Must keep patient euvolemic!!

- Pre and Post-renal: Normal/none

- ATN: Muddy brown/darkly pigmented casts

- Myoglobinuria: Large dipstick + for blood without RBCs

- Glomerulonephritis: Hematuria, proteinuria and RBC casts

- Acute allergic interstitial nephritis: Pyuria/eosinophiluria, hematuria, and WBC casts

1. Loss of viable renal epithelial cells

2. Backleak of glomerular filtrate

3. Intra-tubular obstruction

4. Vascular/endothelial cell injury

5. Inflammation

- Chronic and progressive loss of kidney function that leads to kidney failure over time

- 19 million CKD patients --> Mostly stages I-III

- Assessed by measuring GFR --> Hard to measure especially when Cr is changing (GFR= UsolxUv/Psol)

- GFR normally decreases with age --> 1mL/min/year after age 40

- Patients are usually asymptomatic until >75% of GFR is lost

- Progressing CKD --> Increased incidence of CVD related mortality

- Often not identified until very late --> Pts can have normal Cr levels when they have really lost a substantial portion of their kidney function

- Endogenous substance in myocytes

- Filtered by the glomerulus so present in urine

- Easy and inexpensive to measure in serum and in urine

- Used to monitor kidney function

- CrCl= UCrxUV/PCr

- Problems: Creatinine is also secreted --> overestimates GFR and individuals have different baseline Cr levels depending on muscle mass

- Higher Cr in men, young, and African Americans

- eGFR --> MDRD equation --> Takes into account age, sex, and white/black

- Still does not account for individual-specific changes in muscle mass or protein intake

1. Stage I: GFR >90 with kidney damage 

2. Stage II: GFR 60-89 --> Estimate progression

3. Stage III: GFR 30-59 --> Moderate --> Treat complications if any

4. Stage IV: GFR 15-29 --> Severe --> Prep for kidney replacement therapy

5. Stage V: GFR <15 --> Kidney failure --> Replacement therapy if uremia present

- Stages IV and V carry high risk of CVD complications!!

- Diabetes

- Hypertension

- Glomerulonephritis

- Polycystic Kidney Disease

- Other --> Probably a combination of both diabetes and hypertension

- Often still progresses after successful treatment of whatever the causative disease was

- Likely due to glomerular hypertrophy and increased transglomerular pressure --> Efferent arteriole constriction

- Also focal and segmental glomerular sclerosis (FSGS) and proteinuria are common

1. Keep BP <130/80 --> Control hypertension

2. Good glycemic control --> HbA1c <7.0%

3. ACE-Inhibitors or ARBs --> Vasodilate efferent aretiorle and help to reduce transglomerular pressure

- Also lower proteinuria

- Early treatment can definitely make a difference in progression but it doesn't stop progression

- Volume overload due to sodium overload

- Hyperkalemia --> Inability to excrete

- Metabolic acidosis --> Inability to excrete

- Anemia --> Reduced EPO production

- Bone and mineral absorption --> Increased PTH secretion --> Increased Ca absorption

- Failure to excrete dietary sodium due to decreased GFR

- Leads to hypertension, pulmonary edema, and lower extremity edema

- Treatment: Reduce sodium intake, loop diuretics, and dialysis if severe

- Failure to excrete dietary potassium

- Colonic secretion tries to compensate but can't

- Severe hyperkalemia > 6.5 mEq/L --> Ventricular fibrillation and arrest

- Prevalence is increasing due to increased use of ACE-inhibitors and ARBs

- ACEIs and ARBs predispose to hyperkalemia themselves

- Treatment: Calcium gluconate, insulin/glucose, bicarb, and b-agonists acutely and potassium exchange resins or loop diuretics to properly excrete --> Dialysis may be necessary

1. Non-anion gap acidosis: Stages 3-4 CKD

- Nephron loss leads to reduced ability to generate ammonia and excrete H+

2. High anion gap acidosis: Stages 4-5 --> GFR <20

- Retention of phosphates, sulfates, and organic acid due to kidney failure

- Treatment: Oral NaHCO3 to replenish bicarbonate levels

- Bone buffers H+ over time to maintain bicarb levels --> Increased rate of bone loss and increased muscle breakdown to produce phosphates and sulfates to buffer

- Remember to watch Na and fluid retention with NaHCO3 treatment!!

- Loss of kidney mass leads to reduced serum levels of EPO

- EPO stimulates the bone marrow to produce more RBCs

- Low EPO --> Reduced RBC synthesis

- Other causes of anemia: Iron and vitamin B12 deficiency, hepcidin, IL and TNF-a therapy, and secondary hyperparathyroidism

- Treatment: Recombinant erythropoetin --> SC injections --> Correct Hb only to 10-11 g/dL

- Overcorrection of Hb leads to increased CVD events

- Retention of phosphates along with low active Vit D lead to hypocalcemia

- High phosphates --> Hypocalcemia and visa versa

- Hypocalcemia --> Increased PTH secretion and secondary hyperparathyroidism

- PTH --> Increased phosphate excretion and increased Ca absorption in the kidney

- Extra-skeletal calcifications may result due to hyperphosphatemia and effective hypocalcemia

- Deposits also around the vasculature throughout the body

- Treatment of hyperphosphatemia: Reduce dietary phosphorous (nuts, meats, and soda) and phosphorous binders with meals --> Lower phosphorous <4.6 mg/dL

- Treatment of Vitamin D deficiency: First treat with 25-OH vit D and then add 1,25-OH supplementation

- Treatment of Hyperparathyroidism: Calcimimetic agents --> Ca receptor agonists on the parathyroid gland making gland think there are high Ca levels

- Not usually seen until GFR <15 mL/min

- Signs/symptoms: Volume overload, HTN, anorexia, N/V, malnutrition, uremic encephalopathy, uremic pericarditis, pruritis, and uremic frost

- Patients usually have other severe complications of CKD

- Treatment: Dialysis or other renal replacement therapy

- Solute diffusion down a concentration gradient

- Removes toxins and adjusts the concentrations of electrolytes

- Must check monthly labs to ensure adequate clearance of small molecules

- Fluid removal via hydrostatic pressure (ultrafiltration)

