Farmakoterapi IIRENAL DISEASE

FISIOLOGI RENALoleh: Tunggul Adi P., M.Sc., Apt.

Laboratorium Farmasi Klinik FKIK UNSOED

TUJUAN PEMBELAJARAN

Mahasiswa mampu:- Menjelaskan fungsi fisiologis ginjal- Menjelaskan struktur ginjal- Menjelaskan proses filtrasi, reabsorpsi, dan

sekresi

FUNGSI UTAMA GINJAL

• Pengaturan volume dan osmolalitas cairan tubuh• Pengaturan keseimbangan elektrolit• Pengaturan keseimbangan asam basa• Ekskresi (metabolic product, foreign substance,

excess substance) • Produksi dan sekresi hormon (erythropoitin, 1,25-

dihydroxy vitamin D3 (vitamin D activation), renin)

Renal system – important points• Kidneys have excellent blood

supply: 0.5% total body weight but ~20% of CO (cardiac output).

• Kidneys process plasma portion of blood by removing substances from it, and in a few cases, by adding substances to it.

• Works with cardiovascular system (and others!) in integrated manner

A. Renal Vein

B. Renal Artery

C. Ureter

D. Medulla

E. Renal Pelvis

F. Cortex

1. Ascending loop of Henle

2. Descending loop of Henle

3. Peritubular capillaries

4. Proximal tubule

5. Glomerulus

6. Distal tubule

GINJAL DAN NEFRON

The functional unit of the kidney: the nephron

• Total of about 2.5 million in the 2 kidneys.

• Each nephron consists of 2 functional components:– The tubular component

(contains what will eventually become urine)

– The vascular component (blood supply)

• The mechanisms by which kidneys perform their functions depends upon the relationship between these two components.

• Responsible for urine formation:– Filtration– Secretion– Reabsorption

Characteristics of the renal blood flow:

1, high blood flow. 1200 ml/min, or 21 percent of the cardiac output. 94% to the cortex

2, Two capillary beds

High hydrostatic pressure in glomerular capillary (about 60 mmHg) and low hydrostatic pressure in peritubular capillaries (about 13 mmHg)Vesa Recta

From http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookEXCRET.html

Overview of nephron function

Functions of the Nephron

Filtration

Reabsorption

Secretion

Excretion

HUMAN RENAL PHYSIOLOGY

• Four Main Processes:– Filtration

– Reabsorbtion

– Secretion

– Excretion

HUMAN RENAL PHYSIOLOGY• Functions of the Kidney:

– Filtration:–First step in urine formation–Bulk transport of fluid from blood to

kidney tubule» Isosmotic filtrate» Blood cells and proteins don’t filter

–Result of hydraulic pressure–GFR = 180 L/day

HUMAN RENAL PHYSIOLOGY

• Functions of the Kidney:– Reabsorbtion:

• Process of returning filtered material to bloodstream

• 99% of what is filtered• May involve transport protein(s)• Normally glucose is totally reabsorbed

HUMAN RENAL PHYSIOLOGY

• Functions of the Kidney:–Secretion:

–Material added to lumen of kidney from blood

–Active transport (usually) of toxins and foreign substances»Saccharine»Penicillin

HUMAN RENAL PHYSIOLOGY

• Functions of the Kidney:– Excretion:

– Loss of fluid from body in form of urine:

Amount of solute excreted= amount filtered + amount secreted – amount

reabsorbed

Filtration

THE GLOMERULUS

•Components of plasma cross the three layers of the glomerular barrier during filtration• Capillary endothelium• Basement membrane (net negative charge)• Epithelium of Bowman’s Capsule (Podocytes –filtration slits allow size <60kD)

•The ability of a molecule to cross the membrane depends on size, charge, and shape• Glomerular filtrate therefore contains all molecules not contained by the glomerular barrier - it is NOT URINE YET!

Plasma is filtered through the glomerular barrier

Glomerular filtration• GFR controlled by diameters

of afferent and efferent arterioles

• Sympathetic vasoconstrictor nerves

• ADH and RAAS also have an effect on GFR.

• Autoregulation maintains blood supply and so maintains GFR. Also prevents high pressure surges damaging kidneys.

• Unique system of upstream and downstream arterioles.

