GU Block 1 Flashcards
Where are kidneys and ureters located withing the body?
What are the 3 external layers covering the kidney?
Retroperitoneal, T11-L3
Fascia Adipose Capsules
What are the 3 internal layers of the kidneys
What is the functional organ, tissue and unit of the GU/kidney?
Cortex Medulla Pelvis
Kidney, Parenchyma, Nephron
Where do vessels and nerve structures enter/leave the kidney?
What is the path of blood to and from the kidney
Hilum
Abdominal aorta Renal artery Afferent arterioles Glomerulus Efferent arterioles Peritubular capillaries Vasa recta Renal vein IVC
What part of the NS regulates filtration and urine formation?
What other process is innervated here?
Sympathetic: superior mesenteric, innervates arterioles
RAAS- dec BP
Renin secretion- inc BP
What does a nephron consist of?
Where do ACEIs/ARBS exert their effects?
Renal corpuscle (glomerulus, Bowmans) Renal tubules (PCT, LoH, DCT)
Afferent arteriole
What are the 8 major functions of the kidneys?
Regulate blood ions, pH, volume BP regulation Maintain blood osmolarity Produce hormones Regulate blood glucose Excrete wastes
Kidneys regulate blood levels of what 5 E+
Where is renin secreted from and leads to ? result?
Na K Ca Cl PO4
Juxtaglomerular cells
Inc BP
Kidneys maintain blood osmolarity at ?
What are the two hormones produced in the kidneys?
300/L
Calcitriol- active form of Vit D, regulates PO4/Ca
EPO- stim production of RBCs in marrow
Production of urine is the end result of what 3 processes?
Define Glomerular Filtrate
Glomerular filtration
Tubular reabsorption
Tubular secretion
Fluid entering capsular space
What are the 3 components of glomerular filtration membrane?
Fenestrations- allows proteins/excludes cells/platelets
Basal lamina- allows small/med proteins through
Slit membrane- located between pedicels, only allows very small proteins through
Define Filtration Fraction
How much blood flows through kidneys?
How much GFR flows through kidneys each day?
Ratio of fluid from blood that becomes glomerular filtrate- 20% of total fluid reaching kidney becomes capsular space
1-1.2L/min
140-180L/day
What is a normal net filtration pressure w/in kidneys?
What are the 3 pressures and the changes occurring during glomerular filtration
10mmHg
Glomerular hydrostatic- 55mmHg
Capsular hydrostatic- 15mmHg
Blood colloid- 30mmHG
Water makes up 95% of urine, how much Na and K is found normally?
What is the fluid capacity of the bladder?
Na- 1g/L
K- 0.75g/L
700-800mL
What are the 3 layers of the bladder?
Mucosa- transitional epitherlium
Muscularis- detrusor
Serosa- superior surface covering or,
Adventitia- covers post/inf surface and continuous w/ ureters
2/3 of body water is ? and remaining 1/3 is ?
Of the 1/3 part, how much is intravascular?
2/3: intracellular
1/3: extracellular
1/4
Define Osmolality
Define Osmolarity
Solution concentration expressed as total solute particles/kg
Solution concentration expressed as total milimoles/L
Fat’s water content is ? than muscle
This is why obese people’s ratio is ?
Lower than muscle
Lower ratio of total body water to body weight
Define Tonicity
A solution’s tonicity is related to its ?
Ability of extracellular solution to make water move in/out of cell via osmosis
Osmolarity, total concentration of all solutes in a solution
Define Hypotonic
Define Isotonic
Define Hypertonic
ECF w/ lower osmolarity than the ICF, net flow is into cell
Same osmolarity between ICF/ECF w/ no water movement
ECF w/ higher osmolarity than inside the cell, water moves out of cell
What is the gold standard for evaluating renal E+ excretion?
What is a better method?
24hr urine collection
Fractional excretion of an E+ from spot urine samples
What does a Low FEx indicate?
What does a High FEx indicate?
Renal absorption, high avidity/E+ retention
Renal wasting, low avidity/E+ excretion
What does an FEx below 1% mean?
What does an FEx above 2% mean?
Pre-renal Dz (low output HF)
Acute tubular necrosis
What is the natural physiologic response to a decrease in renal perfusion?
Why is the natural response of sodium wasting seen w/ high FEx
Inc Na reabsorption
Tubular necrosis causes loss of Na/hypervolemia
Physiologic solute concentration is normally between ?
Define Tonicity
285-295mmol/kg
Osmolytes that are impermeable to cell membranes
Define Ineffective Osmoles
What is the major extracellular cation
Substances that easily permeate cell membranes and don’t contribute to tonicity and don’t cause shifts across compartments
Na
Define Osmolal gap
What does the presence of this gap suggest?
Discrepancy between measured and estimated osmolality more than 10mmol/kg
Presence of unmeasured osmoles- ethanol, methanol, ethylene glycol, mannitol, propylene glycol and isopropanol
Normally, how many mosmols need to be excreted each day?
What is the max urine osmolality?
What is the minimum urine output required for neural solute balance
60
1200mosmol/kg
500mL/day
Obligatory renal water loss is mandated by ?
How is serum sodium calculated
Minimum solute excretion required to maintain a steady state
Exchangeable Na + Exchangeable K/ Total body water
What is the primary stimulus for water ingestion?
What mediates this stimulus
Thirst
Inc effective osmolality
Dec ECF volume
Osmoreceptors are stimulated by ?
What is the average osmotic threshold for thirst?
Rise in tonicity
295 mosmol/kg
What is the major stimulus for ADH release
Osmolality is primarily determined by ?
Hypertonicity
Na concentrations
What are the 3 steps required for maintaining homeostasis and normal plasma Na
Filtration, delivery of water/E+ to diluting site of nephron
Active reabsoprtion of Na/Cl w/out water in ascending LoH
Maintenance of dilute urine due to CD impermeability if no ADH is present
Hypotonic fluids often contribute to hospitalized PTs acquiring ?
Hyponatremia start at ? level and reflects ?
Hyponatremia- MC E+ abnormality in hospitalized PTs from too much IV fluid
<135mEq
Excess water relative to Na levels
Define Isotonic Hyponatermia
What two conditions can this occur in?
Pseudohyponatremia- lab error underestimating Na concentrations
Hyperlipidemia
Hyperproteinemia
Pseudohyponatremia does not occur if serum Na is measured by ?
Hypertonic Hyponatremia is AKA and defined as ?
What type of result does this cause?
Ion specific electrode in direct assay of undiluted serum specimen
Translocational Hyponatremia- large amounts of substance can’t cross membrane, added to ECF compartment
Pulls intracellular water into ECF, dilutes sodium
What are two examples of Hypertonic hyponatremia etiologies
What type of d/o is this?
Hyperglycemia
Iatrogenic mannitol administration
Water redistributing in response to change of tonicity
Most causes of hyponatremia are ?
What are the 3 categories
Hypotonic
Hypovolemic Hypo Hypo
Euvolemic Hypo Hypo- STREP
Hypervolemic Hypo Hypo
Hypovolemic Hypotonic Hyponatremia
Occurs d/t extra/renal volume loss w/ hypotonic replacement
Total Na and water dec
ADH release= retained water
Osmolality sacrificed to preserve intravascular volume
What urine Na results indicate if volume loss is renal or extrarenal?
SIADH
Renal: >20 mEq
Extra: <10 mEq
Hypo Hypo Hypo
ADH released d/t hyperosmolality/dec arterial volume
Inappropriate water retained= concentrated urine (+300mEq) w/ high Na (>20mEq)
What are 3 common causes of Hypo Hypo Hypo-SIADH
Hypo Hypo Hypo- Hormonal abnormalities
CNS Pulm d/o and Malignancy
Severe hypothyroid and glucocorticoid insufficiency; can NOT be differentiated from SIADH w/ urine/serum results
Hypo Hypo Hypo Psychogenic Polydipsia and Low Solute diet
Hypo Hypo Hypo- Reset Osmostat
PT ingests normal solute diet but also 10-15L of water; kidney retain water, can’t excrete pure water
Appropriate ADH response to water deprivation/fluid challenges (pregnancy)
Hypo Hypo Hypo Exercise associated
Why are sports drinks not actually that good?
Combo of excessive hypotonic intake w/ inappropriate ADH secretion (basic trainee forced hydration)
Hypotonic compared to serum
Hypervolemic Hypotonic Hyponatremia
Cirrhosis, HF, Nephrotic syndrome, Adv KDz
Cirr/HF- dec volume from dilation/dec output causes ADH secretion
Dec osmolality in attempt to restore arterial volume
What are the Sxs of hyponatremia
What causes more severe Sxs
What labs would be considered?
Mainly neuro/brain edema
Mild 130-135: gait fall Fx
Sev <120: seizure herniation coma death
Sudden/rapid E+ shifts
Serum: E+ Cr Osmolality
Urine: Na K Osmolality
Thyroid/Adrenal function
What will be seen on lab results to Dx SIADH
What will be seen on lab results in Pseudohypnatremia and how is it Tx
Normal thyroid/adrenal function Urine Na >20mEq Dec BUN <5-10mg Hypouricemia <4mg ADH levels not required
HyperTG, Hyperproteinemia
No Tx req’d
How is Translocational Hyponatremia Tx
How fast does chronic hypotonic hyponatremia need to be corrected?
What can happen if Tx is too fast?
Tx hyperglycemia, d/c Mannitol
4-6mEq/L/24hrs
No more than 6-8/24
Osmotic demyelination syndrome (central pontine myelitis)
If hyponatremia is Tx too quickly, what S/Sxs will be seen?
What is the adverse outcome of Tx Translocational HypoNa too quickly?
Flaccid paralysis Dysarthria
Dysphagia
Rapid reduction of osmolality= cerebral edema
How is Hypovolemic HypoNa Tx
How is Hypotonic Hpervol HypoNa Tx
Isotonic fluids to suppress hypovolume stimulus to release ADH
Loop diuretics
PTs w/ A/CKDz- dialysis
How is Psychogenic Hypo Euvo Hypo Tx
How is Hypo Euvo Hypo 2* to SIADH Tx
Psych- Water restriction
Low solute diet- water restriction, inc solute diet
Fluid restriction
D/c offender
Furosemide/Demelocycline
Sxs/resistant- vasopressin 2 antagonist (Tolvaptain)
Do these PTs stay in fluid restricted status when taking Tolvaptain?
How are PTs w/ Sxs or severe hyponatremia Tx
How are PTs w/ chronic hyponatremia Tx to avoid demyelination?
No fluid restrictions, can lead to excessive Na correction
Admit Consult D/c
Seizures= 100mL 3% saline across 10min for Sx relief
24hr correction 4-6mEq
100mL 3% at 0.5-5mL/kg/hr
When Tx HypoNa, what finding may signal excess ADH secretion has stopped and PT is at risk for over correction
What class of med is added to Tx of HypoNa in PTs w/ CHF?
High hourly urine output
Vasopressin 2
How are PTs w/ seizure/coma from HypoNa Tx
100mL 3% over 10-15min Measure levels, stop at 5mEq Rpt, max of 300mL KLO w/ 0.9% NS Max increase of 8mEq in first 24hrs
Causes of Isotonic HypoNa
Causes of Hyper Hypo
Hyperproteinemia
Hyperlipidemia
Hyperglycemia
Mannitol
Contrast
Causes of Hypo Hypo w/ <10 mEq
Causes of Hypo Hypo w/ >20
GI Skin 3rd space
Diuretic Nephropathies
Mineralcorticoid deficiency
CSWSyndrome
Causes of Hypo Euvolume
Causes of HypoNa HyperVol
<100: Pysch, low solute diet
>100: SIAD Hypothyroid Glucocorticoid deficiency
Variable- reset osmostat
HF Cirrhosis Nephrotic syndrome AKDz
When do PTs w/ HypoNa need to be referred?
What are the two main defenses against hypernatremia?
What is used to differentiate renal/non-renal water loss?
Severe Sxs
Hypertonic V2 dialysi
Severe liver/heart dz
Inc thirst/water intake
Urine osmolality
What is the defining criteria for HyperNa
All PTs w/ hypernatremia have ? which usually stimulates ? responses
> 145mEq
Hyperosmolality- usually triggers ADH and thirst
What is a less common form of HyperNa that occurs in hospitalized PTs
What type of HyperNa is usually mild and ASx
Hypervolemic HyperNa
HyerpNa in Primary aldosteronism
What is a renal cause of HyperNa?
What are two non-renal causes of HyperNa?
Diabetes insipidus
GI loss
Burns
S/Sxs of HyperNa
Lethargy Irritable Weak= early signs
Hyperthermia Delirium Seizure/Coma in severe
Since all PTs w/ HyperNa are hyperosmolality too, what S/Sxs are seen at different osmolality ranges?
HyperNa lab results showing urine osmolality is >400 can point to ? non/renal etiologies
320-330: somnolence, confusion
340-350: coma death
Non-renal: low intake, hypotonic fluid loss
Renal- glycosuria
HyperNa lab results showing urine osmolality <250 can be due to ? issues
What are some common causes?
Diabetes insipidus-
Central: dec ADH release
Nephrogenic: ADH insensitivity
Lithium Demecyocycline
Obstruction relief
Interstitial nephritis
HyperCa/HypoK
What happens if HyperNa is Tx too quickly
What is the fluid Tx of choice for hyperna w/ hypo volume
Cerebral edema
Neuro impairment
Isotonic to restore volume then hypotonic
PO water is excellent
How is HyperNa w/ Euvolume Tx
What caution needs to be taken when treating PTs w/ dec GFR?
Water ingestion
IV 5% dextrose
Adding diuretic may increase Na excretion, but impair renal concentration
How is HyperNa w/ Hypervolume Tx
How is acute hyperNa Tx
5% dextrose to red hyperosmolality
Loop diuretics to promote urination/lower Na
Possible dialysis
5% dextrose if lost free water
Continue therapy w/ 0.45%NS w/ dextrose
How is chronic HyperNa Tx
In HyperNa, total body water is ? in men and ? in women
W/ goal to restore 140mEq
Max Na correction- 10mEq/day
PO water preferred if safe or,
5% dextrose IV
M: 50% x kg
F: 40% x kg
When do Pts w/ HyperNa need to be referred or admitted
Equation for free water deficit
Refer: refractory/unexplained
Admit: symptomatic
TBW * Na-140/140
M- 50%
W- 40%
What is used to distinguish renal from non-renal cause of K loss
What is the MC cause of K
Transtubular K concentration gradient
GI- infectious diarrhea
HypoK and acidosis suggests ?
What two med classes need to be avoided to decrease risk of arrhythmias
Profound K depletion
B 2 agonists and diuretics
HypoK increases chances of ? toxicity
What needs to be considered in PTs w/ hypoK that is refractory to Tx
Digitalis
HypoMg
Low k+ can lead to what 2 adverse events
? drug can cause substantial renal loss of K
Arrythmias
Rhabdo
Loop diuretics
S/Sxs of mild HypoK
The presence of HTN may indicate there is excess of ?
Mild: Weak Fatigue Cramps
Sev: flaccid paralysis hyporeflexia hypercapnia
Aldosterone
Mineralcorticiods
What are renal manifestations of hypoK
If working up HypoK, what is seen on urine results?
Nephrogenic Di
Interstitial nephritis
Low: extra renal loss, V/D
High: mineral corticoid excess
What does a Transtubular K Gradient TTKG >4 indicate?
What will be seen on EKG?
K+ loss w/ inc distal K secretion
Dec amplitude
Broad T w/ U waves
Premature V contractions
Depressed ST segments
How is HypoK Tx
PO- safest/easiest for mild/mod
IV 40mEq if severe/non-PO w/ constant EKG monitoring
Avoid glucose fluids
Check Mg if refractory
When is HypoK referred or admitted
How can PTs develop acquired HyperK
R: unexplained refractory alternative Dx
A: Sx and Severe- cardiac manifestations
ACEI/ARB
K+ sparing diuretics
What is the ratio of K+ inc to pH inc
Persistent mild HyperK w/out presence of ACEI/ARB is usually due to ?
K inc 0.7/0.1pH inc
Type 4 tubular acidosis
S/Sxs of HyperK
What is the first step in Dx
Flaccid paralysis
Weakness
Ileus
Repeat labs, especially if no meds are present
What are the indications to Tx HyperK urgently
How is HyperK urgently Tx
Cardiac toxicity
Muscle paralysis
>6.5
Insulin BiCarb B-agonist
Dialysis if A/CKDz
Name of medication used to Tx HyperK in PTs w/ CKD and already on drug that inhibits RAAS
MOA of CaGluconate
MOA of BiCarb, Insulin and Albuterol
Patiromer
Antagonize cardiac conduction
Distributes K into cells
Of the 4 meds used to Tx HyperK, do any remove K from body
When are HyperK PTs referred/admitted
No, all shift K into cells
Ca only one that DOESNT shift K to cells
R: HyperK from renals Dz and reduced K excretion
A: >5.5, any EKG changes or Concomitant
What can cause PTs to develop HypoCa
MC cause of low total serum Ca is ?
What is the most accurate method of measuring
Dec PTH VitD or Mg
Hypoalbuminemia
Ionized Ca concentration
True HypoCa indicated insufficient action of ?
What is the MC cause of HypCa
PTH or Vit D
Adv CKDz- dec Vit D3 production and Hyperphosphatemia catalyze
S/Sxs of HypoCa
What EKG changes will be seen?
Cramps Spasms Convulsions
Chvostek sign
Trousseau sign
QT prolongation predisposes ventricular arrhythmias
How does serum phosphate present during HypoCa
What other E+ is commonly low in HypoCa
Inc in hyperparathyroidism/adv KDz
Dec early CKDz or Vit D deficiency
Mg
How is Sx/Sev HypoCa Tx
How is ASx HypoCa Tx
10-15mg Ca/kg
Monitor serum q4-6hrs
PO Ca and Vit D/sterols
Monitor urinary Ca excretion
When is HypoCa referred/admitted
What are the MC causes of HyperCa
R: Complicated from hyperparathyroid, familial hypoCa or CKDz
A: PTs w/ tetany, arrhythmia seizure or severe
ASx/Mild: Hyperparathyroid
Sev: Malignancy related HyperCa
What PE/lab finding may be seen indicating pending hypercalcemia
HyperCa levels above ? usually indicate malignancy
Hypercalciuria
> 14mg
What is the MC cause of hyperCa in ambulatory PTs
What type of HyperCa presentation suggest benign cases
Primary hyperparathyroidism
Chronic
Nephrolithiasis
What is the MC paraneoplastic endocrine syndrome
What is this the MC cause of
Tumor producing PTH related proteins
HyperCa in InPts
How/why do granulomatous Dzs cause HyperCa
Define Milk-Alkali Syndrome
Sacroidosis/TB cause HyperCa via overproduction of active Vit D3
Ca ingestion to prevent osteoporosis causes AKI from renal constriction
Sxs usually appear when Ca levels pass ?
What Sxs may be seen in mild cases?
What is seen in severe cases
> 12mg
ASx, constipation N/V anorexia
Weak Drowsy Coma Death
What are clinical findings seen w/ HyperCa
Ionized Ca >1.32
Hyperparathyroid- high serum Cl, low serum phosphate
Mild Alkali syndrome- low Cl, high BiCarb- Hypocalciuric Hypercalcemia
Malignancy- >14mg
How to differentiate Hyperthyroid or malignancy induced HyperCa
How is HyperCa Tx
Hyperthyroid- inc PTH
Malignancy- dec PTH, inc PTHrP
Promote excretion- calciuresis
Dec volume but normal Heart/kidney- 0.9% NS
What is the Tx of Choice for malignancy inducer HyperCa
Kidney is most important regulator of serum ?
Bisphosphonates, take 72hrs
Calcitonin as bridge
Phosphate levels
If need to measure serum phosphate is needed, what does PT need to do
What PT population is severe hypophosphatemia commonly seen in?
Fasting, phosphate decreases w/ food intake
Alcoholics
What will be seen on lab findings when investigating hypophosphatemia
How is hypophosphatemia Tx
Urine excretion <100mg/day
If PT has DKA- diet
POR replacement preferred
Chronic- PO repletion mixture of Na/K phosphate
Severe Sx- infusions
S/Sxs of acute/severe hypophosphatemia
S/Sxs of chronic/sev hypophosphatemia
What are c/is to replacing phosphate to Tx hypophosphatemia
Rhabdo Encephalotphaty Parasthesis
Fx Anorexia Pain
Hypoparathyroid
Advanced CKD
Tissue damage/necrosis
Hypercalcemia
What is the MC cause of hyperphosphatemia
How can hyperphophatemia be Tx
Advanced CKD w/ dec urinary excretion
Dec dietary intake
Phosphate binders- Ca carbonate/acetate
Dialysis if A/CKDz
If dec Mg levels are suspected, what is the first lab ordered?
Low levels can manifest w/ ? Sxs
Low Mg will impair the release of ? endocrine hormone?
Urine
Neuro Sxs
Arrhythmias
PTH
What are etiologies of HypoMg
Since HypoMg also suppresses PTH, what other issues will be seen?
Diuretics Diarrhea Alcoholism
Aminoglycosides Amphotericin
Organ resistance to PTH and dec Vit D3 levels= HypoCa that is refractory to Ca Tx methods
S/Sxs of HypoMg
How is it Tx
HypoCa/HypoK
Babinksi response
Athetoid movement
HTN/Tachy
Chronic- Mg Oxide
Sx- Mg sulfate
What are two potential exogenous sources of HyperMg
What are the characteristic manifestations of HyperMg
Antacids
Laxatives
Weak, Dec DTRs, Confusion
What is seen on lab results for HyperMg
What is seen on EKG
Inc MG
If Pt has CKD- inc BUN, Cr, K, PO4 and Uric acid
Low Ca
Inc PR interval
Broad QRS
Peaked T waves d/t HyperK
How is HyperMg Tx
In order to assess PTs acid-base status, what 3 things need to be measured?
IV Ca chloride
Dialysis if severe CKDz
Arterial pH, PCo2- blood gas analyzer
Plasma BiCarb
Since arterial and venous blood gases won’t be equivalent during cardiopulmonary arrest, where/what are the most accurate measurements?
Acidotic is below ? w/ ? PCo2 and BiCarb measurements
Arterial pH and PCO2
<7.40
PCO2 <40
BiCarb >24
There can be mixed acid-base d/os but there will never be ?
What are the 5 steps of determining acid-base d/os
Two primary respiratory d/os
Primary d/o, met/resp Presence of mixed d/o Calculate anion gap Calculate corrected BiCarb concentration Examine PT
What is the Anion Gap formula
What are the two reasons for calculating anion gaps?
Gap= Na - (HCO3 + Cl)
ID abnormal gap w/ normal E+
Gap >20 suggest primary metabolic regardless of pH/bicarb, abnormal anion gap is never compensatory response to respiratory d/o
A wide anion gap means there are ? located in the ?
What 3 issues form the largest anion gaps?
Unaccounted ions in serum
Lactic acidosis
Ketacidosis
Toxins
Metabolic acidosis w/ normal anion gap is caused by what 2 issues
How can the cause be distinguished?
GI BiCarb loss or RTA
Urine anion gap
What is the hallmark of metabolic acidosis
What underlying issues can cause the interpretation of the anion gap to be more difficult
Dec BiCarb
Hypalbumin
ABX
Reduction unmeasured anion/
Inc unmeasured cations
What effect does hypoalbuminemia have on an anion gap?
What are the 4 principle causes of inc anion gap metabolic acidosis
2 mEq dec in gap occurs for every 1g decline of albumin
Lactic acidosis
Ketacidosis
Ingested toxins
Acute/chronic renal failure
What effect does uremia have on an anion gap?
What type of gap does lactic acidosis create?
? types of PTs may present w/ Type B Lactic Acidosis
Inc gap
Elevated gap, dec pH w/out other acid-base disturbances
UnDx/poorly controlled DM
Alcholics
PTs in shock
What type of gap does DKA create
What two pieces of info are used to monitor/track PT improvement during Tx
Hyperglycemia, acidosis and inc gap
Clinical status
pH
What are the 3 types of metabolic acidosis seen in alcoholic PTs
What type of anion gap can develop from volume contraction/vomiting
Ketoacidosis
Lactic acidosis
Hyperchloremic acidosis from BiCarb loss in urine
Metabolic alkalosis
What can cause respiratory alkalosis to develop/
What lab results are used to support a Dx of alcoholic ketoacidosis
Pain Alcohol withdrawal Liver dz Sepsis
No DM Hx
Normoglycemia after initial therapy
What type of poisoning can present w/ a normal anion gap
How would Isopropanol poisoning show?
Toluene poisoning
Inc osmolar gap, unaffected anion gap
Define Uremic Acidosis
What are two major causes of normal anion gap acidosis
GFR <30= kidney can’t synthesize NH3
Reduced H+ and organic acid excretion inc anion gap metabolic acidosis
GI BiCarb loss- N/V/D
Renal tubular acidosis
Use urine anion gap to differentiate