- 3-4 hours a treatment 3 times a week but can be done at home in some patients

- Dialysis fluid and blood run in opposite directions to ensure fast diffusion and continued gradients

- Limitations: Not as good as functional kidneys, cannot secrete or reabsorb like the tubules, and other treatments are necessary (EPO or vit D supplementation)

- AV-fistula: Possible in <50% of patients, technically difficult to form in some patients and need to access during stage IV --> Can't in stage V

- AV graft --> Synthetic material --> Not as good as fistula but not everyone can get a fistula created

- Hemodialysis catheter --> usually in the IJV --> Has highest risk of infection, bacteremia, and thrombosis

- Flexible catheter is inserted into abdominal cavity --> Risk for infection because it is an indwelling cather

- Peritoneum serves as the semi-permeable membrane

- Dialysis solution is introduced through the catheter and left for 4-6 hours

- Solution is then drained and replaced

- Toxins and electrolytes are removed simply by diffusion along gradients

- Fluid removal is accomplished via osmotic gradients --> High concentrations of dextrose in dialysis fluid

- Performed as 4 exchanges per day ever 6 hours 

- Can be done using a programmed machine called a cycler at night

- Alterations in electrolytes --> Must be monitored monthly

- Must also monitor peritoneal membrane to ensure it is adequate as semi-permeable membrane

- Peritonitis and infections

- Hyperglycemia and new onset diabetes --> Dextrose solution

- Scarring of peritoneal membrane --> Over time could render useless for process

- Live or deceased donor --> Both better than dialysis!!

- All donors must be ABO compatible and have HLA cross-matching to find the best suitable donor

- 1 year survival: 95% for living and 90% for deceased

- 50% graft survival: 15-30 years for living and 10 years for deceased

- Extensive pre-transplant testing is required for both donor and recipient --> Evaluate CVD, pulmonary status, infections, malignancies, psychosocial status, and med compliance

- Donor evaluation must also include the elimination of the possibility of the donor ever developing kidney disease themselves

- Only identical twins could undergo transplantation without immunosuppression

- Regimen: Calcineurin inhibitor (tacrolimus/cyclosporine), antimetabolite (mycophenolate) and prednisone

- High doses for the first 6-12 months but immunosuppression therapy of some sort for the rest of their life

- Increased risk of infections --> CMV, PCP, and JC polyoma virus

- Increased risk of malignancy --> Squamous cell cancers and EBV associated lymphomas

- Tubular epithelium: Absorption, secretion, salt, water and acid base homeostasis, and activation of Vit D

- Interstitial cells: EPO and PG production

- Microvasculature (vasa recta and peritubular capillaries): Perfusion and counter exchange mechanism

- Dendritic cells: Antigen presentation

- Stem cells: Tissue regeneration after injury

- Immunologically-induced hypersensitivity to antigen (drug or infectious agent)

- Only occurs in a small percent of patients exposed to drug --> Not dose-dependent

- Associated with extra-renal symptoms --> Maculopapular rash

- Previously most commonly associated with Scarlet Fever and Diptheria infections

- Drug associated: Antimicrobials (penicillins and sulfa drugs), NSAIDs, diuretics (furosemide and HCTZ), anticonvulsants and omeprazole

- WBC casts, WBCs, and hematuria on UA

- Acute/subacute loss of GFR with elevation of Cr

- Urinary eosinophils

- Extra-renal: Peripheral eosinophilia, fever, maculopapular rash, and mild arthralgias

- NSAID-associated: Less likely to have fever, rash, and eosinophilia but can be associated with heavy proteinuria

- Granulomatous AIN: Due to rifampicin, phenytoin, and allopurinol

- Identify and remove the offending agent --> Can be really hard though!!

- Consider a course of steroids --> May reduce duration of disease and may allow renal function to return closer to baseline

- BK Polyomavirus nephropathy

- BK acquired early in life --> Usually asymptomatic

- Replication and lysis of tubular cells in immuno-compromised hosts

- Causes a decline in renal function

- Bland urine sediment

- "Decoy" cells in urine --> Might look like cancer

- Treatment: Reduce immunosuppression to allow immune system to fight virus

1. Sjogren's Syndrome: Dry eyes, dry mouth (sicca syndrome)

2. Tubulointerstitial Nephritis with Uveitis (TINU): Unknown etiology

- Inflammation of kidney and eye (uveitis) 

- Uveitis: Eye pain, redness, blurred vision and photophobia

- Symptoms: Fever, anorexia, abdominal pain, and arthralgias

- Treatment: Usually self-limiting in kids but steroids if serious

- Acute Tubulointerstitial Disease --> Iatrogenic obstruction

- Precipitation of calcium phosphate in/around tubules

- After administration of oral phosphate preps

- Urine sediment: Bland with few cellular elements

- Special von Kossa stain to show phosphate granules

- B cell lymphoma creating monoclonal Ig

- Light chain deposition disease

- Amyloidosis

- Immunotactoid/fibrillary GN

- Fanconi syndrome: Proximal tubule toxicity --> Aminoaciduria, glycosuria, phosphaturia, RTA, and low-MW proteinuria

- Light chain cast nephropathy

- Hypercalcemia from lytic lesions of bone

- Associated with advanced diseae and heavy tumor burden from multiple myeloma

- Light chain deposition in distal tubules

- Precipiated by volume depletion, infection, and hypercalcemia

- Kappa or lambda restriction disease

- Bence-Jones proteinuria: Overexcretion of light chains in urine

1. Drug and toxin induced: Lithium, analgesics, chinese herbal nephropathy, antiviral, chemo or calcineurin meds, and heavy metals (Lead and cadmium)

2. Reflux nephropathy: Chronic pyelonephritis, recurrent UTIs in childhood, bedwetting, and vesiculoureteral (VUR)

3. Sickle cell Nephropathy: Sickling of RBCs in the deep medulla of kidneys

4. Cystic Disorders: ADPKD, ARPKD, nephronophthisis, MCKD, and MSK

5. Metabolic causes: Hyperuricemia, hypercalcemia, hyperoxalosis, and cytinosis

- Incorrectly referred to as chronic pyelonephritis

- Incompetent uretero-vesical junction leading to vesicoureteral reflux (VUR)

