Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

M202 > W26 AKI + CKD > Flashcards

W26 AKI + CKD Flashcards

1
Q

What is an AKI?

A
  • A global healthcare challenge
  • Rapid deterioration of kidney function
  • Most commonly caused by reduced blood flow to the kidneys, usually in someone who is already unwell
  • Excessive vomiting or diarrhoea, blood loss or severe dehydration
  • Sometimes described as ‘angina’ or ‘TIA’ of the kidneys
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the Risk factors for AKI?

A
  • Age >65
  • CKD 3-5
  • History of AKI
  • Cardiac failure
  • Liver disease
  • Diabetes Mellitus
  • Hypovolaemia
  • Sepsis
  • Neurological or cognitive impairment that may restrict access to fluids
  • Symptoms or history of urinary tract obstruction
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Presentation of an AKI:

A

*Variable; depends on the cause:
* Non-oliguric
* Oliguric (urine output < 400mL/ day)
* Anuric (urine output < 100mL/day)
*Rapid or slower rise in serum creatinine
*Different urine solute concentrations
*Different urine cellular concentrations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the Signs & symptoms of an AKI?

A

*Pre-renal:
* Thirst, decreased urine output, dizziness, and
orthostatic hypotension, diarrhoea, sweating,
haemorrhage, vague mental status (esp. elderly)
*Intra-renal:
* Haematuria, oedema, hypertension, recent
nephrotoxins (drugs, contrast media), muscle pain, fevers, rash
*Post-renal:
* Urine retention, flank pain, haematuria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

AKI: Definition & Staging

A

*Over recent years there has been
increasing recognition that relatively small
rises in serum creatinine in a variety of
clinical settings are associated with worse
outcomes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the different aspects in AKI Management?

A

*Treatment mainly supportive
*Early identification & correction of
underlying cause
*Restore intravascular volume
*Correct biochemical abnormalities
*Renal replacement therapy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the aims in AKI management?

A
  1. Maintain volume homeostasis:
    *IV fluids
    *Diuretics
    *Dialysis
  2. Correct anaemia:
    *IV iron
    *Erythropoiesis stimulating agents (ESAs)
    *Blood transfusion
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Correct biochemical abmormalities

A
  1. Acidosis with bicarbonate
  2. Manage hyperkalaemia
    * Stop giving potassium
    * Stop agents that increase potassium
    * IV calcium gluconate
    * Dextrose & insulin
    * Salbutamol
    * Calcium resonium, patiromer, SZC
    * Dialysis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Hyperkalaemia

A
  • Patients with kidney disease are generally less able to excrete K+ and most will have K+ concentrations in the upper limits of the ‘normal range’ (3.5-5.3 mmol/L)
  • ECG changes, ventricular fibrillation and cardiac arrest
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Drug causes of hyperkalaemia?

A

*Potassium supplements
*ACE inhibitors
*A2RBs
*Spironolactone
*Amiloride (diuretic)
*NSAIDs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Fluid Management in AKI

A
  • Dehydration or volume depletion is considered a high risk factor for developing AKI
  • Much of clinical practice in critical care and the
    peri-operative setting is geared to reducing the
    risk of hypovolaemia
  • During the early stages of critical illness adequate volume resuscitation remains a goal for optimizing tissue perfusion and oxygen delivery
  • Observational studies in critically ill patients have suggested that fluid overload may have a
    negative influence on kidney function & mortality
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Diuretics in AKI

A

*Patients with AKI can develop anuria or
oliguria and fluid retention, which are
associated with further complications such
as respiratory failure
*In many studies, oliguric AKI has been
associated with worse outcomes than
nonoliguric AKI
*The use of diuretics in oliguric AKI is frequent
but the benefits remain unproven

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Diuretics to prevent AKI?

A

*KDIGO guidelines:
*Do not use furosemide to prevent AKI
*Furosemide does not reduce the risk
of renal replacement therapy (RRT)
or mortality

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Diuretics to treat AKI

A

*KDIGO Guidelines:
*Diuretics should not be used to treat
AKI, except for the management
of volume overload

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the 3 classes of AKI?

A

Pre-renal
Renal
Post-renal

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Pre-renal (haemodynamic) AKI:
What can cause an acute reduction in GFR?

