rft

RENAL FUNCTION TESTS

Dr.Kishore

Why test renal function? To assess the functional capacity of kidney Early detection of possible renal impairment. Severity and progression of the impairment. Monitor response to treatment Monitor the safe and effective use of drugs which

are excreted in the urine.

When should we assess renal function? Older age Family history of Chronic Kidney disease (CKD) Decreased renal mass Low birth weight Diabetes Mellitus (DM) Hypertension (HTN) Autoimmune disease Systemic infections Urinary tract infections (UTI) Nephrolithiasis Obstruction to the lower urinary tract Drug toxicity

Biochemical Tests of Renal Function• Measurement of GFR

▫ Clearance tests▫ Plasma creatinine▫ Urea, uric acid and β2-microglobulin

• Renal tubular function tests▫ Osmolality measurements▫ Specific proteinuria▫ Glycosuria▫ Aminoaciduria

• Urinalysis▫ Appearance▫ Specific gravity and osmolality▫ pH▫ Glucose▫ Protein▫ Urinary sediments

Glomerular Filtration Rate (GFR) Affected by:1). Total filtration surface area2). Membrane permeability 3). Net Filtration Pressure (as NFP goes up so does the GFR)

In the normal adult, this rate is about 120 ml/min; about 180 liters/DayGlomerular filtration rate (GFR) :▫GFR = rate (mL/min) at which substances in plasma are filtered through the glomerulus ▫Best indicator of overall kidney function ▫Can be measured or calculated using a variety of markers

Glomerular Filtration Rate

Markers of GFR• Ideal characteristics: ▫Freely filtered at the glomerulus ▫No tubular secretion or reabsorption ▫No renal/tubular metabolism

• Exogenous or endogenous ▫Exogenous – not normally present in the body

Inulin ▫Endogenous – normally present in the body

Creatinine .• Radiolabeled or non-radiolabeled .

Biochemical Tests of Renal Function

Measurement of GFR Clearance tests Plasma creatinine Urea, uric acid and β2-

microglobulin

Direct Measures of GFR: Clearance• C = (U x V)/P ▫C = clearance ▫U = urinary concentration ▫V = urinary flow rate (volume/time) ▫P = plasma concentration

• Clearance = GFR • Clearance is defined as the quantity of blood or

plasma completely cleared of a substance per unit time.

Inulin clearance• The Volume of blood from which inulin is cleared or completely

removed in one min is known as the inulin clearance and is equal to the GFR.

• Gold standard for renal clearance ▫ Freely filtered at glomerulus ▫No tubular metabolism ▫No tubular reabsorption or secretion

• Protocol ▫ IV infusion ▫ Blood samples ▫Urine catheter

• Limitations ▫ Expensive, hard to obtain ▫Difficult to assay ▫ Invasive



microglobulin

Creatinine to Calculate GFR• Creatinine clearance in adults is normally about of

120 ml/min. • Advantages ▫Endogenous ▫Produced at a constant rate per day ▫Routinely measured ▫Freely filtered at glomerulus -Inversely related to GFR

• Disadvantages ▫Estimate of GFR ▫10% is secreted by renal tubules ▫Secretion increases as kidney function decreases.

1 to 2% of muscle creatine spontaneously converts to

creatinine daily and released into body fluids at a constant

rate. Endogenous creatinine produced is proportional to muscle

mass, it is a function of total muscle mass the production

varies with age and sex Dietary fluctuations of creatinine intake cause only minor

variation in daily creatinine excretion of the same person. Creatinine released into body fluids at a constant rate and

its plasma levels maintained within narrow limits Creatinine

clearance may be measured as an indicator of GFR.

Creatinine

The most frequently used clearance test is based on the

measurement of creatinine.

Small quantity of creatinine is reabsorbed by the tubules and

other quantities are actively secreted by the renal tubules So

creatinine clearance is approximately 7% greater than inulin

clearance.

The difference is not significant when GFR is normal but when

the GFR is low (less 10 ml/min), tubular secretion makes the

major contribution to creatinine excretion and the creatinine

clearance significantly overestimates the GFR.