- Chronic scarring occurs due to reflux

- Presentation: UTIs in childhood, unexplained HTN, proteinuria, CKD, bed wetting, and nephrolithiasis

- Features: Insidious onset with slow but steady progresion, normocytic anemia, polyuria, nocturia, and occassional WBC casts

- Ultrasound shows chronic changes in the kidneys

- Treatment: ACEI/ARB

- Occurs in up to 20% of sickle cell patients

- Occlusion of renal microvasculature of the medulla due to RBC sickling

- Leads to tubular damage, nephron loss, glomerular hyperfiltration, and secondary FSGS

- Microalbuminuria can progress to overt proteinuria

- Sickle cell hematuria can result too

- Precipitating factors: Dehydration, infection, and sickle cell crisis

- Pathology: Juxtamedullary nephron loss, obliteration of vasa recta, papillary necrosis, and hyperfiltration with secondary FSGS

- Causes: Sickle cell disease, analgesic nephropathy, diabetes/UTI, and obstruction

- Presentation: Asymptomatic, gross hematuria, and sloughed papilla with/without renal colic and obstruction

- Causes chronic interstitial nephritis

- Results after long-term use of analgesics --> 2-3 kg range daily --> Analgesics used to be taken in huge quantities by people

- Drug becomes concentrated to toxic levels in the inner medulla --> Papillary necrosis and irregular renal contours

- Rarely seen in the US today

- Causes Chronic Interstitial Nephritis

- Not common today in the US due to elimination of lead in paints, gas, etc

- Exposure sources: Moonshine distilled in lead-tainted containers, battery manufacturers, and shooting ranges

- Toxicity to PT

- Hyperuricemia from diminished urate secretion

- "Saturnine gout" --> HTN and renal insufficiency

- Treatment: Lead chelator

- Causes: Autoimmune pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis, chronic sclerosing sialadenitis, and interstitial nephritis

- Dense inflammatory infiltration composed of IgG4-expressing plasma cells

- Infiltrates may give way to fibrotic (sclerosing) pseudotumors

- Treatment: Glucocorticoids

- Can cause nephrogenic diabetes insipidus --> Polyuria and secondary polydipsia

- Lithium --> Enters tubular cell via ENaC channel --> Inhibits adenylate cyclase --> Reduced AQP2 in luminal membrane

- Results in free water loss

- Biopsy: Tubular atrophy and dilatation, microcyst formation, interstitial fibrosis, and glomerulosclerosis --> Little to no inflammatory infiltrates!!

- Autosomal dominant polycystic kidney disease (ADPKD)

- Autosomal recessive polycystic kidney disease (ARPKD)

- Von Hippel Lindau Disease

- Tuberous Sclerosis

- Acquired Cystic Disease

- Presentation: Hypertension, cyst rupture/hemorrhage, cyst infection, nephrolithiasis, FHx

- Leads to progressive kidney failure and HUGE kidneys

- Extra-renal manifestations: Hepatic cysts, cerebral aneurysms, valve defects, and hernias

- Genetics: Autosomal dominant mutation in either PKD1 (Ch 16) or PKD2 (Ch 4)

- PKD1 mutations associated with TSC (tuberous sclerosis) mutations too --> Ch 16

1. Polycystin 1: Expressed in tubule cells during development

- Detection of mutations is complicated by the duplication of the PDK1 locus on other chromosomes

- Most mutations are identified thus far as involving the 3' cytoplasmic region

- Normal function: Helps developing cells properly differentiate and develop correct polarity --> Acts as a flow sensor in the tubular lumen

- 2nd Hit Hypothesis: Mutation present in all cells but need another mutation to make cells homozygous to actually develop cysts --> Adult presentation

- PKD1 has many mutation hot spots to make 2nd hit possible

2. Polycystin 2 (PKD2): Functions as a calcium channel

- Transmembrane protein

- Interacts with PKD1

- PKD2 mutation --> Increased Ca influx --> Increased cAMP intracellularly

- Target receptors or intracellular signaling

- mTOR inhibitors (sirolimus)

- Vasopressin 2 Receptor (V2R) Antagonists (tolvaptin) --> Blocks V2R receptor activation which normally increases cAMP intracellularly

- Somatostatin analog --> Reduced cAMP intracellularly

- Also MEK, ErbBTK, Src, and CDK inhibitors

- Presentation: Polyuria, dilute urine, polydipsia, and hypernatremia if limited from water (in hospital or child)

- Symptoms in children: Vomiting, fever, growth retardation, and mental retardation --> All due to inability to control access to water

- More severe in males than in females

- V2R mutation --> Inappropriate response to ADH binding

- No increase in urinary cAMP levels and no release of vWF and Factor VIII from endothelial cells

- Females have just as severe disease as males

- Mutation in AQP2 gene --> Proper response to ADH but AQP2 cannot be incorporated back into the apical membrane

- No increase in urine cAMP levels but appropriate response in vWF and Factor VIII --> Independent of V2R

- Autosomal dominant

- Presentation: Hypertension at young age, hypokalemia, and metabolic alkalosis

- Pseudo-aldosteronism --> Low renin and aldo

- Mutation: Gain-of-function ENaC mutation --> Increased Na reabsorption in DT and CD

- ENaC channels are not properly cycled away from the membrane --> Always at apical membrane

- Extra-renal: Lung, colon, and sweat glands --> ENaC present in these locations 

- Low sodium diety

- ENaC channel inhibitors --> Amiloride or triamterene

- Spironolactone does NOT work --> Not associated with aldosterone increases

- Presentation: Hematuria, slowly progressing renal failure, sensorineural hearing loss, and lenticonus/perimacular stippling

- More severe in males --> X-linked, autosomal dominant, autosomal recessive, or sporadic inheritance

- Pathology in most males: Irregularly thickened GBM --> Basket weave pattern with foot process fusion

- Less involvement of tubule BMs and Bowman's capsule

- Pathology in females: Thin GBM disease

- a5 Type IV collagen mutation --> Leads to degradation of basement membrane

- Activation of metallomatrixproteases and TGF-b leads to fibrosis and repair of the BM --> Thickening and basket-weave pattern