• Remember: high hydrostatic pressure (PGC) at glomerular capillaries is due to short, wide afferent arteriole (low R to flow) and the long, narrow efferent arteriole (high R).

GFR depends on diameters of afferent and efferent arterioles

GFR GFR

Glomerulus

Afferent arteriole Efferent arteriole

Glomerular filtrate

Aff. Art. dilatation Eff. Art. dilatationEff. Art. constriction

Aff. Art. constriction

Prostaglandins, Kinins, Dopamine (low dose), ANP,

NO

Angiotensin II (low dose)

Angiotensin II blockade

Ang II (high dose), Noradrenaline (Symp

nerves), Endothelin, ADH, Prost. Blockade)

Glomerular Filtration Rate (GFR)

• Measure of functional capacity of the kidney

• Dependent on difference in pressures between capillaries and Bowman’s space

• Normal = 120 ml/min =7.2 L/h=180 L/day!! (99% of fluid filtered is reabs.)

Oncotic pressure

Oncotic pressure is the component of total osmotic pressure due to colloid particles.

Water molecules cross the membrane to equalize the concentration of colloid particles on each side.

Glomerular filtration rate (GFR)• Depends on the difference in hydrostatic and oncotic

pressure on either side of the glomerular basement membrane GFR

=

Kf(PGC - PBS - COPGC)

P = hydrostatic pressure

COP = colloid osmotic pressure

Kf determined by surface area and permeability of H2O

PGC PBS

COPGC COPBS

GlomerularCapillary (GC)

Bowman’s space (BS)

Reabsorption and secretion

Peritubular reabsorption• Peritubular capillaries provide

nutrients for tubules and retrieve the fluid the tubules reabsorb.

• Oncotic P is greater than hydrostatic P in these capillaries, so therefore get reabsorption NOT filtration.

• Must occur since we filter 180l/day, but only excrete 1-2l/day of urine.

• Reabsorb 99% H2O, 100% glucose, 99.5% Na+ and 50% urea. Most of this occurs at proximal convoluted tubule.

Reabsorption

• Active Transport –requires ATP– Na+, K+ ATP pumps

• Passive Transport-– Na+ symporters (glucose, a.a., etc)– Na+ antiporters (H+)– Ion channels– Osmosis

Renal transport systems• Lots of transporter proteins for

different molecules/ions so they can be reabsorbed.

• They all have maximum transport (TM) capacities where transport saturates i.e. 10mmol/l for glucose.

• Over this value, you excrete the excess in urine, so can be useful sign of disease either in kidneys or other systems.

• Amino acids also have a high TM value because you try and preserve as much of these useful nutrients as possible.

Factors influencing Reabsorption

• Saturation: Transporters can get saturated by high concentrations of a substance - failure to resorb all of it results in its loss in the urine (eg, renal threshold for glucose is about 180mg/dl).

• Rate of flow of the filtrate: affects the time available for the transporters to reabsorb molecules.

What is Reabsorbed Where?

Proximal tubule - reabsorbs 65 % of filtered Na+ as well as Cl-, Ca2+, PO4, HCO3

-. 75-90% of H20. Glucose, carbohydrates, amino acids, and small proteins are also reabsorbed here.

Loop of Henle - reabsorbs 25% of filtered Na+.

Distal tubule - reabsorbs 8% of filtered Na+. Reabsorbs HCO3-.

Collecting duct - reabsorbs the remaining 2% of Na+ only if the hormone aldosterone is present. H20 depending on hormone ADH.

Secretion

• Proximal tubule – uric acid, bile salts, metabolites, some drugs, some creatinine

• Distal tubule – Most active secretion takes place here including organic acids, K+, H+, drugs

Countercurrent exchange• The structure and transport

properties of the loop of Henle in the nephron create the Countercurrent multiplier effect.

• A substance to be exchanged moves across a permeable barrier in the direction from greater to lesser concentration.

Image from http://en.wikipedia.org/wiki/Countercurrent_exchange

Loop of Henle– Goal= make isotonic filtrate into

hypertonic urine (don’t waste H20!!)

– Counter-current multiplier:• Descending loop is permeable to

Na+, Cl-, H20• Ascending loop is impermeable to

H20- active NaCl transport• Creates concentration gradient in

interstitium• Urine actually leaves hypotonic but

CD takes adv in making hypertonic

Na+ absorption• Na+ absorbed by active transport

mechanisms, NOT by TM mechanism. Basolateral ATPases establish a gradient across the tubule wall.