Creatinine clearance and clinical utility

The 'clearance' of creatinine from plasma is directly related to

the GFR if:

The urine volume is collected accurately

There are no ketones or heavy proteinuria present to

interfere with the creatinine determination.

It should be noted that the GFR decline with age (to a greater

extent in males than in females) and this must be taken into

account when interpreting results.

Creatinine clearance and clinical utility

Use of Formulae to Predict Clearance

• Plasma creatinine derived from muscle mass which is related to body mass, age, sex.

• Cockcroft & Gault Formula: Creatinine Clearance =(140-age)* weight in kg / S.creat.*72 (multiplied by 0.85 for females)



microglobulin

Catabolism of proteins and nucleic acids results in formation

of so called nonprotein nitrogenous compounds.

Protein

Proteolysis, principally enzymatic

Amino acids

Transamination and oxidative deamination

Ammonia

Enzymatic synthesis in the “urea cycle”

Urea

Measurement of nonprotein nitrogen-containing

compounds

Urea is the major nitrogen-containing metabolic product of protein

catabolism in humans,

Its elimination in the urine represents the major route for

nitrogen excretion.

More than 90% of urea is excreted through the kidneys, with

losses through the GIT and skin

Urea is filtered freely by the glomeruli

Plasma urea concentration is often used as an index of renal

glomerular function

Urea production is increased by a high protein intake and it is

decreased in patients with a low protein intake or in patients with

liver disease.

Plasma Urea

Many renal diseases with various glomerular, tubular, interstitial or vascular

damage can cause an increase in plasma urea concentration.

The reference interval is 8-20 mg/dl.

Plasma concentrations also tend to be slightly higher in males than females.

Measurement of plasma creatinine provides a more accurate assessment

than urea because there are many factors that affect urea level.

Nonrenal factors can affect the urea level (normal adults is level 8-20 mg/dl)

like:

Mild dehydration,

high protein diet,

increased protein catabolism, muscle wasting as in starvation,

GIT haemorrhage,

treatment with cortisol or its synthetic analogues.

Plasma Urea

Clinical Significance • States associated with elevated levels of urea in

blood are referred to as uremia or azotemia.• Causes of urea plasma elevations:

Prerenal: renal hypoperfusionRenal: acute tubular necrosisPostrenal: obstruction of urinary flow.

In human, uric acid is the major product of the catabolism of the

purine nucleosides, adenosine and guanosine.

Purines are derived from catabolism of dietary nucleic acid

(nucleated cells, like meat) and from degradation of endogenous

nucleic acids.

Overproduction of uric acid may result from increased synthesis

of purine precursors.

In humans, approximately 75% of uric acid excreted is lost in the

urine; most of the reminder is secreted into the GIT .

Uric acid

Uric acidRenal handling of uric acid is complex and involves four sequential steps:

Glomerular filtration of virtually all the uric acid in capillary plasma

entering the glomerulus.

Reabsorption in the proximal convoluted tubule of about 98 to 100%

of filtered uric acid.

Subsequent secretion of uric acid into the lumen of the distal portion

of the proximal tubule.

Further reabsorption in the distal tubule.

Hyperuricemia is defined by serum or plasma uric acid concentrations

higher than 7.0 mg/dl (0.42mmol/L) in men or greater than 6.0 mg/dl

(0.36mmol/L) in women.

It is present on the surface of most cells and in low concentrations

in the plasma.

It is completely filtered by the glomeruli and is reabsorbed and

catabolized by proximal tubular cells.

The plasma concentration of β2-microglobulin is a good index of

GFR in normal people, being unaffected by diet or muscle mass.

It is increased in certain malignancies and inflammatory diseases.

Since it is normally reabsorbed and catabolized in the tubules,

measurement of β2-microglobulin excretion provides a sensitive

method of assessing tubular integrity.

Plasma β2-microglobulin


• Renal tubular function tests:▫Osmolality measurements▫Specific proteinurea▫Glycosuria▫Aminoaciduria

Renal tubular function tests

• To ensure that important constituents such as water, sodium, glucose and a.a. are not lost from the body, tubular reabsorption must be equally efficient

• Compared with the GFR as an assessment of glomerular function, there are no easily performed tests which measure tubular function in quantitative manner

• Osmolality measurements in plasma and urine; normal urine : plasma osmolality ratio is usually between 1.0-3.0

Tubular function testsUrine Concentration Test The ability of the kidney to concentrate urine is a test of

tubular function that can be carried out readily with only minor inconvenience to the patient.

This test requires a water deprivation for 14 hrs in healthy individuals.

A specific gravity of > 1.02 indicates normal concentrating power.

Specific gravity of 1.008 to 1.010 is isotonic with plasma and indicates no work done by kidneys.

The test should not be performed on a dehydrated patient.

Vasopressin Test More patient friendly than water deprivation test. The subject has nothing to drink after 6 p.m. At 8 p.m. five

units of vasopressin tannate is injected subcutaneously. All urine samples are collected separately until 9 a.m. the next morning.

Satisfactory concentration is shown by at least one sample having a specific gravity above 1.020, or an osmolality above 800 m osm/kg.

The urine/plasma osmolality ratio should reach 3 and values less than 2 are abnormal.

Urine Dilution (Water Load) Test After an overnight fast the subject empties his bladder

completely and is given 1000 ml of water to drink. Urine specimens are collected for the next 4 hours, the

patient emptying bladder completely on each occasion. Normally the patient will excrete at least 700 ml of urine in

the 4 hours, and at least one specimen will have a specific gravity less than 1.004.

Kidneys which are severely damaged cannot excrete a urine of lower specific gravity than 1.010 or a volume above 400 ml in this time.

The test should not be done if there is oedema or renal failure; water intoxication may result.

Proteinuria may be due to:

1. An abnormality of the glomerular basement membrane.

2. Decreased tubular reabsorption of normal amounts of filtered proteins.

3. Increased plasma concentrations of free filtered proteins.

4. Decreased reabsorption and entry of protein into the tubules

consequent to tubular epithelial cell damage.

Measurement of individual proteins such as β2-microglobulin have

been used in the early diagnosis of tubular integrity.

Assessment of glomerular integrity

The glomerular basement membrane does not usually allow

passage of albumin and large proteins. A small amount of albumin,

usually less than 30 mg/24 hours, is found in urine.

Urinary protein excretion in the normal adult should be less

than 150 mg/day.

When larger amounts, in excess of 300 mg/24 hours, are detected,

significant damage to the glomerular membrane has occurred.

Quantitative urine protein measurements should always be made on

complete 24-hour urine collections.

Albumin excretion in the range 30-300 mg/24 hours is termed

microalbuminuria.

Proteinuria

▫Normal < 150 mg/24h. TYPES OF PROTEINURIA

Glomerular proteinuria Tubular proteinuria Overflow proteinuria

Proteinuria

Glomerular proteinuria• Glomerular proteinuria — Glomerular proteinuria is

due to increased filtration of macromolecules (such as albumin) across the glomerular capillary wall.

• The proteinuria associated with diabetic nephropathy and other glomerular diseases, as well as more benign causes such as orthostatic or exercise-induced proteinuria fall into this category.

• Most patients with benign causes of isolated proteinuria excrete less than 1 to 2 g/day

Tubular proteinuria• Low molecular weight proteins — have a

molecular weight ≤ 25,000 in comparison to the 69,000 molecular weight of albumin.

1. ß2-microglobulin, 2. immunoglobulin light chains, 3.retinol-binding protein, and amino acids — • These smaller proteins can be filtered across the

glomerulus and are then almost completely reabsorbed in the proximal tubule.

• Interference with proximal tubular reabsorption, due to a variety of tubulointerstitial diseases or even some primary glomerular diseases, can lead to increased excretion of these smaller proteins.

Overflow proteinuria • Increased excretion of low molecular weight

proteins can occur with marked overproduction of a particular protein, leading to increased glomerular filtration and excretion.

• Due to 1. immunoglobulin light chains in multiple myeloma(most common)

2. lysozyme (in acute myelomonocytic leukemia),

3.myoglobin (in rhabdomyolysis), or 4.hemoglobin (in intravascular hemolysis).


• Urinalysis▫Appearance▫Specific gravity and osmolality▫pH▫Glucose▫Protein▫Urinary sediments

Urine Analysis Urine examination is an extremely valuable and

most easily performed test for the evaluation of renal functions.

It includes physical or macroscopic examination, chemical examination and microscopic examination of the sediment.

Macroscopic examinationColour: Normal- pale yellow in colour due to pigments

urochrome, urobilin and uroerythrin. Cloudiness-caused by excessive cellular

material or protein, crystallization or precipitation of salts upon standing at room temperature or in the refrigerator.

Red colour -If the sample contains many red blood cells.

To maintain water homeostasis, the kidneys must produce urine in a

volume precisely balances water intake and production to equal water

loss through extra renal routes.

Minimum urine volume is determined by the solute load to be excreted

whereas maximum urine volume is determined by the amount of excess

water that must be excreted.

Urine volume

Volume Normal- 1-2.5 L/day Oliguria- Urine Output < 400ml/day

Seen in ▫Acute glomerulonephritis▫Renal Failure

Polyuria- Urine Output > 2.5 L/daySeen in ▫Increased water ingestion▫Diabetes mellitus and insipidus.

Anuria- Urine output < 100ml/daySeen in renal shut down.

Specific Gravity Measured by urinometer or refractometer. It is measurement of urine density which reflects the ability

of the kidney to concentrate or dilute the urine relative to the plasma from which it is filtered.

Normal :- 1.000- 1.030.

S.G Osmolality (mosm/kg)

1.001 100

1.010 300

1.020 800

1.025 1000

1.030 1200

1.040 1400

Increase in Specific Gravity seen in Low water intake Diabetes mellitus Albuminuria Acute nephritis.

Decrease in Specific Gravity is seen in Absence of ADH Renal Tubular damage.

Isosthenuria-Persistent production of fixed low Specific gravity urine isoosmolar with plasma despite variation in water intake.

Urinalysis: Osmolality measurements in plasma and urine

– Osmolality serves as general marker of tubular function. Because the

ability to concentrate the urine is highly affected by renal diseases.

– This is conveniently done by determining the osmolality, and then

comparing this to the plasma.

– If the urine osmolality is 600mosm/kg or more, tubular function is

usually regarded as intact

– When the urine osmolality does not differ greatly from plasma (urine:

plasma osmolality ratio=1), the renal tubules are not reabsorbing water

pH Urine pH ranges from 4.5 to 8 Normally it is slightly acidic lying between 6 – 6.5. On exposure to atmosphere, urea in urine splits

causing NH4+ release resulting in alkaline

reaction.

Biochemical testing of urine involves the use of commercially available disposable strips When the strip is manually immersed in the urine specimen, the reagents react with a specific component of urine in such a way that to form color

Colour change produced is proportional to the concentration of the component being tested for.

To test a urine sample:

fresh urine is collected into a clean dry container

the sample is not centrifuged

the disposable strip is briefly immersed in the urine specimen;

The colour of the test areas are compared with those provided on a colour chart.

Urinalysis using disposable strips

Chemical Analysis

Urine Dipstick

GlucoseGlucose

BilirubinBilirubin

KetonesKetones

Specific GravitySpecific Gravity

BloodBlood

pHpH

ProteinProtein

UrobilinogenUrobilinogen

NitriteNitrite

Leukocyte EsteraseLeukocyte Esterase

Urine Sediments-Microscopic examination of sediment from freshly

passed urine involves looking for cells, casts, fat droplets -Blood: haematuria is consistent with various

possibilities ranging from malignancy through urinary

tract infection to contamination from menstruation. -Red Cell casts could indicate glomerular disease-Crystals -Leucocytes in the urine suggests acute inflammation

and the presence of a urinary tract infection.

-are cylindrical structures produced by the kidney and present in the

urine in certain disease states. - They form in the distal convoluted tubule and collecting ducts of

nephrons, then dislodge and pass into the urine, where they can be

detected by microscope.- They form via precipitation of Tamm-Hrsfall mucoprotein which is

secreted by renal tubule cells, and sometimes also by albumin.

Urinary casts

Red blood cell cast in urineWhite blood cell cast in

urine

Urinary casts. (A) Hyaline cast (200 X); (B) erythrocyte cast (100 X); (C) leukocyte cast (100 X); (D) granular cast (100 X)

Crystals

Urinary crystals. (A) Calcium oxalate crystals; (B) uric acid crystals (C) triple phosphate crystals with amorphous phosphates ; (D) cystine crystals.

Clinical significance of RFT in AKI The RIFLE criteria, proposed by the Acute Dialysis Quality

Initiative (ADQI) group, aid in the staging of patients with AKI (previously ARF).

Cystatin CNovel biomarker for non-invasive estimation of Glomerular Filtration Rate and Early Renal Impairment.• Cystatin C is a nonglycosylated basic protein produced at

a constant rate by all nucleated cells.• It is freely filtered by the renal glomeruli and primarily

catabolized in the tubule (not secreted or reabsorbed as an intact molecule).

• As serum cystatin C concentration is independent of age, sex, and muscle mass, it has been postulated to be an improved marker of glomerular filtration rate (GFR) compared with serum creatinine level.

Drugs and Kidney

• The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) definition of chronic kidney disease is the presence of kidney damage or a reduction in the glomerular filtration rate (GFR) for three months or longer.

• The K/DOQI chronic kidney disease staging system is based on GFR.

• Inappropriate dosing in patients with chronic kidney disease can cause toxicity or ineffective therapy.

• Older patients are at a higher risk of developing advanced disease and related adverse events caused by age-related decline in renal function and the use of multiple medications to treat comorbid conditions.

• Chronic kidney disease can affect glomerular blood flow and filtration, tubular secretion and reabsorption, and renal bioactivation and metabolism.

• Drug absorption, bioavailability, protein binding, distribution volume, and non-renal clearance (metabolism) can also be altered in these patients.

• In patients with a GFR < 60 mL/min/1.73 m2, the MDRD equation has been shown to be superior to the Cockcroft-Gault equation.

• The MDRD equation has been shown to be the best method for detecting a GFR < 90 ml /min/ 1.73 m2 in older patients.

• Because the production and excretion of creatinine declines with age, normal serum creatinine values may not represent normal renal function in older patients.

Dosing Adjustments• Loading doses usually do not need to be adjusted in patients

with chronic kidney disease.• For Maintenance dosing adjustments: 1.dose reduction, 2.lengthening the dosing interval, or both.• Dose reduction involves reducing each dose while

maintaining the normal dosing interval. • This approach maintains more constant drug concentrations,

but associated with a higher risk of toxicities if the dosing interval is inadequate to allow for drug elimination.

Dosing Adjustments• Lengthening of dose interval- Normal doses are maintained with the extended

interval method, but the dosing interval is lengthened to allow time for drug elimination before re-dosing.

• Lengthening the dosing interval has been associated with a lower risk of toxicities but a higher risk of subtherapeutic drug concentrations.

Anti Hypertensives• Thiazide diuretics -first-line agents for treating uncomplicated

hypertension, but they are not recommended if the serum creatinine level is higher than 2.5 mg per dL or if the creatinine clearance is lower than 30 mL per minute.

• Loop diuretics -most commonly used to treat uncomplicated hypertension in patients with chronic kidney disease.

• Potassium-sparing diuretics and aldosterone blockers - avoided in patients with severe chronic kidney disease because of the rise in serum potassium that typically accompanies renal dysfunction.

Diuretics

ACE Inhibitors/ARB• Angiotensin-converting enzyme (ACE) inhibitors and

angiotensin receptor blockers (ARBs) are first-line hypertensive agents for patients with type 1 or 2 diabetes mellitus and proteinuria or early chronic kidney disease.

• These 1.reduce blood pressure and proteinuria, 2.slow the progression of kidney disease, and provide

long-term cardiovascular protection.• Inhibit the renin-angiotensin-aldosterone system in patients

with chronic kidney disease and in patients with normal baseline serum creatinine levels, causing efferent arteriolar dilation.

• This causes –• 1.Acute decline in GFR of > 15% from baseline with• 2. proportional elevations in serum creatinine within the first

week of initiating therapy.• This most commonly occurs in patients with congestive heart

failure, in patients using concomitant diuretics or nonsteroidal anti-inflammatory drugs (NSAIDs), and in patients receiving high doses of ACE inhibitors or ARBs.

• ACE inhibitors and ARBs can be continued safely if the rise in serum creatinine is < 30%.

• Typically, the levels will return to baseline in four to six weeks.• Because of long-term renoprotective and cardioprotective

effects, no patient should be denied an ACE-inhibitor or ARB trial

without careful evaluation.

• Hydrophilic beta blockers - Atenolol, Bisoprolol, Nadolol, Acebutolol-eliminated renally -dosing adjustments are needed in patients with chronic kidney failure.

• Metoprolol tartrate , Metoprolol succinate, Propranolol,and Labetalol are metabolized by the liver and adjustments are not required.

• Other AHA’s that do not require dosing adjustments include calcium channel blockers, clonidine and alpha blockers.

Oral hypoglycemics• METFORMIN-is 90 to 100 percent renally excreted,• Not recommended when the serum creatinine level is higher

than 1.5 mg/dL in men or higher than 1.4 mg/dl in women, • In patients older than 80 years, or• In patients with chronic heart failure.• The primary concern about the use of metformin in patients

with renal insufficiency is that other hypoxemic conditions (e.g., acute myocardial infarction, severe infection, respiratory disease, liver disease) increase the risk of lactic acidosis.

OHA• Sulfonylureas -Chlorpropamide , Glyburide• Should be avoided in patients with stages 3 to 5 chronic

kidney disease.• The half-life of chlorpropamide is significantly increased in

these patients, which can cause severe hypoglycemia.• Glyburide has an active metabolite that is eliminated renally,

and accumulation of this metabolite can cause prolonged hypoglycemia in patients with chronic kidney disease.

• Glipizide, however, does not have an active metabolite and is safe in these patients.

Antibiotics• Penicillins-Excessive serum levels of injectable penicillinG or

carbenicillin may be associated with neuromuscular toxicity, myoclonus, seizures,or coma.

• Carbapenems- Imipenem/cilastatin can accumulate in patients with chronic kidney disease, causing seizures if doses are not reduced.

• Patients with advanced disease should receive a different carbapenem, such as meropenem.

• Tetracyclines- with the exception of doxycycline , have an antianabolic effect that may significantly worsen the uremic state in patients with severe disease.

• Nitrofurantoin - has a toxic metabolite that can accumulate in patients with chronic kidney disease, causing peripheral

neuritis.

Antibiotics• Aminoglycosides -avoided in patients with chronic

kidney disease when possible. • If used, initial doses should be based on an accurate GFR

estimate.

Opioids• Patients with stage 5 kidney disease are more likely to experience

adverse effects from opioid use.• Metabolites of meperidine ,dextropropoxyphene(propoxyphene ),

morphine , tramadol , and codeine can accumulate in patients with chronic kidney disease, causing central nervous system and respiratory adverse effects.

• These agents are not recommended in patients with stage 4 or 5 disease.

• A 50 to 75 percent dose reduction for morphine and codeine is recommended in patients with a creatinine clearance less than 50 mL per minute.

Opioids• Extended-release tramadol should be avoided in patients with

chronic kidney disease. The dosing interval of tramadol (regular release) may need to be increased to every 12 hours in patients with a creatinine clearance < 30 mL/ min .

Opioids• Morphine is metabolized primarily by hepatic glucuronidation to

form morphine-6-glucuronide and morphine-3-glucuronide, both of which are excreted renally .

• Morphine-6-glucuronide is more potent than morphine and may accumulate in renal patients causing prolonged respiratory depression.

• Meperidine is metabolized by the liver to normeperidine, which is eliminated both renally and hepatically.

• Accumulation of high levels of normeperidine can produce excitatory central nervous symptoms including seizures in extreme cases.

• More appropriate narcotics in renal patients include fentanyl , sufentanil, alfentanil, and remifentanil that do not undergo transformation to long-acting renally excreted metabolites.

• At doses of 1–2 mg/kg, Morphine does not decrease blood pressure or urine flow.

• Fentanyl may decrease GFR, urine flow, and mean arterial pressure (MAP), though with conflicting data regarding renal blood flow .

NSAIDS• Adverse renal effects - 1.Acute renal failure; 2.Nephrotic syndrome with interstitial nephritis; and 3.chronic renal failure with or without glomerulopathy, 4.interstitial nephritis, and 5. papillary necrosis.• The risk of ARF is three times higher in NSAID users .• Other adverse effects - include decreased potassium excretion -

hyperkalemia, and decreased sodium excretion-peripheral edema, elevated blood pressure, and decompensation of heart failure.

• NSAIDs can blunt antihypertensive treatment, especially if beta blockers, ACE inhibitors, or ARBs are Used.

NSAIDS• Although selective cyclooxygenase-2 (COX-2) inhibitors may

cause slightly fewer adverse gastrointestinal effects, adverse renal effects are similar to traditional NSAIDs.

• Short-term use - generally safe in patients who are well hydrated; who have good renal function; and who do not have heart failure, diabetes, or hypertension.

• Long-term use and high daily dosages of COX-2 inhibitors and other NSAIDs should be avoided if possible.

NSAIDS• Patients at high risk of NSAID-induced kidney disease

should receive serum creatinine measurements every two to four weeks for several weeks after initiation of therapy because renal insufficiency may occur early in the course of therapy.

• Acetaminophen can be used safely in patients with renal impairment.

ANAESTHETIC DRUGS AND KIDNEY

• While multiple anaesthetic drugs have direct effects on the kidneys and their function due to hemodynamic effects, they are often also dependent on the kidney for renal excretion of either the drug itself or of its metabolites.

• Hydrophilic and ionized drugs depend primarily on renal excretion.

• Mechanisms of renal excretion depend on renal blood flow. • Thus renal blood flow decreases due to surgery, anaesthesia,

or pre-existing conditions may result in decreased renal excretion by the kidneys.

• In addition to accumulation of drugs and their metabolites, renal failure patients may also have an altered volume of distribution, hypoalbuminemia, anaemia, hyperkalemia, and metabolic acidosis.

General Anesthesia• There is a reversible depression of renal function observed

during and after surgery in most patients, which is likely attributable to interplay between surgical procedure and duration, anaesthetic techniques, and the cardiovascular and renal status of the patient.

• General anesthesia is associated with a transient decrease in renal function evidenced by decreases in GFR, renal blood flow (RBF), urine output, and solute excretion.

• The deeper the level of anesthesia, the greater the degree of depression in renal function, particularly in the presence of hypovolemia.

Intra venous anesthetics• Multiple intravenous anesthetics have effects on renal

function.

• Thiopental- ↓ GFR ,Urine flow as well as Renal blood flow and Sodium excretion.

• The effect of this medication gradually reverses, and animal studies on high-dose thiopental show renal blood flow remains unchanged in spite of a decrease in myocardial contractility, cardiac preload and blood pressure, and a reflex increase in systemic vascular resistance.

• Thiopental, a highly protein-bound drug, has an increased unbound fraction in the presence of hypoalbuminemia, acidemia, and uremia.

• This increase in free drug in renal failure patients should theoretically decrease the dose required.

• However, renal failure patients also experience an increased volume of distribution, which counteracts the increase in unbound fraction.

• Thus patients with renal dysfunction usually require a normal to slightly decreased dose of thiopental.

• Thiopental’s elimination half-life and clearance are only slightly

prolonged as the drug is primarily metabolized by the liver.

• The effects of Propofol on renal injury remain controversial. Recent rat studies suggest propofol may have a protective effect in acute kidney injury .

• Midazolam, in induction doses, decreases urine flow but does not significantly affect renal blood flow, renal vascular resistance, or sodium excretion.

• Ketamine has been shown in dogs to increase blood pressure, renal blood flow, and renal vascular resistance though studies are conflicting.

• The more protein-bound barbiturates, ketamine, propofol, and benzodiazepines require no alteration in induction doses in patients with renal failure.

Inhalational anesthetics• Elimination of these drugs is not dependent on renal function.• Volatile anesthetics are variably metabolized by the liver to

metabolites including inorganic fluoride, which is dependent on renal excretion and is nephrotoxic.

• This metabolization is highest in halothane (12–20%) and followed by sevoflurane, enflurane, isoflurane, and desflurane (3%,2%,0.2%, and 0.02%, respectively).

• Sevoflurane has not been reported to cause renal toxicity in patients despite this laboratory data.

• Halothane - Most studies show a decrease in GFR, sodium excretion, and

urine output with a variable effect on renal blood flow during halothane administration. Data suggest that halothane may not decrease renal blood flow .

• Enflurane decreases GFR, RBF, and urine flow in humans. • Isoflurane decreases GFR and urine output in pigs with little

change in renal blood flow.

• Sevoflurane metabolism to inorganic fluoride has been implicated in experimental studies of renal toxicity; however, no human studies are available to indicate this effect.

• Desflurane decreases renal vascular resistance as well as RBF, thus maintaining renal blood flow .

Depolarizing muscle relaxants• Succinylcholine increases serum potassium by 0.5 meq/l.• This increase is no larger in renal patients than in nonrenal

patients: however, the baseline potassium must be taken into consideration.

• Succinylcholine is metabolized by the hepatically produced plasma cholinesterase.

• This cholinesterase may be decreased in uremic renal patients, but this does not usually lead to any clinically significant effect.

• A metabolite of succinylcholine, succinylmonocholine, is excreted by the kidney and may be active as nondepolarizing neuromuscular blocker. Thus continuous infusions of succinylcholine should be avoided in patients with renal failure.

Non depolarizing muscle relaxants• Pancuronium, metocurine, gallamine, doxacurium, and

pipercurium are renally excreted and will exhibit prolonged elimination half-lives in patients with renal failure.

• Atracurium, vecuronium, and cisatracurium are the paralytics of choice for intermediate duration as their pharmacodynamics are minimally affected.

• Atracurium metabolism depends on ester hydrolysis and Hoffman’s elimination, which do not require renal function. However, a metabolite of atracurium, laudanosine, is a central nervous system excitatory agent, which may accumulate in renal patients, though has not been documented to reach clinical significance.

• Cisatracurium is metabolized by Hoffman’s elimination and is safe in renal failure.

• Vecuronium is metabolized by the liver; however, the clinical duration of the drug may be increased in renal failure due to an increase in elimination half-life and decrease in clearance.

• The elimination half-life of Rocuronium is increased in renal dysfunction due to the increased volume of distribution; however, there is no clinical difference noted in terms of onset, duration, and recovery of neuromuscular blockade.

• Mivacurium is hydrolyzed by plasma cholinesterase and shows a prolonged duration of action in renal failure.

Anticholinesterases• Neostigmine, pyridostigmine, and edrophonium .• All highly dependent on renal excretion . • As a result they have prolonged durations of action in patients

with renal failure. • Anticholinergics such as atropine and glycopyrrolate also

have prolonged durations of actions in these patients.

Regional Anesthesia• A spinal block as high as T1 produces only slight depressions in

GFR and RBF in humans as long as systemic blood pressure is maintained .

• Likewise, epidural blocks to thoracic levels with epinephrine- free local anesthetics produce minimal decreases in GFR and renal blood flow .

• However, epidural blocks to the thoracic region with epinephrine containing local anesthetics induce moderate reductions in GRF and RBF that parallel reductions in mean arterial pressure.

• Most likely the effects of neuraxial blockade on renal function depend on the hemodynamic effects induced by the sympathetic blockade.

rft

Health & Medicine