- Failure of repair would lead to hematuria and progressive renal failure/deafness due to BM in the ear

- Benign familial hematuria --> Microscopic hematuria without proteinuria

- Little tendency for developing renal insufficiency

- Defect may be similar to the genetics in Alport Syndrome

- Mutation in a4 of Type IV collagen --> Recessive disease

- Normal GFR is 80-120 mL/min --> ~180 L/day

- Injured in >50% of kidney diseases

- Injury is characterized by reduced GFR, retention of wastes, loss of selectivity in filtration barrier, and salt and water retention

- Podocytes filter out proteins via filtration slits

- Endothelial cell filters out RBCs via fenestrations

- Endothelial cell functions: Antithrombotic and anti-inflammatory

- Focal: <50% of glomeruli are affected

- Diffuse: All glomeruli are affected

- Segmental: Only part of glomerulus is affected

- Global: All of the glomerulus is affected

- Proliferative: Increased number of cells --> Usually inflammatory cells

- Crescentic: Cellular or fibrocellular infiltrate in Bowman's capsule

- Membranous: Thickened GBM

- Collapsing: Capillaries collapse on themselves

- IF Staining patterns: Granular (capillary or mesangium), linear, and pauci-immune (ANCA associated)

- Acute onset

- Hematuria

- Hypertension

- Oliguria

- Swelling or edema --> Mild to moderate

- Proteinuria (<3 g/day)

- Renal dysfunction or azotemia

- Usually microscopic hematuria discovered incidentally

- Normal renal function

- No proteinuria

- With or without FHx

- DDx: Inherited nephropathy (TBM or Alport) and mild IgA nephropathy

- Rapidly progressive renal failure --> Days to weeks

- Hematuria with RBC casts

- Hypertension

- Proteinuria (<3 g/day)

- Pathology: Crescentic and necrotizing glomerulonephritis

- Severe proteinuria (>3 g/day): Often reported as protein/Cr ratio

- Hypoalbuminemia

- Severe edema

- Hyperlipidemia

- Hypercoagulability

- Lipiduria

- Commonly in children 6-10 years old --> Epidemic/endemic or sporadic cases

- Commonly presents 1-3 weeks after streptococcal infection or impetigo wth nephritogenic strains of group A or B hemolytic streptococci

- Serology: Elevated anti-strep antibodies, reduced C3 with normal C1, C2, and C4 levels

- Prognosis: Usually resolves on its own but steroids if really severe

- Pathology: Diffuse proliferative pattern --> IgG granular pattern --> Subendothelial IgG deposits

- Causes isolated hematuria, acute nephritis or nephrotic syndrome

- Presentation: Synpharyngitic nephritis

- Pathophysiology: Abnormal glycosylation of IgA hinge region --> Anti-IgA IgG Abs

- Prognosis: ~60% never progress but heavy proteinuria, hypertension, and renal dysfunction are indicators of poor prognosis

- Pathology: Mesangial immune deposits with granular IgA immunoflourescence

- Often associated with IgA nephropathy

- Presentation: Athralgias, rash on legs, hypertension, elevated BUN+Cr, hematuria and proteinuria

- Presents with both pulmonary and respiratory disease

- Respiratory hemorrhage is often the cause of death

- Presentation: Hypertension, hematuria, RBCs, proteinuria, and elevated BUN/Cr

- Pathology: Crescenting glomerulonephritis --> Rapidly progressing glomerulonephritis (RPGN) --> Focal or diffuse pattern

- IF Pattern: Fibrin deposition

- Necrotizing and crescenting GN

1. No immune deposits on IF --> 81%

- Systemic causes: Granulomatous polyangitis/Wegners, microscopic polyangitis, and Churg-Strauss syndrome

- Renal limited: Pauci-immune 

- Usually only presents acutely with nephritic syndrome or RPGN

2. Granular Immune Deposits on IF --> 8%

- Systemic causes: Lupus, post-infectious GN, cryoglobulinemia (HBV), and Henoch-Schonlein purpura (IgA nephropathy)

- Renal limited: Severe IgA nephropathy and membranoproliferaive GN (MPGN)

- MPGN: Mixed nephritic/nephrotic pattern

3. Linear GBM deposits on IF --> 11%

- Systemic: Goodpasture Syndrome

- Renal limited: Anti-GBM GN

- Complement levels

- ANA and anti-dsDNA --> Lupus

- Anti-streptococcal antibodies --> Post infectious

- HBV and HCV serologies --> Cryoglobulinemia

- Cryoglobulins

- ANCA --> Wegner's, etc --> 80% sensitive and 95% specific for pauci-immune GN

- Anti-GBM Ab

- Crescentic GN with no immune deposits --> Pauci-immune on IF

- Presents with RPGN with or without systemic vasculitis --> Pulmonary hemorrhage, upper respiratory involvement, and skin purpura

- Associated with circulating Anti-Neutrophil Cytoplasmic Antibodies (ANCA)

- Treatment: Steroids, chemotherapy and emergent plasmapheresis

- Presentation: Rash, sensitivity to sunlight, hemolytic anemia, joint pains, hematuria and proteinuria

- Serology: ANA, Anti-dsDNA Ab with low C3 and C4 complement levels

- Treatment: Steroids, chemotherapy and biologics

- Class I: Mesangial IgG deposits

- Class II: Mesangial proliferative pattern, microscopic hematuria, mild proteinuria, and normal renal function --> Granular IgG on IF

- Class III: Focal Proliferative pattern --> Nephritic syndrome --> Variable renal insufficiency --> IgG and C1q on IF

- Class IV: Diffuse proliferative pattern --> Nephritic presentation

- Class V: Membranous pattern --> Nephrotic syndrome --> Complement levels often normal --> IgG granular pattern on IF

- Autoimmune disease causing anti-GBM antibodies

- Crescentic GN with linear IgG deposits

- Presentation: RPGN and possible pulmonary hemorrhage (Goodpasture)

- Antigen: NC1 domain of a3 chain of type IV collagen

- Predisposition: Smoking, volatile solvents, and viral respiratory infections

- Treatment: Immediate plasmaphoresis, steroids and immunosuppressive drugs

- Females: Hematuria from birth with no proteinuria or chronic renal failure

- Males: Hematuria from birth, proteinuria in adolescence, progressive renal failure, deafness and ocular defects