• Proximal tubule is very permeable to Na+, so ions flow down gradient, across membranes.

• Microvilli create large surface area for absorption.

• Electrical gradient created also draws Cl- across.

• H2O follows Na+ due to osmotic force.• Means fluid left in tubule is

concentrated.

Glucose handling• Glucose absorption

also relies upon the Na+ gradient.

• Most reabsorbed in proximal tubule.

• At apical membrane, needs Na+/glucose cotransporter (SGLT)

• Crosses basolateral membrane via glucose transporters (GLUT’s), which do not rely upon Na+.

Amino acid handling

• Preserve as much of these essential nutrients as possible.• Can be absorbed by GI tract, products of protein catabolism, or de novo

synthesis of nonessential amino acids.• TM values lower than that of glucose, so can excrete excess in urine.• Amino acid transporters rely upon Na+ gradient at apical membrane, but a

couple of exceptions don’t.• Exit across basolateral membrane via diffusion , but again, some exceptions rely

on Na+.

K+ handling• K+ is major cation in cells and balance

is essential for life.• Small change from 4 to 5.5 mmoles/l

= hyperkalaemia = ventric. fibrillation = death.

• To 3.5 mmoles/l = hyperpolarise = arrhythmias and paralysis = death.

• Reabsorb K+ at proximal tubule.• Changes in K+ excretion due to

changes in K+ secretion in distal tubule• Medullary trapping of K+ helps to

maximise K+ excretion when K+ intake is high.

K+ handling• K+ reabsorption along the

proximal tubule is largely passive and follows the movement of Na+ and fluid (in collecting tubules, may also rely active transport).

• K+ secretion occurs in cortical collecting tubule (principal cells), and relies upon active transport of K+ across basolateral membrane and passive exit across apical membrane into tubular fluid.

Hormones Produced by the Kidney• Renin:

– Released from juxtaglomerular apparatus when low blood flow or low Na+. Renin leads to production of angiotensin II, which in turn ultimately leads to retention of salt and water.

• Erythropoietin: – Stimulates red blood cell development in bone marrow. Will increase

when blood oxygen low and anemia (low hemoglobin).

• Vitamin D3: – Enzyme converts Vit D to active form 1,25(OH)2VitD. Involved in

calcium homeostasis.

Renin, Angiotensin, Aldosterone:

Regulation of Salt/Water Balance

Renin/AII and Regulation of GFR

GFR = Kf(PGC - PBS - COPGC)

• “flight or fright” • sympathetic tone • afferent arteriolar constriction (divert cardiac output to other organs)

•PGC

•GFR and renal blood flow

Renin/AII and Regulation of GFR

GFR = Kf(PGC - PBS - COPGC)

•Low BP sensed in afferent arteriole or low Na in distal tubule •renin released •renin converts angiotensinogen to Angiotensin I •ACE converts AI to AII •efferent > afferent arteriolar constriction

• PGC GFR (this is AUTOREGULATION of GFR)

PGC

constricts

Aldosterone

• Secreted by the adrenal glands in response to angiotensin II or high potassium

• Acts in distal nephron to increase resorption of Na+ and Cl- and the secretion of K+ and H+

• NaCl resorption causes passive retention of H2O

Anti-Diuretic Hormone (ADH)

• Osmoreceptors in the brain (hypothalamus) sense Na+ concentration of blood.

• High Na+ (blood is highly concentrated) stimulates posterior pituitary to secrete ADH.

• ADH upregulates water channels on the collecting ducts of the nephrons in the kidneys.

• This leads to increased water resorption and decrease in Na concentration by dilution

ACUTE RENAL FAILURE/GAGAL GINJAL AKUT

Tunggul Adi P., M.Sc., Apt.Lab Farmasi Klinik, Farmasi, FKIK,

UNSOED

Tujuan pembelajaran

• Mahasiswa mampu menjelaskan definisi, epidemiologi, prognosis, etiologi, patofisiologi ARF atau GGA

• Mahasiswa mampu menjelaskan gejala/tanda dan pemeriksaan ARF

• Mahasiswa mampu menjelaskan manajemen terapi ARF

Primary references

• Di Piro • Koda-KimbleChapter of Acute Renal Failure

KEY CONCEPTS• Acute renal failure (ARF) is a common complication in the

hospitalized patient and is associated with a high mortality rate.

• ARF is predominantly categorized based on the anatomic area of injury or malfunction: (a) prerenal—decreased renal blood flow, (b) intrinsic—a structure within the kidney is damaged, and (c) postrenal—an obstruction is present within the urine collection system.

• Risk factors for ARF include advanced age, acute infection, pre-existing chronic respiratory or cardiovascular disease, dehydration, and chronic kidney disease

KEY CONCEPTS

• ARF lacks a specific and sensitive sign to herald its onset. Hence, a thorough patient history, including medications, recent procedures and illnesses, physical examination, and laboratory assessment of serum and urine are necessary components of an ARF evaluation after an elevated serum creatinine (Scr ) is noted.

• Prevention is key; there are very few therapeutic options for the therapeutic management of established ARF.

KEY CONCEPTS

• Supportive management remains the primary approach to prevent or reduce the complications associated with ARF. Supportive therapies include: renal replacement therapies (RRTs), nutritional support, avoidance of nephrotoxins, and blood pressure and fluid management.

• For those patients with prolonged or severe ARF, RRTs are the cornerstone of support and facilitate an aggressive approach to fluid, electrolyte and waste management.

DEFINISI• ARF is broadly defined as a decrease in glomerular filtration rate

(GFR), generally occurring over hours to days, sometimes over weeks, that is associated with an accumulation of waste products, including urea and creatinine.

• This relatively abrupt decline in renal function is in contrast to CKD, which is defined by the presence of proteinuria/albuminuria for at least 3 months, in combination with a GFR of <90 mL/min/1.73 m2. A decrease in urine output is often observed, but is not required for ARF to be present.

• Compared to a normal urine output of ≥ 1,200 mL/day, patients with ARF are often categorized as being anuric (urine output < 50 mL/day), oliguric (urine output < 500 mL/day), or nonoliguric (urine output > 500 mL/day).

Epidemiologi dan prognosis

ETIOLOGI• The etiology of ARF can be divided into broad categories based

on the anatomic location of the injury associated with the precipitating factor(s). The management of patients presenting with this disorder is largely predicated on identification of the specific etiology responsible for the patient’s current acute kidney injury.

• Traditionally, the causes of ARF have been categorized as (a) prerenal, which results from decreased renal perfusion in the setting of undamaged parenchymal tissue, (b) intrinsic, the result of structural damage to the kidney, most commonly the tubule from a ischemic or toxic insult, and (c) postrenal, caused by obstruction of urine flow downstream from the kidney

ETIOLOGI

• The most common cause of hospital-acquired ARF is prerenal ischemia as the result of reduced renal perfusion secondary to sepsis, reduced cardiac output, and/or surgery.

• Drug-induced ARF may account for 18% to 33% of in-hospital occurrences.

• Other risk factors for developing ARF while hospitalized include advanced age (>60 years of age), male gender, acute infection, and preexisting chronic diseases of the respiratory or cardiovascular systems.

ETIOLOGI

PATOFISIOLOGI

Fungsional ARF• In functional ARF, a decline in GFR secondary to a reduced

glomerular hydrostatic pressure, which is the driving force for the formation of ultrafiltrate, can occur without damage to the kidney itself. The decline in glomerular hydrostatic pressure may be a direct consequence of changes in glomerular afferent (vasoconstriction) and efferent (vasodilation) arteriolar circumference.

• These clinical conditions are most commonly seen in individuals who have reduced effective blood volume (e.g., heart failure, cirrhosis, severe pulmonary disease, or hypoalbuminemia) or renovascular disease (e.g., renal artery stenosis) and who cannot compensate for changes in afferent or efferent arteriolar tone.

Fungsional ARF

• Functional ARF is very common in individuals with heart failure who receive an ACEI or an ARB in an attempt to improve their left ventricular function. Because the decline in efferent arteriolar resistance resulting from the inhibition of angiotensin II occurs within days, if the dose is increased too rapidly, a decline in GFR with a concomitant rise in the serum creatinine will be noticeable. If the increase in the serum creatinine is mild to moderate (an increase of less than 30% from baseline) the medication can be continued

PRERENAL ARF• Prerenal ARF results from hypoperfusion of the renal

parenchyma, with or without systemic arterial hypotension. • Renal hypoperfusion with systemic arterial hypotension may be

caused by a decline in intravascular or effective blood volume that can occur in those with acute blood loss (hemorrhage), dehydration, hypoalbuminemia, or diuretic therapy.

• Renal hypoperfusion without systemic hypotension is most commonly associated with bilateral renal artery occlusion, or unilateral occlusion in a patient with a single functioning kidney. Other the most common cause is atherosclerosis, with severe abrupt occlusion sometimes occurring as the result of an embolism

INTRINSIC

• Acute intrinsic renal failure results from damage to the kidney itself. Conceptually, acute intrinsic renal failure can be categorized on the basis of the structures within the kidney that are injured: the renal vasculature, glomeruli, tubules, and the interstitium.

• Penyebab terbesar (sekitar 85 %) adalah tubular damage.

• Lihat tabel etiologi

POST RENAL• Postrenal ARF may develop as the result of obstruction at any level

within the urinary collection system from the renal tubule to urethra• It is often caused by a prostatic process (hypertrophy, cancer or

infection)• It may also be the result of an improperly placed urinary catheter.

Anticholinergic medications may also prevent bladder emptying and cause ARF.

• Lihat tabel etiologi• Wherever the location of the obstruction, urine will accumulate in

the renal structures above the obstruction and cause increased pressure upstream. The ureters, renal pelvis, and calyces all expand, and the net result is a decline in GFR.

CLINICAL PRESENTATION OF ARF

General

• The initiating sign or symptom prompting the eventual diagnosis of ARF is highly variable, depending on the etiology. It may be an elevated Scr , decreased urine output, blood in the urine, pain during voiding, or severe abdominal or flank pain.

• Determine if the renal complication is acute, chronic, or the result of an acute change in a patient with known CKD.

URINE OUTPUT

• Acute anuria (< 50 mL/day of urine output) is typically caused by either complete urinary obstruction or a catastrophic event (e.g., shock or acute cortical necrosis).

• Oliguria (< 500 mL/day of urine output), which often develops over several days, suggests prerenal azotemia.

• Nonoliguric (> 500 mL/day of urine output) renal failure usually results from acute intrinsic renal failure or incomplete urinary obstruction.

Physical examination finding in ARF

Diagnostic Parameters for Differentiating Causes of ARF

Urine Analysis Findings as a Guide to the Etiology of ARFailure

ISSUE of SCr

• There is currently no consensus on the degree and time frame of changes in Scr values that clearly defines the presence of ARF. The difficulty of using Scr as a diagnostic laboratory test for patients with ARF is its lack of sensitivity to rapid changes in GFR. An abrupt cessation in glomerular filtration will not yield an immediate measurable change in Scr.

ISSUE of SCr• Glomerular filtration rate (GFR;

mL/min) and serum creatinine (Scr ; g/dL) versus time following acute renal injury. Prior to time 0, a GFR of 120 mL/min and a Scr of 1.0 g/dL exist. At time 0, an abrupt renal artery thrombus forms, depriving one kidney of renal blood flow. Composite GFR immediately declines by 50% to approximately 60 mL/min. However, Scr does not increase immediately, as it is dependent on creatinine production and attainment of steady-state serum concentrations.

Perhatian dalam membaca hasil lab

• Instead of using fixed numbers to determine renal function, changes in the value, even if it remains within the normal range, may indicate marked impairment of renal function.

• Patients with reduced creatinine production, such as those with low muscle mass either because of being bedridden for long periods of time, may have very low baseline Scr values (<0.6 mg/dL) and thus the presence of a gradual Scr rise to normal values (0.8 to 1.2 mg/dL) may actually indicate reduced GFR.

• Scr and BUN are extensively removed during acute hemodialysis treatments, so when assessing any change in these parameters in the ARF patient, one must pay close attention to when the lab specimens were collected relative to the dialysis procedure.

ACUTE RENAL FAILURE(PREVENTION, TREATMENT, AND

MANAGEMENT)

Tujuan pembelajaran

• Mahasiswa mampu menjelaskan manajemen pencegahan dan terapi ARF

PREVENTION AND TREATMENT

Desired Outcome• Prevention is critical. • The goals are (a) to prevent ARF, (b) avoid or minimize further renal

insults that would worsen the existing injury or delay recovery, and (c) provide supportive measures until kidney function returns.

• The risk of developing ARF may be predictable (such as decreased perfusion secondary to abdominal surgery, coronary bypass surgery, acute blood loss in trauma, and uric acid nephropathy)

• When patients with risk factors for developing ARF are scheduled for surgery, the clinician should be aware that the likelihood of the patient developing ARF is high and consider preventative measures, including discontinuation of medications that may enhance the likelihood of renal damage (e.g., NSAIDs, angiotensin-converting enzyme inhibitors).

General Approach to Prevention• Optimal daily fluid intake (approximately 2 L/day) to avoid

dehydration, • Fluid balance can be evaluated by measuring acute changes in

weight, as other typical sources for weight changes in an adult occur over more prolonged periods, and blood pressure changes.

• If the patient has a history of nephrolithiasis, they may benefit from dietary restrictions, depending on the type of stones that were present in the past.

• If a patient has a Foley catheter in place, proper care and monitoring needs to be performed to ensure that postobstructive ARF does not develop.

Nonpharmacologic Therapies

Radiocontrast dye nephrotoxic and hydration• Adequate hydration and sodium loading prior

to radiocontrast dye administration have been shown to be beneficial therapies. A trial comparing infusions of 0.9% NaCl or 5% dextrose with 0.45% NaCl administered prior to radiocontrast dye infusion conclusively demonstrated that normal saline was superior in preventing ARF.

Nonpharmacologic Therapies

Radiocontrast dye nephrotoxic and hydration• The benefits of 0.9% NaCl infusions have been found in

similar studies, suggesting this regimen should be used in all at-risk patients who can tolerate the sodium and fluid load. In addition to the correction of dehydration, saline administration may result in dilution of contrast media, prevention of renal vasoconstriction leading to ischemia, and avoidance of tubular obstruction.

• Sodium bicarbonate provides more protection than saline, perhaps by reducing the formation of pH-dependent oxygen free radicals.

Nonpharmacologic Therapies

Radiocontrast dye induced nephrotoxic (RCIN) and preventive dialysis

• Overall, evidence to date does not support any consistent significant benefit with the routine use of extracorporeal blood purification to prevent RCIN over standard medical therapy

Nonpharmacologic Therapies

Amphotericin B nephrotoxic• The nephrotoxic potential of amphotericin B

deoxycholate can be reduced significantly simply by slowing the infusion rate from a standard 4-hour infusion to a slower 24-hour infusion of the same dose. In a patient with risk factors for the development of ARF, liposomal forms of amphotericin B can be used. These liposomal formulations are more expensive, but have been associated with a lower incidence of kidney damage.

Pharmacologic Therapies

Low-dose dopamine (≤2 mcg/kg/min) common practice, but less evidence supported

Forrest plot showing relative risks (diamonds) and 95% confidence intervals (lines) forall studies and for sub groups A, B,and C. Subgroup A included 14 studies enrolling 661 patients but excluded studies using radiocontrast dye. Subgroup B was limited to heart disease and included four studies enrolling 271 patients. Subgroup C excluded statistical outliers in terms of either control group event rate or the effect size for each outcome as determined by analysis of variance.

Pharmacologic TherapiesDiuretics• The use of diuretics to prevent nephrotoxicity may actually result in

intravascular volume depletion and thereby increase the risk of ARF. A trial of forced diuresis, in which mannitol, furosemide, and/or dopamine were given, and the resultant urinary losses were replaced with intravenous solutions, found that diuretic use resulted in little benefit compared to the administration of IV solutions alone. Interestingly, these investigators noted that patients who were unable to increase their urine output after diuretic administration were more likely to develop ARF than were patients who did respond to diuretics. While this unresponsiveness to diuretics might simply be an indication of preexisting kidney damage, similar reports have linked diuretic unresponsiveness to increased mortality rates in critically ill patients with ARF

Pharmacologic Therapies

Acetylcysteine• The mechanism for N-acetylcysteine’s ability to reduce

the incidence of contrast dye induced nephrotoxicity is not clear, but likely is due to its antioxidant effects. Given the consistent findings of its efficacy and its relatively low cost, N-acetylcysteine should be given to all patients at risk for CIN.

• The recommended N-acetylcysteine dosing regimen for prevention of CIN is 600 mg orally every 12 hours for 4 doses with the first dose administered prior to contrast exposure.

Pharmacologic Therapies

Glycemic control• Strict glycemic control is recognized as an

important goal for outpatient diabetics; however, intensive insulin therapy may now also become the standard of care for all critically ill patients to prevent ARF and improve mortality.

ESTABLISHED ARF

FOUNDATIONS

• Treat any life threatening conditions• Identify any cause of ARF that warrants

specific treatment

Desired outcome

• Short-term goals include minimizing the degree of insult to the kidney, reducing extrarenal complications, and expediting the patient’s recovery of renal function. The ultimate goal is to have the patient’s renal function restored to their pre-ARF baseline.

General Approach to Treatment• Prerenal sources of ARF should be managed with hemodynamic support and

volume replacement. • If the cause is immune related, as may be the case with interstitial nephritis or

glomerulonephritis, appropriate immunosuppressive therapy must be promptly initiated.

• Postrenal therapy focuses on removing the cause of the obstruction. • It is important to approach the treatment of established ARF with an understanding

of the patient’s comorbidities and baseline renal function. • Loss of kidney function combined with other clinical conditions, such as cardiac and

liver failure, are associated with higher mortality than that associated with the development of ARF alone.

• At times, the most efficacious remedy for ARF is management of the comorbid precipitating event. Appreciation of the baseline renal function is also important at the outset of ARF management, because the presence of CKD indicates the highest degree of renal function that can be attained after ARF resolution. Finally, the presence of CKD indicates that the kidneys have less reserve, and thus there is a greater likelihood that the individual may not fully recover from the current insult.

General Approach to Treatment• Once acute renal failure is established, the cause is

known, and any specific therapy implemented, supportive care is the mainstay of ARF management regardless of etiology. RRT may be necessary to maintain fluid and electrolyte balance while removing accumulating waste products. The slow process of renal recovery cannot begin until there are no further insults to the kidney. In the case of ATN, the recovery process typically occurs within 10 to 14 days after resolution of the last insult. The recovery period will be prolonged if the kidney is exposed to repeated insults.

Management priorities

NONPHARMACOLOGIC• Initial modalities to reverse or minimize prerenal ARF include removal of medications

associated with diminished renal blood flow or the physical removal of a prerenal obstruction.

• If dehydration is evident, then appropriate fluid replacement therapy, should be initiated. • Moderately volume-depleted patients can be given oral rehydration fluids; however, if

intravenous fluid is required, isotonic normal saline is the replacement fluid of choice, and large volumes may be necessary to provide adequate fluid resuscitation.

• Typically, IV fluid challenges are initiated with 250 to 500 mL of normal saline over 15 to 30 minutes with an assessment after each challenge of the patient’s volume status. Unless profound dehydration is present, as may be seen in diabetic ketoacidosis or hyperosmolar hyperglycemic states, 1 to 2 L is usually adequate.

• Patients with diabetic ketoacidosis or a hyperosmolar hyperglycemic state often have a 10% to 15% total-body water deficit, and more aggressive fluid replacement is necessary.

• The patient should be monitored for pulmonary edema, peripheral edema, adequate blood pressure (diastolic blood pressure >60 mm Hg), normoglycemia and electrolyte balance.

• Urine output may not be promptly observed, as the kidney continues to retain sodium and water until rehydration is achieved. Up to 10 L may be required in the septic patient during the first 24 hours, because of the profound increase in vascular capacitance and fluid leakage into the extravascular, interstitial space.

Special conditionHyperkalemia

Special condition

• Pulmonary oedemaOxygenationOpioid or nitrate to treat decompensated heartFurosemide 250 mg in 50 ml 0.9% saline over one hour,

with an effect seen within 1-2 h for diuresisIf not successfull RRT• AcidosisModerate acidosis Sodium bicarbonateSevere acidosis (blood pH <7.2 and oligoanuric) RRT

Indications for RRT

Indications for RRT

Diuretic resistance in ARF patients

Monitoring for patients with establishes ARF