A
  • Drugs that decrease renal perfusion will have an adverse effect on renal function
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Pre-renal: volume depletion

A
  • Water & electrolyte loss
  • Excessive use of laxatives and diuretics especially loop diuretics (furosemide &
    bumetanide)
  • Non-steroidal anti-inflammatory drugs
    (NSAIDs) e.g. Ibuprofen and naproxen,
    can exacerbate pre-renal effects by
    further decreasing renal perfusion
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

NSAIDs

A
  • Prostaglandins are produced in response to pain, temperature, inflammation and a variety of other stimuli
  • NSAIDs inhibit the production of prostaglandins E2, I2 & D2 within the kidney
  • These are potent vasodilators that are crucial in maintaining renal circulation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

NSAIDs

A
  • Renal function usually recovers if NSAID
    therapy is withdrawn early enough
  • Permanent damage can occur

Causes reduction and dilation in afferent arteriole

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Pre-renal: altered renal haemodynamics

A
  • Recognised complication of treatmemt with
    angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (A2RB)
  • ACE inhibitors e.g.
  • Ramipril, lisinopril
  • A2RBs e.g.
  • Losartan, candesartan
  • Vasodilator effects on the efferent glomerular
    arterioles

ACEi reccomended for CKD but can cause AKI (dilates effertent artery in kidney)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

NSAIDs And RAASi lead to..
Effect on nephrons in the kidney?

A

NSAID= Constricts AA
RAASi= Dilate EA
= Reduced GFR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Other drugs that can reduce GFR?

A
  • Ciclosporin & tacrolimus
  • Anti-rejection drugs used in kidney transplant recipients
  • Cause intense vasoconstriction of the microvasculature within the kidney
  • Reduced renal perfusion and a fall in GFR
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Metformin

A

*Decreases gluconeogenesis and
increases peripheral utilisation of glucose
*Promotes conversion of glucose to
lactate
*Results in additional lactate
*Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation
*Occurs primarily in diabetic patients with significant renal impairment
*Not nephrotoxic but metformin is renally excreted, so eGFR values should be determined before initiating treatment and regularly thereafter

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Drugs that can cause hypokalaemia:

A
  • Loop diuretics e.g. Furosemide, bumetanide
  • Thiazide and related diuretics e.g. chlortalidone, indapamide & bendroflumethiazide
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Renal (intrinsic renal toxicity)

A
  1. Glomerular= Glomerulo-nephritis
  2. Tubular= Acute tubular necrosis
  3. Interstitial= Acute interstitial nephritis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Glomerular

A
  • Drug induced glomerulonephritis (GN)
  • Immune mediated disease
  • Antigen-antibody complex accumulate within
    the glomerulus
  • Inflammatory response due to depositing
    immunoglobulins and complement in base
    membranes and blood vessels
  • Reduced GFR, salt and water retention,
    hypertension
  • Many drugs are known to cause GN
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Drug-induced glomerulonephritis

A
  • Allopurinol
  • NSAIDs
  • Hydralazine
  • Penicillins
  • Sulfonamides
  • Gold
  • Rifampicin
  • Thiazide diuretics
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Tubular

A
  • Acute tubular necrosis (ATN) can occur due to renal ischaemia or nephrotoxic agents or both
  • Direct toxic affect of drugs & metabolites
  • Can occur with normal doses but more likely with higher and prolonged dosing and in those with pre-existing renal disease, hypertension, heart disease & diabetes
  • Avoid nephrotoxic agents in high risk patients
  • May require renal replacement therapy (RRT)
  • Maintain adequate hydration and TDM where
    indicated
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Drug induced ATN

A
  • Aciclovir
  • Aminoglycosides
  • Cephalosporins
  • Contrast media
  • Ciclosporin
  • Furosemide
  • Lithium
  • NSAIDs
  • Paracetamol
  • Tacrolimus
  • Vancomycin
30
Q

Gentamicin

A

*Highly cationic
*Binds to the anionic phospholipid
membrane of renal tubule cell
*Endocytosis of gentamicin into renal
tubule cell
*Tubular damage and dysfunction are the
main causes of renal insufficiency

31
Q

Interstitial

A
  • Acute interstitial nephritis (AIN) is a
    hypersensitivity reaction characterised by a fall in GFR within hours, days or months of exposure to a particular drug
  • Often associated with proteinuria & haematuria
  • Intestitium is infiltrated by inflammatory cells
  • Low-grade pyrexia, rash, arthralgia
  • AIN is thought to account for up to 15% of
    hospital admissions due to AKI
32
Q

Drugs causing Acute interstitial nephritis?