- Basket woven GBM with Hereditary Nephritis or Alport syndrome in males

- Thin GBM: Hereditary disease in females and some males

1. Hereditary --> Presents in infants

- Congenital Nephrotic Syndrome (NPHS1) --> Nephrin mutation

- Steroid-resistant Nephrotic Syndrome (NPHS2) --> Podocin mutation

2. Secondary Causes

- Diabetes

- SLE --> Lupus nephritis

- HIV, HBV, and HCV infections

- Amyloidosis --> Paraproteinaemia

- NSAIDs, gold, or other meds

- Lymphoma or solid tumors

- Pre-eclampsia

3. Primary Causes

- Minimal change disease

- Focal and segmental glomerulosclerosis (FSGS)

- Collapsing glomerulopathy

- Membranous nephropathy

- Membranoproliferative GN

- Immunotactoid nephropathy (rare)

- Fibrillary nephropathy (rare)

- The Finnish type

- Autosomal recessive nephrotic syndrome --> Nephrin (NPHS1) mutation (19q13)

- Onset in utero --> Early death from renal failure in infancy

- Survival depends on early nephrectomy, dialysis, and later renal transplantation

- Histology: Podocyte slit-diaphragm and foot process abnormalities

- Type 1 diabetes --> ~35% incidence --> 15-20 years after diagnosis

- Type 2 diabetes --> 15-50% incidence --> Interval is often much shorter

- Clinical features: Microalbuminuria, nephrotic syndrome, hypertension, retinopathy (preceeding symptom), and progressive renal failure

- Therapy: Strict glycemic control, ACEI or ARB but not combination therapy

- Diabetic glomerulosclerosis: Proteinuria, nephrotic syndrome, progressive renal failure, HTN and retinopathy

- Nephrosclerosis: HTN and progressive renal failure

- Papillary necrosis: Hematuria with urinary tract obstruction

- Autonomic bladder dysfunction

- Histology: Kimmelstiel-Wilson nodules and hyalinosis on LM and subepithelial deposits on EM

- KW nodules --> Round expanded mesangium

- Multi-systemic involvement

- Primary (AL with Ig light chain): Due to tumor

- Secondary (AA) due to inflammatory condition

- Causes nephrotic syndrome and progressive renal failure --> RPGN and tubule damage

- Diagnosis: Free l and k light chains (AL) serology and AA usually requires fat or kidney biopsy

- Histology: Amyloid lesions seen on biopsy via Congo Red stain --> Binds B-pleated sheets in amyloid

- BM completely distorted by light chain deposition

- Treatment: Aggressive chemo (AL) and treat chronic inflammatory disease (AA)

- Present in multiple myeloma

- Similar to amyloidosis

- Presentation: Systemic monoclonal IG disease, heavy albuminuria, nephrotic symdrome, microscopic hematuria, and hypertension

- Serology: Free light chains (k or l)

- Progressive renal failure that often recurs after renal transplants

- Histology: k or l staining on IF

- Treatment: Chemotherapy and autologous stem cell transplant

- Most common primary cause of nephrotic syndrome in children

- Nephrotic syndrome, steroid-sensitive, normal BP and renal function, and no abnormal serologies

- >80% respond to corticosteroids or immunosuppressive treatment

- Relapse is common (~20%) and does not progress to chronic renal failure

- Secondary cause of MCD pattern: Hodgkin's lymphoma and NSAIDs

- Normal histology on LM

- EM: Foot process effacement, microvilli present with vacuolated podocytes due to cytoskeletal rearrangement

- Most common cause of primary nephrotic syndrome in African-Americans

- Presentation: Nephrotic syndrome

- Steroid-resisant --> Worse prognosis than MCD

- Histology: Fibrous tissue deposition --> Scarring/sclerosis, protein reabsorption granules in podocytes, and podocyte effacement

- Causes: Idiopathic, hereditary/familial, reflux nephropathy, sickle cell disease, obesity, and renal ablation

- APOL1 mutations are common in FSGN --> Allows patients to become resistant to African sleeping sickness --> Also predisposes to FSGN and hypertension

- Variant of FSGN --> Associated with African-Americans and HIV positive patients

- Presentation: Minimal edema, normal BP, deteriorating renal function, and heavy proteinuria --> Rapid decline in renal function

- Causes: Idiopathic or drug/autoimmune associated

- Histology: Capillaries collapse on eachother and most severe podocyte injury  --> Podocytes engorged with protein and detach from BM on EM

- Most common cause of nephrotic syndrome in Caucasian adults

- Presentation: Nephrotic syndrome with weight gain and progressive leg swelling --> BP and renal function are normal

- Urinalysis: High proteinuria, high albumin, and hypercholesterolemia

- Serologies: ANA negative and normal complemet levels --> Autoimmune disease though (PLA2R Ab)

- Histology: Thickened BM with or without mesangial growth --> Spikes in BM due to IgG granular deposition on IF (subepithelial) --> Podocyte foot process effacement

- Treatment: 20-30% remit spontaneously but immunosuppressive treatment if necessary

- Secondary causes: Class V lupus, drug allergy, and HBV infection

- Mixed nephritic/nephrotic pattern --> Hematuria and proteinuria

- Causes: Lupus or HCV infection

- RPGN can occur occassionally

- HTN and azotemia are poor prognostic features

- Often progresses to end-stage kidney failure despite treatments

- Histology: Membranoproliferative pattern, double contours and "tram tracks" seen on LM --> Endothelium becomes displaced from BM and creates new BM to re-anchor

1. IgG and C3 on IF --> Immune complex disease and reduced C1-C4 --> Idiopathic, HCV with cryoglobulinemia, and other infections

- Dense deposit disease

2. C3 only on IF --> C3 nephropathy and DDD with reduced C3 --> Complement dysregulation disorders

- Often recurs after transplant

3. No IgG or C3 on IF --> Thrombotic microangiopathy or malignant hypertension

- ACE Inhibitors and ARBs --> Prevention of diabetic nephropathy and hypertension

- Desmopressin: ADH analogue for Central DI

- Thiazides and Amiloride (ENaC Inhibtor): For Nephrogenic DI

- Treat Type II or III hypersensitivity reactions in the kidney

- Prevent and treat renal transplant rejection

- Polyclonal antibodies against human thymocytes

1. Antithymocyte globulins: From rabbits

- Antibodies to many of the T-cell surface antigens

- Causes cytokine release reaction --> Fever, chills and hypotension

- Cytokine release results in T-cell depletion

2. Anti-IL2 Receptor Monoclonal antibodies (Basiliximab)

- Selectively binds to CD25 on activated T-cells and does not cause cytokine release or T-cell depletion

- Mycophenolate mofetil (prodrug) or azathoprine

- Inhibits the synthesis of purines by inhibiting IMP dehydrogenase

- Blocks immune cell and other rapidly dividing cell replication

- Activity markedly increases upon T-cell activation

- Purines are required for DNA replication in the S phase --> Stops cell cycle

- Blocks both B and T-cell replication

- Side effects: Due to inhibition of cell replicated in non-target tissues --> GI and bone marrow

- Macrolides of microbial origin

- Inhibit the calcineurin-mediated dephosphorylation of cytosolic transcription factors --> Upregulate IL-2 transcription

- Effective in reduced acute transplant rejection and increasing graft survival

- Tacrolimus and cyclosporine --> Similar effects but different binding sites

- Side Effects: CYP4503A variants affect the half-life and appropriate dosing, CYP450A related drug interactions, hypertension, hyperlipidemia, and diabetes

- Decreased GFR via afferent arteriole vasoconstriction and obliterative vascular pathology

- Tubular vacuolization and atrophy

- Interstitial fibrosis

- AKA sirolimus --> Macrocyclic polyketide

- m-TOR inhibitor --> Binds FKBP12 like tacrolimus but the complex then inhibits mTOR

- Discovered from streptomyces

- mTOR usually helps move cells from G1 to S phase

- Blocks IL-2 mediated T and B cell activation

- Therapeutic Role: Less toxic than calcineurin inhibitors but still nephrotoxic and less efficacious than calcineurin inhibitors

- Induction with protein therapeutic (ATG or Anti-CD25 antibody) --> At time of surgery

- Chronic PO therapy of a calcineurin inhibitor (Tacrolimus), mycophenolate and prednisone

- Goal is to tapper of the prednisone over time

- Emerging approaches: New combinations less reliant on steroids and calcineurin inhibitors

- Inadequate drug efficacy leading to late graft loss

- Nephrotoxicity and diabetes

- Immune-related toxicities --> Cancers and infection

- Chronic interstitial nephritis and papillary necrosis or calcifications

- Incresed risk of end-stage renal disease

- Dose-dependent risk

- Acetominophen induced effect is also linked to P450 reactive metabolites

- Acute and reversible renal insufficiency

- Leads to Na and water retention --> Edema

- Attributed to the decreased synthesis of prostaglandins by NSAID inhibition of COX2

- Increased risk by age, hypertension, diuretics, diabetes, and pre-existing renal disease

- Acute interstitial nephritis with nephrotic syndrome

- Leads to tubular damage, granuloma formation and infiltration of eosinophils

- Valacyclovir and sulfa drugs are common causes

- Crystal structures can be distinguished by microscopy

- Ethanol: Inhibits pituitary ADH release

- Lithium: Inhibits the downstream signalling of V2 receptor --> Diuresis can be antagonized with ENaC blockers (Amiloride) by preventing Li uptake into cell

- Hyponatremia with CNS deficits

- Causes: Oral hypoglycemics (sulfonylureas), antineoplastics (vincristine), and psychoactive agent (haloperidol)

- Saline --> Increase serum sodium

- Furosemide --> Decrease medullary hypertonicity that is driving force for water reabsorption

- V2R antagonists (-vaptan) --> Blocks vasopressin-mediated water reabsorption

- Reduce infusion rate or maintenance dose

- Increase dosing interval

- Dose adjustment based on the change of ClR of a drug

- This can be determined using ClCr/GFR and nomograms

- Sometimes renal impairment actually does change non-renal clearance --> Renal transformation

- Uremic toxins downregulate P450 enzymes and transporters in the liver --> Directly affecting hepatic clearance

- Increased drug effect if metabolites are active such as morphine-6-glucuronide (M-6-G)

- MUDPIES

- Methanol/metformin overdose

- Uremia --> Kidney failure

- DKA --> Diabetes

- Paraledhyde: No longer used

- Idiopathic/Lactic acidosis/Isoniazid

- Ethanol or ethylene glycol

- Salicylates

- RUN-DIC

- Renal tubular acidosis (RTA)

- Uremia (early) or uretero-colonic fistula

- NaCl infusion

- Diarrhea

- Inorganic acid administration (HCl or HCl salts)

- Carbonic anhydrase inhibitors

- Presentation: Acute cystitis or urethritis in health women

- Common organisms: E. coli, Staph. saprophyticus, Klebsiella, Proteus, and Strep. agalactiae

- Nonsecretors of ABH blood group antigens --> Prevent bacterial attachment to uroepithelial cells

- Sexual intercourse

- Spermicide use kills normal lactobacillus flora, maintains acidic pH, and prevents colonization

- Recent antimicrobial therapy, uncontrolled diabetes, and shorter urethra in women predispose to infection

- Inflammatory response with leukocyte recruitment and cytokine production

- Production of IgA and IgG with no protection from re-infection

- Symptoms: Dysuria, frequent urination, urgency, low back pain, gross hematuria, and vaginal discharge or irritation in women

- Urine cultures: Must be cultured immediately or stored at 4 C for no more than 18 hours --> Diagnosed by number of CFUs >10^5

- Antimicrobial susceptibility

- Microscopic examination of unspun urine for blood, pyuria, and WBC casts

- Urine dipstick tests: Determine the presence of bacteria and leukocytes with leukocyte esterase --> Also determine hematuria and proteinuria

- Treatment: Empiric therapy for most common (E. coli, Staph saprophyticus, etc) --> G- and aerobes

- Prevention: Good fluid intake to dilute bacteria and possible effect of cranberry juice, void immediately after sexual intercourse, antibiotic prophylaxis, and probiotics

- Occurs in patients with structural or functional abnormalities of GU tract --> Indwelling catheters too

- Most common organisms: E. coli, Klebsiella, Enterobacter, Citrobacter, Pseudomonas, Urease-producing (Proteus, Morganella, and Providencia spp.), Enterococcus, and Candida albicans

- Host response: Not well understood

- Presentation: Fever or other non-specific symptoms

- Diagnosis: Urine cultures and antibiotic sensitivity testing

- Treatment: Longer courses of antibiotics

- Prevention: Use antibiotic bladder rinses and catheters treated with antimicrobials

- Most commonly associated with bladder catheterization

- Organisms: E. coli, Klebsiella, Proteus, Pseudomonas, Enterococcus faecalis, and Candida albicans

- Biofilms develop on plastic medical devices

- Infections of the kidneys --> Uncomplicated or complicated

- Occurs when organisms travel up the ureters from the bladder

- Host response: Local response with cytokine production, pyuria, and systemic response with fever, leukocytosis, and IgM and IgG production

- Symptoms: Fever, chills, flank pain or costovertebral angle pain/tenderness --> Sepsis, multi-organ dysfunction, shock, and possible acute renal failure

- Diagnosis: Urine culture and antimicrobial susceptibility testing

- Bacteria in urine in the absence of symptoms

- Organisms: E. coli, Enterococcus and coag-negative Staph species

- Host response: Pyuria and local immune response

- Treatment: Only needed in children, pregnant women and immunocompromised patients

- Bacterial infection of the prostate gland --> Acute or chronic

- Oranisms move from the urethra into the prostate ducts

- Organisms: S. aureus or E. coli --> Chronic cases are polymicrobial

- Symptoms: Severe fever, pelvic pain, urinary retention with swollen and tender prostate

- Found worldwide and year round --> Normal flora of skin around GU tract

- Transmission: Sexual contact --> Common in sexually active women

- Pathogenesis: G+ cell wall, teichoic acid, and glycocalyx

- Diagnosis: White, non-hemolytic colonies on blood agar, coag-neg, and novobiocin resistant

- Treatment: Quinolone (levofloxacin) or trimethyoprim-sulfamethoxazole (Bactrim)

- Group B strep

- Colonizes lower GI tract and GU tract of women

- Transmission: Endogenous or mother to baby

- Pathogenesis: G+ cell wall including teichoic acid, capsule, and production of protective antibodies

- Diagnosis: Translucent, B-hemolytic colonies on blood agar, bacitracin-resistant, hydrolyzes sodium hippurate, and positive CAMP test

- Treatment: Penicillin G

- Part of normal flora of the colon, urethra and female GU tract --> Can get into bloodstream to cause endocarditits

- No significant virulence factors

- Diagnosis: G+ cocci, can be a,b, or non-hemolytic, grows in 6.5% NaCl and hydrolyzes esculin in bile

- Treatment: Multiply antibiotic resistant including vancomycin --> CRE strains

- G- rods, facultative anaerobes, flagella (motile), pili (sex or fimbrae), oxidase-neg, some ferment lactose, and grow on blood and MacConkey agar

- Virulence factors: LPS, capsule, antigen phase variation, type III secretion systems, sequestration of growth factors, and acquisition of antibiotic resistance

- Most common and medically relevant species in the genus --> Part of normal flora of the colon

- Facultative anaerobe, encapsulated, motile, and lac +

- Virulence factors: Adhesins and exotoxins to promote cell binding and disease production

- Septicemia: Bacteria enter the blood through UTI or GI tract --> Right rate of mortality in immunocompromised

- UTIs: Bacteria moving from colon to urethra and ascending to the bladder, kidney or prostate --> Most common in women and associated with uropathogenic strains with adhesins and hemolysins

- Diagnosis: Lac + (red)

- Treatment: Antibiotics for severe or disseminated infections, UTIs, septicemia, and neonatal meningitis

- Encapsulated G- bacteria --> Lac + and urease-pos

- Treatment: Antibiotics --> Susceptibility testing

- Motile and swarm on plates

- Found in soil and water --> Normal flora of colon

- Presentation: UTIs, pneumonia, wound infections, and septicemia

- Diagnosis: Swarm on agar plates, Lac - and urease-pos

- Treatment: Antibiotics, catheter care, and prompt removal of catheters

- G- rods in pairs, motile, obligate aerobe, lac -, and encapsulated

- Very resistant to disinfectants and can grow in water

- Big problem in hospitals --> Opportunistic pathogen --> ~10% of all hospital acquired infections

- Pathogenesis: Can colinze without symptoms causing localized and systemic diseases

- Virulence factors: LPS, pili, flagella, capsule, exotoxin A (inhibits protein synthesis), elastase, proteases, pyocyanin (tissue damage), and type III secretion systems

- Commonly causes UTIs, pneumonia, and wound infections

- Sepsis is possible from any of these infections --> >50% mortality

- Diagnosis: Gram stain, isolation in culture, lac - on MacConkey agar, B-hemolytic on blood agar, blue-green pigment (pyocyanin), oxidase-pos, and fruity aroma

- Treatment: Antibiotics but susceptibility testing is crucial --> Combination therapy with aminoglycoside and extended-spectrum antiseudomonal penicillin

- Prevention: Treating conditions that predispose patients to infection

- Yeast that has the ability to form pseudohyphae and hyphae in tissue

- Normal flora of vagina and can overgrow

- Treatment: Eliminate the predisposing condition, use topical preps such as azoles or fluconazole, and OTC preps

- 10-12% of men and 5% of women

- 5 year recurrence is 30-50% 

- Calcium stones (calcium oxalate or calcium phosphate) 70-80%

- Uric acid 10%

- Struvite 10%

- Cystine or drug-related <1%

- Calcium and uric acid stones are more common in men

- Struvite stones are more common in women

- Increased risk for stone formation: Water conservation and excretion of substances with low solubility

- Supersaturation of insoluble material: Increased by decreased urine output or overexcretion of substances

- Inhibitor: Citrate --> Reduces supersaturation and chelates calcium ions

- Urine pH: Alkaline urine favors calcium phosphate stones and acidic urine favors uric acid stones

- Crystals need to be in the renal pelvis long enough to grow and aggregate

- Calcium oxalate stones form by deposition over collections of interstitial suburothelial particles (Randall's plaques) in renal papillae

- Randall's plaques: Form in medullary interstitium and spread to the BM of papillary urothelium

- Urothelium then gets damaged and the plaque becomes exposed to urine --> Calcium oxalate crystallization and stone formation begins

- Mostly composed of calcium oxalate

- Risk factors: Hypercalciuria, low urine volume, hypocitraturia, hyperoxaluria, and alkaline urine

- Alkaline urine favors calcium phosphate deposition but NOT calcium oxalate stones

- Hypercalciuria: Due to vitamin D excess, hyperparathyroidism, and sarcoidosis --> Increased Ca absorption

- Hyperoxaluria: Bowel disease and genetic disorders of oxalate metabolism --> Also dietary oxalate consumption (spinach) or low Ca in diet --> Increased oxalate absorption and hyperoxaluria results

- Malabsorption syndromes: Reduced fatty acid and bile reabsorption --> Ca binds these so less Ca can bind oxalate --> Increased oxalate absorption and hyperoxaluria

- Metabolic acidosis due to diarrheal bicarb loss --> Low urinary pH and hypocitraturia --> Increased calcium and uric acid stone formation

- Weight loss surgery induces a malabsorptive state --> Stone formation

- Due to hyperuricosuria

- Occurs in patients with acidic urine (pH <5.5)

- Risk factors: Diets high in animal proteins

- Uric acid stones are not visible on plain films but easily visible on CT scans

- 15-20% of patients with uric acid stones have a history of gout

- Triple phosphate stones or infection stones --> Form in the presence of upper urinary tract infections with urease-positive bacteria (Proteus or Klebsiella)

- Normal urine has low ammonia phosphate levels --> Ammonia production is increased and the urine pH becomes elevated to decrease solubility

- Bacterial urease: Crucial for development of these stones --> Elevation of ammonia, carbonate, and urianry pH at the same time

- Phosphate combines with ammonium, magnesium, and carbonate --> Magnesium ammonium phosphate (struvite) and calcium carbonate-apatite

- Risk factors: Recurrent urinary tract infections, abnormal urinary tract anatomy, and frequent bladder catheterization

- Three times more common in women --> Higher incidence of UTIs

- Can produce huge "staghorn calculus" and recurrence is common 

- Patients with cystinuria --> Autosomal recessive disorder affected 1 in 15,000 patients --> <1% of stones

- Abnormal renal tubule cystine transport leading to large amounts of urinary cystine excretion

- Occurs equally in males and females --> Males are more severely effected

- Stones begin to form in the 1st-4th decades of life

- Stones tend to be large, multiple and bilateral --> UTIs and obstruction are common --> Recurrent ever 1-4 years

- Diagnosis: Hexagonal crystals in the urine

- Acidic urine favors cystine stone formation

- Hematuria with no other symptoms in non-obstructing stones

- Acute renal colic: Excruciatingly painful but doesn't fully subside like other types of colicky pain

- Costovertebral angle tendernes

- Associated symptoms: Nausea and vomitting due to schared splanchnic innervation

- Location of pain: Flank pain (upper ureter), ipsilateral testicle/labium (lower ureter), and urinary frequency/urgency (ureterovesical junction)

- Lab tests: Leukocytosis, elevated Cr with volume depletion, or bilateral/unilateral ureteral obstruction

- Urinalysis: RBCs or WBCs

- Radiological imaging: Helical (spiral) CT scan --> Can detect stones as small as 1 mm and ultrasound for kidney and proximal ureter stones

- Analgesia and parenteral NSAIDs

- Pain often due to renal capsule dilation --> May require decompression

- Volume expansion with intravenous fluids --> Corrects volume depletion and increases likelihood of stone passage --> Want to adjust so urine output is > 2.5 L/day

- Stones >5-6 mm are not likely to pass spontaneously

- Patients must monitor their urine for stone passage

- Urgent surgical intervention: Obstructed or infected urinary tract, worsening renal function, intractable pain or vomiting, or obstruction of a solitary or transplanted kidney

- Extracorporeal shock wave lithotripsy (ESWL): Shock waves are used to fragment stones into small pieces --> Obese patients may not be effectively treated with ESWL and cystine stones are very hard

- Flexible ureteroscopic stone removal: Invasive but has a better chance of becoming stone free --> Can be complicated by ureteral injury or stricture

- Percutaneous nephrostolithostomy: More invasive and necessary for large stones --> Rare today to require open ureterolithotomy

- Recurrent stone former should undergo an evaluation for metabolic cause of kidney stones

- Requires a comprehensive Hx, urine sediment examination, 24 hour urine collection, and lab values for supersaturation

- Dietary calcium restriction NOT recommended --> Dietary calcium is needed to bind oxalate in the GI tract

- Dietary sodium restriction and animal protein restriction

- Thiazide diuretics: Increased renal calcium reabsorption, increased serum Ca levels, and reduced urine calcium levels

- Urine alkalinization with potassium citrate

- Decreased intake of animal proteins

- Allopurinol: Xanthine oxidase inhibitor --> Reduces uric acid production

- Alkalinization of urine to pH of 7-7.5

- Thiol containing drugs (Penicillamine and Tiopronin): Increase solubility of cystine --> Tiopronin is better tolerated

- Captopril (ACE Inhibitor): Sulfhydryl group forms a thiol-cystine disulfide bond that is more soluble that cystine

- Surgical removal

- ~50% of patients without treatment will need nephrectomy

- Antibiotic therapy may slow growth and is important to halt infection

- Must culture stone material to help direct antibiotic therapy

1. Female Anatomy

2. Age

3. Genetic factors --> ABH blood group non-secretors

4. Menopause or pregnancy --> Urination issues

5. Sexual intercourse --> Especially new partners or spermicide use (kills off Lactobacilli in vagina)

6. Diabetes

7. Enlarged prostate

8. Recent antibiotic use

9. Hospitalization --> Urinary catheters