A
  • Allopurinol
  • Amlodipine
  • Azathioprine
  • Bumetanide
  • Carbamazepine
  • Co-trimoxazole
  • Diltiazem
  • Erythromycin
  • Furosemide
  • Gentamicin
  • Lithium
  • Mesalazine
  • NSAIDs
  • Penicillins
  • Phenytoin
  • Proton pump inhibitors
  • Ranitidine
  • Rifampicin
  • Thiazides
  • Vancomycin
33
Q

PPI induced AIN

A

PPI use is associated with an increased risk
of AKI, CKD and progression to ESRD
*A delay in diagnosis and continued PPI use
a contributory factor
*Inflammatory process associated with the
development of interstitial fibrosis
*Incidence unknown but considered to be
relatively rare

*End-stage renal disease

*Omeprazole most frequently implicated
PPI
*Relatively few reports with other PPIs but
this may simply reflect volume of use
*A class effect is suspected
*Ranitidine has rarely been associated
with AIN but is used as an alternative to
PPIs

34
Q

Management of PPI induced AIN?

A

*Withdrawal of the PPI
*Monitor renal function recovery
*Corticosteroids sometimes used but no
evidence of improved outcomes

35
Q

Post-renal damage (obstructive uropathy)

A
  • Obstruction to urine flow through the kidneys
    can be caused by a number of factors
  • Ureteric fibrosis
  • Renal calculi
  • Blood clots
  • Mechanical blockage
  • Prostatic hypertrophy or malignancy
  • Bladder tumour
  • All can occur with drug therapy
36
Q

Post-renal damage (obstructive
uropathy)

A

*Tubular blockage – crystalluria:
* Tumour-lysis syndrome: uric acid crystals,
sulphonamides, MTX, cisplatin, aciclovir
*Tubular blockage - calcium nephropathy:
* Over consumption of vitamin D & calcium
containing antacids
*Tubular blockage - myoglobin:
* Statins (esp. with concurrent fibrates or
enzyme inhibitors such as erythromycin)

37
Q

AKI: Compounding factors?

A
  • Dehydration
  • Diarrhoea
  • Chronic kidney disease
  • Liver disease
  • Heart failure
  • Infection/sepsis
  • Increasing age
  • Poly-pharmacy
38
Q

Which drugs can cause a ‘Loss of drug effectiveness’ on others? (2)

A
  • Nitrofurantoin
  • Thiazide and related diuretics
    e.g. chlortalidone, indapamide,
    bendroflumethiazide
39
Q

Nitrofurantoin

A
  • Antibacterial efficacy in UTI infection
    depends on the renal secretion of
    nitrofurantoin into the urinary tract
  • In patients with renal impairment, renal
    secretion of nitrofurantoin is reduced, which
    can result in treatment failure
  • Nitrofurantoin is therefore contraindicated in
    those with GFR <45 mL/min creatinine
    clearance (short courses can be used with
    caution between 30-44mL/min)
40
Q

Thiazide & related diuretics

A

*Inhibits the renal tubular absorption of salt
and water by its action at the beginning
of the distal convoluted tubule
*The effect on the kidney depends upon
excretion into the renal tubule; efficacy
falls with increasing renal impairment
*Thiazide diuretics are unlikely to be of use
once GFR<30 mL/min

41
Q

Which drugs are useful in blocking creatinine secretion in tubules? (4)

A
  • Trimethoprim
  • Amiloride
  • Spironolactone
  • Cimetidine
  • Administration in patients with renal impairment may increase creatinine without altering GFR
42
Q

Summary: Key prescribing principles

A
  1. Determine the degree of renal impairment
  2. If a drug is nephrotoxic or known to exacerbate kidney function, consider an alternative
  3. Reduce dose or increase dosage interval (if
    necessary) to accommodate reduced renal
    clearance & alterations to kinetics
  4. Consider the need to load the drug
  5. For narrow therapeutic index drugs, monitor levels
  6. For all drugs monitor for efficacy, safety &
    tolerability
43
Q

The kidneys and drug excretion
What are the 3 processes involved?

A

They are the final common route of elimination for many drugs and drug
metabolites

  1. Glomerular filtration
  2. Active tubular secretion
  3. Passive tubular re-absorption
44
Q

Absorption of orally administered drugs
Drug absorption may be reduced due to what..? (4)

A
  • Nausea, vomiting or diarrhoea associated
    with uraemia
  • Hypoproteinaemic oedema of the GI tract e.g. in nephrotic syndrome
  • Reduced intestinal motility and gastric
    emptying time e.g. uraemic neuropathy
  • Co-administration of chelating agents e.g. phosphate binders
45
Q

Changes in drug distribution
May occur as a result of what..? (3)

A
  • Changes in hydration state of the patient
  • Alterations in plasma protein binding
  • Alterations in tissue binding
46
Q

Hydration state of the patient

A
  • Drugs with a small volume of distribution (Vd)
  • E.g. Gentamicin in oedematous patients
  • Important with therapeutic drug monitoring
  • Particularly important when the state of
    hydration is fluctuating with the use of IV
    fluids, diuretics or intermittent renal
    replacement therapy (RRT)
47
Q

Alterations in protein binding
E.g. phenytoin (antiepileptic):

A
  • Requires therapeutic drug monitoring (TDM)
  • Unbound drug is pharmacologically active
  • In renal impairment, need to consider altered serum albumin concentration and decreased binding affinity
48
Q

Alterations in protein binding

A
  • Altered due to:
  • Hypoalbuminaemia
  • Uraemia, which will compete with drugs for
    binding to albumin
  • Clinically important for highly protein-
    bound drugs
  • A reduction in bound drug in plasma will
    result in a higher proportion of unbound,
    and therefore active drug in the plasma
49
Q

Metabolism

A
  • Phase I and II metabolism slower in CKD
  • Increase serum concentrations of the
    parent drug
  • Higher prevalence of adverse drug
    effects and toxicity
  • Kidney itself is also a site of metabolism
    for some drugs:
    -Insulin
    -Vitamin D
50
Q

Insulin

A

*Insulin is freely filtered in the kidney. Of the total renal insulin clearance, approximately 60% occurs by glomerular filtration and 40% by tubular secretion
* In advanced renal failure there is a
marked fall in insulin clearance
* This may allow lower doses of insulin to be
given or even the cessation of insulin
therapy
* Decreased calorie intake due to uraemia-
induced anorexia, also may contribute to
the decrease in insulin requirements

51
Q

When does Elimination of drugs and metabolites occur? (2)

A
  • Glomerular filtration
  • Renal tubular secretion
52
Q

Elimination (for info)

A
  • In renal impairment these functions are
    reduced
    -Glomerular filtration – higher plasma levels
    -Tubular secretion - higher plasma levels
  • Extent to which drugs are affected depends on the % of active drug or metabolite that would normally be excreted by this route
53
Q

Morphine sulphate

A
  • The half-life of morphine-6-glucuronide is
    increased from 3–5 hours in normal renal
    function to about 50 hours in end stage
    renal disease
  • Often avoid slow release oral
    preparations as any side effects may be
    prolonged
54
Q

Pharmacodynamic alterations

A
  • The effect the drug has on the body
  • There are changes in the body’s response to drugs in renal impairment
  • Patients with uraemia have:
    -Increased sensitivity to drugs acting on the
    CNS e.g. benzodiazepines
    -An increased risk of GI bleeding with irritant
    drugs such as NSAIDs
55
Q

Estimation of renal function

A
  • Cannot be measured directly therefore
    estimates are used:
  • eGFR
    -MDRD
    -CKD-EPI
  • GFR absolute
  • Creatinine clearance (CrCl)
    -Cockroft-Gault equation
56
Q

Why is creatinine measured to estimate kidney function?

A
  • One of many molecules cleared by the kidneys that will accumulate in renal impairment
  • Glomerular filtration & secretion in proximal tubule
  • Product of muscle breakdown
  • Production fairly constant in people with stable diets
  • Production varies between individuals
  • Proportional to muscle mass and meat intake
  • May increase by up to 25% in individuals with
    normal kidney function following a meat
    containing meal
  • Important to consider age, sex, race & weight
57
Q

eGFR (MDRD)

A
  • Modification of Diet in Renal Disease (MDRD) study group compared different methods of calculating GFR and found an equation with a good prediction of GFR
  • Age, sex, race (Caucasians, African Americans)
  • eGFR calculated automatically by laboratory
  • GFR measured in ml/min/1.73m2
  • If BSA < 1.73m2, eGFR is likely to overestimate kidney function
58
Q

GFR absolute

A
  • Using patient’s BSA will overcome this
    problem but requires an additional
    calculation
  • GFR absolute = (eGFR x BSA/1.73)
    E.g.
  • eGFR = 32ml/min/1.73m2
  • BSA 1.5m2
  • GFR absolute = 28ml/min
59
Q

Creatinine Clearance (CrCl)

A
  • Calculated using a different equation:
    Cockroft-Gault, which includes:
  • Age, bodyweight, serum creatinine, sex
  • Measures creatinine clearance in ml/min
  • Very accurate when used correctly
60
Q

Which weight do I use in calculating CrCl?

A
  • Average build or height – actual body
    weight
  • Obese – adjusted body weight
  • Very muscular – actual body weight
  • Underweight – actual body weight
61
Q

Creatinine Clearance (CrCl)

A
  • CrCl overestimates GFR (15-20%) at normal
    kidney function due to tubular excretion of a
    small amount of creatinine which is unrelated to glomerular filtration and therefore not affected by changes in GFR
  • Tubular secretion usually maintained as
    glomerular filtration is lost
  • In advanced CKD this route can account for
    up to 50% of CrCl
62
Q

eGFR or CrCl?
* For nephrotoxic drugs with small safety
margins and for patients at extremes of
weight you should use which equations? (2)

A
  • eGFR and CrCl not interchangeable
  • eGRF or CrCl OK for most drugs and for
    most patients of average build and height

-GFR absolute
-CrCl using appropriate body weight

63
Q

Adjusting doses in renal impairment

A
  • Not an exact science
  • Many reference sources are available
    with suggested doses but advice is not
    always consistent
  • Apply pharmacological knowledge
  • Limit the potential problems with adverse
    effects and toxicity
64
Q

Key prescribing principles

A
  1. Determine the degree of renal impairment
  2. If a drug is nephrotoxic or known to exacerbate kidney function, consider an alternative
  3. Reduce dose or increase dosage interval (if necessary) to accommodate reduced renal clearance & alterations to kinetics
  4. Consider the need to load the drug
  5. For narrow therapeutic index drugs, monitor levels
  6. For all drugs monitor for efficacy, safety & tolerability
65
Q

Loading doses

A
  • Loading doses may be required:
  • If therapeutic levels required quickly
  • Drugs that have a prolonged half-life in renal failure
  • E.g. Teicoplanin
  • Glycopeptide antibiotic
  • Bactericidal activity against aerobic and
    anaerobic Gram-positive bacteria including
    multi-resistant staphylococci
66
Q

NICE CKD Guidelines: key points

A
  • Early identification key to limit progression
    and complications
  • Prevalence of CKD increases with age,
    DM, HTN and obesity
  • GFR & ACR independently related to
    mortality, CV events, progression to ESRD &
    AKI
  • Annual renal testing for patients with DM
  • Advice on when to refer to renal
  • Lifestyle advice: smoking cessation,
    exercise, healthy diet and weight loss
  • Anaemia management
  • Mineral and bone disorder management
  • Patient education
67
Q

NICE CKD CG: DRUG TREATMENT

A
  • RAAS inhibitors recommended for patients
    with proteinuria, diabetes & HTN to control
    blood pressure and proteinuria
  • SGLT2-i recommended for people with CKD + T2DM taking ARB or ACEi + ACR >30mg/mmol
  • Offer SGLT2-i if ACR 3-30mg/mmol
  • Statins: CKD considered highest risk group
  • Aspirin: recommended for 2° CVD prevention
68
Q

SGLT-2 Inhibitors

A
  • Large-scale placebo-controlled trials have
    demonstrated that sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces the risk of kidney disease progression and cardiovascular death
  • CREDENCE and DAPA-CKD trials demonstrated SGLT-2 inhibition’s efficacy at reducing risk of kidney disease progression in people with CKD, T2DM and albuminuric diabetic kidney disease
  • Subgroup analyses from DAPA-CKD suggest these benefits extend to certain types of albuminuric CKD, irrespective of the presence of DM.
69
Q

DAPAGLIFLOZIN FOR CKD: NICE TA775

A

*Recommended as an option for
treating CKD in adults only if:
* Add-on to optimised standard care
including RAASi (unless c/i or n/t)
* eGFR 25 to 75 ml/min/1.73 m2 and:
* Have type 2 diabetes or
* uACR ≥ 22.6 mg/mmol

70
Q

NICE CKD Guidelines: Bone metabolism
and osteoporosis

A
  • Measure serum CCa, phosphate, PTH and vitamin D levels in people with eGFR <30ml/min/1.73m2
  • Offer bisphopshonates if indicated if eGFR
    >30ml/min/1.73m2
  • Offer colecalciferol or ergocalciferol to treat vitamin D deficiency in people with CKD and vitamin D deficiency
  • If vitamin D deficiency corrected and symptoms of CKD– MBD persist, offer alfacalcidol or calcitriol if GFR <30ml/min/1.73m2
  • If in doubt speak to a specialist
71
Q

Anaemia of CKD

A
  • ACKD services in Wales are coordinated from renal centres in secondary care
  • In SWW our renal anaemia team includes renal pharmacist and anaemia nurse specialists
  • CKD should be considered as a possible cause of anaemia when GFR <60ml/min/1.73m2
  • More likely to be the cause if GFR is <30ml/min/1.73m2 (<45/min/1.73 m2 in patients with diabetes) and no other cause is identified

M202 (72 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions