Plasma sodium concentration x Plasma creatinine concentration

FENa is a measure of the percentage of sodium excreted by the kidney. A FENa of less than 1% may indicate prerenal AKI as it represents the response of the kidney to decreased renal perfusion by decreasing sodium excretion. Loop diuretics such as fur-osemide enhance sodium excretion and increase FENa, confounding the interpretation of the test.

Common Diagnostic Procedures

• Urinary catheterization (insertion of a catheter into a patient's bladder; an increase in urine output may occur with postrenal obstruction)

• Renal ultrasound (uses sound waves to assess size, position, and abnormalities of the kidney; dilatation of the urinary tract can be seen with postrenal AKI)

• Renal angiography (administration of IV contrast dye to assess the vasculature of the kidney)

• Retrograde pyelography (injection of contrast dye into the ureters to assess the kidney and collection system)

• Kidney biopsy (collection of a tissue sample of the kidney for the purpose of microscopic evaluation; may aid in the diagnosis of glomerular and interstitial diseases)

Patient Encounter, Part 1

A 73-year-old man with a history of diabetes mellitus, chronic kidney disease, gout, osteoarthritis, and hypertension is hospitalized with pyelonephritis and possible urosepsis. He recently completed a 14-day course of antibiotics and was ready for discharge when his morning labs showed an increase in BUN (42 mg/dL or 15 mmol/L) and SCr (2.9 mg/dL). His serum creatinine 24 hours earlier was 2.4 mg/dL (212 prnol/ L). Upon examination, he was found to have 2+ pitting edema, weight gain, nausea, elevated blood pressure, and rales on chest auscultation.

What signs and symptoms does the patient have that may indicate AKI?

What risk factors does he have for the development of AKI?

What additional information do you need to fully assess this patient?

Patient Encounter, Part 2: The Medical History, Physical Examination, and Laboratory Tests

PMH: Type 1 diabetes mellitus since the age of 32; chronic kidney disease (BUN and serum creatinine were 30 mg/dL [10.7 mmol/L] and 2.5 mg/dL [221 p,mol/L], respectively, on admission); hypertension; gout; osteoarthritis

FH: Father with a history of type 2 diabetes mellitus, hypertension, and stage 5 chronic kidney disease; he died from a myocardial infarction at age 68; mother with a history of hypertension; she died from injuries sustained in a motor vehicle accident at the age of 52

SH: Retired coal miner; no smoking, occasional alcohol use

Hospital Meds: Gentamicin 120 mg IV piggyback every 12 hours (dose discontinued after 3 days); gentamicin 120 mg IV piggyback every 24 hours (days 4 through 14, discontinued this morning); ampicillin 2 g IV piggyback every 8 hours (14-day course, discontinued this morning); sliding scale insulin; allopurinol 100 mg orally daily; ranitidine 150 mg orally every 12 hours; atenolol 50 mg orally daily; naproxen 275 mg orally every 12 hours; enalapril 2.5 mg orally daily

Home Meds: NPH insulin 20 units in the morning and 10 units in the evening; regular insulin 10 units in the morning and 10 units in the evening; allopurinol 100 mg orally daily; naproxen 275 mg orally every 12 hours; atenolol 50 mg orally daily

VS: BP 154/95 mm Hg, pulse 80 bpm, RR 26/min, temperature 37.7°C, current wt 79 kg (admission wt 75 kg), ht 5'10" (178 cm)

Chest: Basilar crackles, inspiratory wheezes

MS/Exts: 2+ pedal edema

Urinalysis: Color, yellow; character, hazy; glucose (-); ketones (-); specific gravity 1.020; pH 5.0; (+) protein; coarse granular casts, 5 to 10/low-powered field; WBC count, 5 to 10/high-powered field; RBC count, 2 to 5/high-powered field; no bacteria; nitrite (-); blood small; osmolality 325 mOsm; urinary sodium 77 mEq/L (77 mmol/ L); urinary creatinine 63 mg/dL (5,569 p,mol/L)

Day 3 Labs:

Gentamicin Concentrations:

= trough concentration drawn immediately prior to the = peak concentration drawn 1 hour after the end of the

Given this additional information, what is your assessment of the patient's condition? Identify your treatment goals for the patient.

Loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid) are all equally effective when given in equivalent doses. Therefore, selection is based on the side-effect profile, cost, and pharmacokinetics of the agents. The incidence of ototox-icity is significantly higher with ethacrynic acid compared to the other loop diuretics; therefore, its use is limited to patients who are allergic to the sulfa component in the other loop diuretics.18 While ototoxicity is a well-established side effect of furosemi-de, its incidence may be greater when administered by the IV route at a rate exceeding 4 mg/min. Torsemide has not been reported to cause ototoxicity.

There are several pharmacokinetic differences between loop diuretics. Fifty percent of a dose of furosemide is excreted unchanged by the kidney with the remainder undergoing glucuronide conjugation in the kidney.19 In contrast, liver metabolism accounts for 50% and 80% of the elimination of bumetanide and torsemide, respectively.19 Thus, patients with AKI may have a prolonged half-life of furosemide. The bioavailability of both torsemide and bumetanide is higher than for furosemide. The

IV: oral ratio for bumetanide and torsemide is 1:1, bioavailability of oral furosemide

is approximately 50%, with a reported range of 10% to 100%.

Furosemide and bumetanide are both available in generic formulations and are generally less expensive than torsemide.

The pharmacodynamic characteristics of loop diuretics are similar when equivalent doses are administered. Because loop diuretics exert their effect from the luminal side of the nephron, urinary excretion correlates with diuretic response. Substances that interfere with the organic acid pathway, such as endogenous organic acids which accumulate in renal disease, competitively inhibit secretion of loop diuretics. Therefore, large doses of loop diuretics may be required to ensure that adequate drug reaches the nephron lumen. In addition, loop diuretics have a ceiling effect where maximal natri-uresis occurs.19,21 Thus, very large doses of furosemide (e.g., 1 g) are generally not considered necessary and may unnecessarily increase the risk of ototoxicity.

Several adaptive mechanisms by the kidney limit effectiveness of loop diuretic therapy. Postdiuretic sodium retention occurs as the concentration of diuretic in the loop of Henle decreases. This effect can be minimized by decreasing the dosage in-

terval (i.e., dosing more frequently) or by administering a continuous infusion. In patients with a CrCl of 25 mL/min or higher, furosemide at a dose of 10 mg/h would be a reasonable starting dose.19 A starting dose of 20 mg/h would be reasonable in patients with a CrCl of less than 25 mL/min.19 With a continuous infusion, a loading dose is recommended. Continuous infusion loop diuretics may be easier to titrate than bolus dosing, requires less nursing administration time, and may lead to fewer adverse reactions.

Prolonged administration of loop diuretics can lead to a second type of diuretic resistance. Enhanced delivery of sodium to the distal tubule can result in hypertrophy of distal convoluted cells.19 Subsequently, increased sodium chloride absorption occurs in the distal tubule which diminishes the effect of the loop diuretic on sodium excretion. Addition of a distal convoluted tubule diuretic, such as metolazone or hydrochlorothiazide, to a loop diuretic can result in a synergistic increase in urine output. There are no data to support the efficacy of one distal convoluted tubule diuretic over another. The common practice of administering the distal convoluted tubule diuretic 30 to 60 minutes prior to the loop diuretic has not been studied, although this practice may first inhibit sodium reabsorption at the distal convoluted tubule before it is inundated with sodium from the loop of Henle.

A usual starting dose of IV furosemide for the treatment of AKI is 40 mg (Fig.

25-2). Reasonable starting doses for bumetanide and torsemide are 1 mg and 20 mg, respectively.19 Efficacy of diuretic administration can be determined by comparison of a patient's hourly fluid balance. Other methods to minimize volume overload, such as fluid restriction and concentration of IV medications, should be initiated as needed.

If urine output does not increase to about 1 mL/kg/h, the dosage can be increased

to a maximum of 160 to 200 mg of furosemide or its equivalent (Fig. 25-2). Dosing frequency is based on the patient's response, the ability to restrict sodium intake, and the duration of action of the diuretic. Other methods to improve diuresis can be initiated sequentially, such as: (a) shortening the dosage interval, (b) adding hydrochlorothiazide or metolazone, and (c) switching to a continuous infusion loop diuretic. A loading dose should be administered prior to both initiating a continuous infusion and increasing the infusion rate. When high doses of loop diuretics are administered, especially in combination with distal convoluted tubule diuretics, the hemodynamic and fluid status of the patient should be monitored every shift, and the electrolyte status of the patient should be monitored at least daily to prevent profound diuresis and electrolyte abnormalities, such as hypokalemia. Patients will not benefit from switching from one loop diuretic to another because of the similarity in mechanisms of action.

Other Diuretics

Thiazide diuretics, when used as single agents, are generally not effective for fluid removal. Mannitol is also not recommended for the treatment of volume overload associated with AKI. Mannitol is removed by the body by glomerular filtration. In patients with renal dysfunction, mannitol excretion is decreased, resulting in expanded blood volume and hyperosmolality. Potassium-sparing diuretics, which inhibit sodium reabsorption in the distal nephron and collecting duct, are not sufficiently effective in removing fluid. In addition, they increase the risk of hyperkalemia in patients already at risk. Thus, loop diuretics are the diuretics of choice for the management of volume overload in AKI.

Dopamine

Low-dose dopamine (LDD), in doses ranging from 0.5 to 3 mcg/kg/min, predominantly stimulates dopamine-1 receptors, leading to renal vascular vasodilation and increased renal blood flow. While this effect has been substantiated in healthy, euvolem-ic individuals with normal kidney function, a lack of efficacy data exists in patients with AKI. The most comprehensive study evaluating efficacy of LDD, the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group study, did not find that LDD alters peak SCr, need for RRT, duration of stay in the intensive care

unit, or survival to discharge compared to placebo. A recent meta-analysis was performed on all published human trials that used LDD in the prevention or treatment of

AKI. A total of 61 studies were identified that randomized more than 3,300 patients to LDD or placebo. Results reveal no significant difference between the treatment and control groups for mortality, requirement for RRT, or adverse effects.

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FIGURE 25-2. Algorithm for treatment of extracellular fluid expansion. (CrCl, creatinine clearance; ECF, extracellular fluid; HCTZ, hydrochlorothiazide; po, oral.)

LDD is not without adverse reactions and most studies have failed to evaluate its potential toxicities. Adverse reactions that may be associated with LDD include: tachycardia, arrhythmias, myocardial ischemia, depressed respiratory drive, gut ischemia, and impaired resistance to infection. Furthermore, significant overlap in receptor activation occurs. Therefore, doses considered to activate only dopamine receptors may increase cardiac output and blood pressure through dopamine's effect on P- or a-adrenergic receptors.

Based on the results of the ANZICS trial, the lack of conclusive evidence in many earlier studies, and several meta-analyses, there is no indication for the use of LDD in the treatment of AKI.

Fenoldopam

Fenoldopam is a selective dopamine-1 receptor agonist that is approved for short-term management of severe hypertension. Because it does not stimulate dopamine-2, a-

adrenergic, and P-adrenergic receptors, fenoldopam causes vasodilation in the renal vasculature with potentially fewer nonrenal effects than dopamine. In normotensive individuals with normal kidney function, IV fenoldopam increases renal blood flow without lowering systemic blood pressure.25 While preliminary studies in animal models of AKI are encouraging, few studies are available assessing its effectiveness in the treatment of AKI. A prospective randomized study comparing fenoldopam to placebo in early ATN did not find a difference in need for dialysis or mortality26. A

second prospective, randomized study in septic patients did find less of an increase in SCr in the fenoldopam group compared to placebo, but no difference in survival 27

or need for RRT. Large, prospective trials are needed before fenoldopam can be recommended. Other agents that are under evaluation for the treatment of AKI include atrial natriuretic peptide, urodilatin, and nesiritide.

Nonpharmacologic Treatment

Renal Replacement Therapy

RRT using dialysis may be necessary in patients with established AKI to treat volume overload that is unresponsive to diuretics, to minimize the accumulation of nitrogenous waste products, and to correct electrolyte and acid-base abnormalities while renal function recovers. Five to thirty percent of patients with AKI treated with dialysis will not have recovery of their renal function and will need to remain on long-term

dialysis. This may be due in part to underlying illnesses, as AKI is often seen in the setting of multiorgan failure. There are two types of dialysis modalities commonly used in AKI: intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT). IHD is a higher-efficiency form of dialysis which is provided for several hours a day at a variable frequency (usually daily or three to five times per week) at a higher blood flow rate. CRRT is a pump-driven form of dialysis which provides slow fluid and solute removal on a continuous, 24-hour basis. The primary advantage of CRRT is hemodynamic stability and better volume control, particularly in patients who are unable to tolerate rapid fluid removal. The primary disadvantages associated with CRRT are continuous nursing requirements, continuous anticoagulation, frequent clotting of the dialyzer, patient immobility, and increased cost. There is no conclusive evidence that one type of dialysis is preferred to another in terms of mortality and re-

covery of renal function. Thus, selection of CRRT over IHD is often governed by the critical illness of the patient and by the comfort level of the institution with one particular type of dialysis.

With either type of dialysis, studies suggest that recovery of renal function is decreased in AKI patients who undergo dialysis compared with those not requiring dialysis. Decreased recovery of renal function may be due to hemodialysis-induced hypotension causing additional ischemic injury to the kidney. Also, exposure of a patient's blood to bioincompatible dialysis membranes (cuprophane or cellulose acetate) results in complement and leukocyte activation which can lead to neutrophil infiltration into the kidney and release of vasoconstrictive substances that can prolong renal dysfunction.30 Synthetic membranes composed of substances such as polysulfone, polyacrylonitrile, and polymethylmethacrylate are considered to be more biocompatible and would be less likely to activate complement. Synthetic membranes are generally more expensive than cellulose-based membranes. Several recent metaanalyses found no difference in mortality between biocompatible and bioincompatible membranes. Whether biocompatible membranes lead to better patient outcomes continues to be debated.

Supportive Therapy

Supportive therapy in AKI includes adequate nutrition, correction of electrolyte and acid-base abnormalities (particularly hyperkalemia and metabolic acidosis), fluid management, and correction of any hematologic abnormalities. Because AKI is often associated with multiorgan failure, treatment includes the medical management of in fections, cardiovascular and GI conditions, and respiratory failure. Finally, all drugs should be reviewed, and dosage adjustments made based on an estimate of the patient's GFR.

Patient Encounter, Part 3: Creating a Care Plan

Based on the information presented, create a care plan for this patient's AKI. Your plan should include: (a) a statement of the drug-related need and/or problems, (b) the goals of therapy, (c) a detailed patient-specific therapeutic plan, and (d) a plan for follow-up to determine whether the goals have been achieved and adverse effects avoided.

PREVENTION OF ACUTE RENAL FAILURE Avoidance

The best preventive measure for AKI, especially in individuals at high risk, is to avoid medications that are known to precipitate AKI. Nephrotoxicity is a significant side effect of aminoglycosides, ACE inhibitors, angiotensin receptor antagonists, amphotericin B, NSAIDs, cyclosporine, tacrolimus, and radiographic contrast agents.8 Unfortunately, an effective, non-nephrotoxic alternative may not always be appropriate for a given patient and the risks and benefits of selecting a drug with nephrotoxic potential must be considered. For example, serious gram-negative infections may require double antibiotic coverage, and based on culture and sensitivity reports, aminoglyc-oside therapy may be necessary. In cases such as this, other measures to reduce the risk of AKI should be instituted. Thus, identifying patients at high risk for development of AKI and implementing preventive methods to decrease its occurrence or severity is critical.

Drug-Induced ARF

Aminoglycosides

Aminoglycosides (gentamicin, tobramycin, and amikacin) can cause nonoliguric intrinsic AKI. Injury is due to binding of aminoglycosides to proximal tubular cells in the renal cortex, and subsequent cellular uptake and cell death.31 In clinical practice, all aminoglycosides are considered equally nephrotoxic, and similar precautions should be used for all of the agents. High cumulative drug exposure increases the in cidence of aminoglycoside-induced AKI. Additional risk factors include a prolonged course of aminoglycoside therapy (typically longer than 7-10 days), pre-existing chronic kidney disease, and increased age.3 Alternative antibiotics should be considered in individuals with AKI or those who are at a high risk for developing AKI, although resistance of some strains of gram-negative organisms to other antibiotics may necessitate their use.

Methods to minimize drug exposure with conventional (multiple doses per day) dosing include maintaining trough concentrations less than 2 mcg/mL for gentamicin and tobramycin (less than 10 mcg/mL for amikacin), minimizing length of therapy, and avoiding repeated courses of aminoglycosides. Concurrent exposure to other nephrotoxic medications and dehydration may also worsen AKI. There is conflicting evidence as to whether the combination of vancomycin and an aminoglycoside has a higher incidence of AKI than aminoglycoside therapy alone. Aminoglycoside-induced AKI is usually reversible upon drug discontinuation; however, dialysis may be needed in some individuals while kidney function improves.

Another method to minimize toxicity is with extended-interval dosing (e.g., once daily). The goal of extended-interval dosing is to provide greater efficacy against the microorganism with a lower incidence of nephrotoxicity. Aminoglycosides demonstrate concentration-dependent killing and a prolonged postantibiotic effect. The mechanism by which extended-interval aminoglycoside dosing may reduce the incidence of nephrotoxicity is by providing high, transient concentrations of drug which saturate proximal tubule uptake sites. Once saturated, the remaining aminoglycoside

molecules pass through the proximal tubule and are excreted in the urine. Thus, less drug is available for cellular uptake during a 24-hour period. A consistent finding in studies is that extended-interval aminoglycoside dosing is as effective as conventional dosing and is not more nephrotoxic, and in some studies is less nephrotoxic than conventional dosing. Aminoglycosides can also cause hearing loss and/or vestibular tox-icity, although the incidence of ototoxicity appears to be similar with extended-dosing and conventional dosing. Prolonged exposure to the drug, repeated courses of therapy, and concurrent use of other ototoxic drugs increase toxicity. Extended-interval dosing is not recommended in patients with pre-existing kidney disease, conditions where high concentrations are not needed (e.g., urinary tract infections), hyperdynamic patients that may demonstrate increased drug clearance (e.g., burn patients), and others where you would suspect altered pharmacokinetics or increased risk of ototoxicity.

Amphotericin B

Amphotericin B-induced AKI occurs in as many as 49% to 65% of patients treated with the conventional desoxycholate formulation.34 Nephrotoxicity is due to renal arterial vasoconstriction and distal renal tubule cell damage. Risk factors include high daily dosage, large cumulative dose, preexisting kidney dysfunction, dehydration, and concomitant use of other nephrotoxic drugs.34 Three lipid-based formulations of am-photericin B have been developed in an attempt to improve efficacy and limit toxicity, particularly nephrotoxicity: amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B. The range of nephrotoxicity reported is 15% to 25% for these formulations. The mechanism for decreased nephrotoxicity has not been completely elucidated, but it is thought to be due to preferential delivery of amphotericin B to the site of infection, with less of an affinity for the kidney.35 Lipid-based formulations are recommended in individuals with risk factors for development of AKI. Administration of IV normal saline may also attenuate nephrotoxicity associated with amphotericin B.

Whether there are significant differences in nephrotoxicity between the three lipid-

based formulations remains unclear. A recent review of the literature from 1997

through 2007 summarized the studies to date comparing lipid-based formulations. Only amphotericin B lipid complex and liposomal amphotericin B have been compared, mainly in observational studies. Nine studies showed a similar incidence of AKI between amphotericin B lipid complex and liposomal amphotericin B. However, in one prospective, randomized study, the incidence of nephrotoxicity was lower with liposomal amphotericin B dosed at 5 mg/kg/day (14.8%) compared to amphotericin B lipid complex dosed at 5 mg/kg/day (42%) in febrile, neutropenic patients.36 Large, prospective studies comparing the incidence of nephrotoxicity between these agents are needed to ascertain differences in nephrotoxicity.

Radiocontrast Agents

Intravascular radiographic contrast agents are administered during radiologic studies and carry with them the well-documented risk of AKI. Patients at risk for developing AKI include patients with chronic kidney disease, diabetic nephropathy, dehydration,

and higher doses of contrast dye. Contrast agents are water-soluble, triiodinated, benzoic acid salts that cause an osmotic diuresis due to their osmolality, which exceeds that of plasma. The mechanism of nephrotoxicity is not fully understood; however,

direct tubular toxicity, renal ischemia, and tubular obstruction have been implicated. Diatrizoate and iothalamate are ionic contrast agents. Iohexol, iopamidol, ioversol, and iopromide represent nonionic agents. The incidence of nephrotoxicity with ionic and nonionic agents is similar in patients at low risk for developing AKI; however, in high-risk patients, nephrotoxicity is significantly greater when ionic contrast agents are used. In diabetic patients with chronic kidney disease and an SCr of greater than

1.5 mg/dL (133 ^mol/L), nephrotoxicity occurred in 33.3% and 47.7% of patients re-

ceiving nonionic and ionic contrast agents, respectively. The cost of nonionic agents is approximately 10-fold higher, which may limit their routine use in all patients undergoing radiographic studies.

Therapeutic measures that have been used to decrease the incidence of contrast-induced nephropathy include extracellular volume expansion, minimization of the amount of contrast administered, and treatment with oral acetylcysteine. Theophyl-line, fenoldopam, loop diuretics, mannitol, dopamine, and calcium antagonists have no effect or may worsen AKI.

The most effective therapeutic maneuver to decrease the incidence of contrast-induced nephropathy is extracellular volume expansion.40 Several recent studies have compared the efficacy of isotonic sodium chloride (0.9%) to half normal saline (0.45%) or to oral hydration.41,42 Isotonic fluid is superior to hypotonic fluid in prevention of nephropathy. A common regimen is IV isotonic sodium chloride (1 mL/ kg of body weight/hour) administered for 12 hours before and 12 hours after the procedure. Fluid should be administered cautiously to patients with CHF, left ventricular dysfunction, and significant renal dysfunction. Recent evidence suggests that hydration, plus sodium bicarbonate to alkalize renal tubule fluid, may reduce free radical formation and lead to less oxidant damage, although studies have been conflicting.43,44 Most studies investigating sodium bicarbonate hydration administered therapy at a rate of 3 mL/kg/h (154 mEq/L) for one before the procedure, and 1 mL/kg/h during and 6-hour postcontrast. A large, randomized clinical trial that provides definitive conclusions is needed.

Minimizing the quantity of contrast media administered may be beneficial in preventing nephropathy. Some studies, but not all, have directly associated dose of contrast media and nephrotoxicity. Avoidance of contrast dye with alternative diagnostic procedures should be considered in high-risk patients, but may not always be feasible. In addition, avoidance of multiple contrast studies in a short time period will allow renal function to return to normal between procedures.

Because production of reactive oxygen species has been implicated in the pathophysiology of contrast-induced AKI, prophylactic administration of the antioxidant acetylcysteine has been investigated. An oral dose of 600 mg twice daily the day before and the day of the procedure decreased the incidence of AKI in one small study, although patient outcomes such as mortality and length of hospitalization were not evaluated.45 Since then, at least 25 additional studies evaluating the efficacy of oral acetylcysteine have been conducted, with mixed results. In addition, a series of metaanalyses have also analyzed the results of the studies with varying conclusions. The studies were varied in terms of study population, sample size, definition of contrast nephropathy, type of contrast agent used, hydration, and formulation of acetyl-cysteine administered, thus making collective interpretation of the results difficult. It is routinely used in many hospitals due to its low cost and safe side effect profile at low oral doses, although data are not conclusive that it prevents development of AKI, particularly on patient outcomes such as mortality, need for dialysis, and length of hospitalization. It is noted that acetylcysteine is not considered a replacement for adequate hydration, which remains the standard of care for prevention of contrast neph-ropathy.

Fenoldopam does not decrease the incidence of contrast nephropathy.46 Due to its hypotensive effect, it may worsen kidney function.

Cyclosporine and Tacrolimus

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for AKI is renal vascular vaso-47

constriction. It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy

with other nephrotoxic drugs. Cyclosporine and tacrolimus are extensively metabolized by the liver through the cytochrome P450 3A4 pathway and drugs that inhibit their metabolism (e.g., erythromycin, clarithromycin, fluconazole, ketoconazole, verapamil, diltiazem, and nicardipine) can precipitate AKI. Because AKI is dose dependent, careful monitoring of cyclosporine or tacrolimus trough concentrations can minimize its occurrence; however, AKI can develop with normal or low blood concentrations. In addition, there is some evidence that calcium channel blockers have a renoprotective effect through dilation of the afferent arterioles and are often used preferentially as antihypertensive agents in kidney transplant recipients.

It is often difficult to differentiate AKI from acute rejection in the kidney transplant recipient, as both conditions may present with similar symptoms and physical examination findings. However, fever and graft tenderness are more likely to occur with rejection while neurotoxicity is more likely to occur with cyclosporine or tacrolimus toxicity. Kidney biopsy is often needed to confirm the diagnosis of rejection.

ACE Inhibitors and ARBs

In instances of decreased renal blood flow, production of angiotensin II increases, resulting in efferent arteriole vasoconstriction and maintenance of glomerular capillary pressure and GFR (Fig. 25-3). In patients initiated on ACE inhibitors or ARBs, angiotensin II synthesis decreases, thereby dilating efferent arterioles and decreasing glomerular capillary pressure and GFR. Risk factors for developing AKI are pre-existing renal dysfunction, severe atherosclerotic renal artery stenosis, volume depletion,

and severe CHF. AKI often develops within days, with a rapid rise in blood urea nitrogen (BUN) and SCr. Discontinuation of the drug usually results in return of renal function to baseline, although a small decrease in kidney function may be acceptable in patients with severe CHF who would benefit from the hemodynamic effect of ACE inhibitors or ARBs.

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs (e.g., inbuprofen, naproxen, sulindac) can likewise cause prerenal AKI through inhibition of prostaglandin-mediated renal vasodilation. Risk factors are similar to those of ACE inhibitors and ARBs. Additional risk factors include hepatic disease with ascites, systemic lupus erythematosus, and advanced age. The onset is often within days of initiating therapy and patients typically present with oliguria. It is usually reversible with drug discontinuation. Agents that preferentially inhibit cyclooxy-genase-2 pose a similar risk as traditional, nonselective NSAIDs.4

Other Drugs

Other drugs that are commonly implicated in causing AKI include acyclovir, adefovir, carboplatin, cidofovir, cisplatin, foscarnet, ganciclovir, indinavir, methotrexate, pentamidine, ritonavir, sulfinpyrazone, and tenofovir.50

OUTCOME EVALUATION

Goals of therapy are to maintain a state of euvolemia with good urine output (at least 1 mL/kg/h), to return serum creatinine to baseline, and to correct electrolyte and acid-

base abnormalities. In addition, appropriate drug dosages based on kidney function and avoidance of nephrotoxic drugs are goals of therapy. Assess vital signs, weight, fluid intake, urine output, BUN, creatinine, and electrolytes daily in the unstable patient.

FIGURE 25-3. Normal glomerular autoregulation serves to maintain intra-glomerular capillary hydrostatic pressure, glomerular filtration rate, and ultimately, urine output. This is accomplished by modulation of afferent and efferent arterioles. Afferent and efferent arteriolar vasoconstrictions are primarily mediated by angiotensin II, whereas afferent vasodilation is primarily mediated by prostaglandins. (PGE2, prostaglandin E2.)

Patient Care and Monitoring

1. Assess kidney function by evaluating a patient's signs and symptoms, laboratory test results, and urinary indices. Calculate a patient's CrCl to evaluate the severity of kidney disease.

2. Obtain a thorough and accurate drug history, including the use of nonprescription drugs such as NSAIDs.

3. Evaluate a patient's current drug regimen to:

• Determine if drug therapy may be contributing to AKI. Consider not only drugs that can directly cause AKI (e.g., aminoglycosides, amphotericin B, NSAIDs,

Auioregulation

Auioregulation

Filtrate

Tubule cyclosporine, tacrolimus, ACE inhibitors, and ARBs), but also drugs that can predispose a patient to nephrotoxicity or prerenal AKI (i.e., diuretics and anti-hypertensive agents).

• Determine if any drugs need to be discontinued, or alternate drugs selected, to prevent worsening of renal function.

• Adjust drug dosages based on the patient's CrCl or evidence of adverse drug reactions or interactions.

4. Develop a plan to provide symptomatic care of complications associated with AKI, such as diuretic therapy to treat volume overload. Monitor the patient's weight, urine output, electrolytes (such as potassium), and blood pressure to assess efficacy of the diuretic regimen.

Abbreviations Introduced in This Chapter

ANZICS Australian and New Zealand Intensive Care t"R RI Continuo us rcna 1 replaccm cnt t herapy

FE N A Fraci ion a J excre I ion of sod iu ffl

N S AI Ds Non ste ro id a I a nt i- i f la m mator y d rugs

SCr Seru m c re at i n i ne GO ncent ia t ion wwvit

^ Self-assessment questions and answers are available at ht-tp://www. mhpharmacotherapy. com/pp.html.

REFERENCES

1. Kellum JA, Levin N, Bouman C, Lameire N. Developing a consensus classification system for acute renal failure. Curr Opin Crit Care 2002;8:509-514.

2. Bellomo R, Ronco C, Kellum, et al. and the ADQI Workgroup. Acute renal failure-definition, outcome measures, animal models, and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care 2004;8:R204-R212.

3. Kellum JA. Acute kidney injury. Crit Care Med 2008;36:S141-S145.

4. Pruchnicki MC, Dasta JF. Acute renal failure in hospitalized patients: Part I. Ann Pharmacother 2002;36:1261-1267.

5. Joannidis M, Metnitz PGH. Epidemiology and natural history of acute renal failure in the ICU. Crit Care Clin 2005;21:239-249.

6. Ympa YP, Sakr Y, Reinhart K, et al. Has mortality from acute renal failure decreased? A systematic review of the literature. Am J Med 2005;118:827-832.

7. Schetz M. Diuretics in acute renal failure? Contrib Nephrol 2004;144:166-181.

8. Dishart MK, Kellum JA. An evaluation of pharmacological strategies for the prevention and treatment of acute renal failure. Drugs 2000;59: 79-91.

9. Bellomo R. Defining, quantifying, and classifying acute renal failure. Crit Care Clin 2005;21:223-237.

10. Nissenson AR. Acute renal failure: Definition and pathogenesis. Kidney Int 1998;53:S7-S10.

11. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.

12. Brater DC. Drug Use in Renal Disease. Balgowlah, Australia: ADIS Health Science Press, 1983;22-56.

13. Jelliffe R. Estimation of creatinine clearance in patients with unstable renal function, without a urine specimen. Am J Nephrol 2002;22: 320-324.

14. Chiou WL, HSU FH. A new simple rapid method to monitor renal function based on pharmacokinetic considerations of endogenous creatinine. Res Commun Chem Pathol Pharmacol 1975;10:315-330.

15. Bellomo R, Kellum JA, Ronco C. Defining acute renal failure: Physiologic principles. Intensive Care Med 2004;30:33-37.

16. Venkataraman R. Prevention of acute renal failure. Crit Care Clin 2005;21:281-289.

17. Mehta RL, Pascual MT, Soroko S, et al. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002;288:2547-2553.

18. Greenberg A. Diuretic complications. Am J Med Sci 2000;319:10-24.

19. Shankar SS, Brater DC. Loop diuretics: From the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol 2003;284:F11-F21.

20. Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319:38-50.

21. Rudy DW, Gehr TW, Matzke GR, et al. The pharmco dynamics of intravenous and oral torsemide in patients with chronic renal insufficiency. Clin Pharmacol Ther 1994;56:39-47.

22. Rudy DW, Voelker JR, Greene PK, et al. Loop diuretics for chronic renal insufficiency: A continuous infusion is more efficacious than bolus therapy. Ann Intern Med 1991;115:360-366.

23. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: A placebo-controlled randomized trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000;356:2139-2143.

24. Friedrich JO, Adhikari N, Herridge MS, et al. Meta-analysis: Low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005;142:510-524.

25. Mathur VS, Swam SK, Lambrecht LJ, et al. The effects of fenoldopam, a selective dopamine receptor agonists, on systemic and renal hemodynamics in normotensive subjects. Crit Care Med 1999;27: 1832-1837.

26. Tumlin JA, Finkel KW, Murray PT, et al. Fenoldopam mesylate in early acute tubular necrosis: A randomized, double-blind, placebo-controlled clinical trial. Am J Kidney Dis 2005;46:26-34.

27. Morelli A, Ricci Z, Bellomo R, et al. Prophylactic fenoldopam for renal protection in sepsis. A randomized, double-blind, placebo-controlled pilot study. Crit Care Med 2005;33:2451-2456.

28. Silvester W. Outcome studies of continuous renal replacement therapy in the intensive care unit. Kidney Int 1998;66:S138-S141.

29. Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the intensive care unit: A systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002;40: 875-885.

30. Jaber BL, Lau J, Schmid CH, et al. Effect of biocompatibility of hemodialysis membranes on mortality in acute renal failure: A meta-analysis. Clin Nephrol 2002;57:274-282.

31. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: Nephrotoxicity. Antimicrob Agents Chemother 1999;43:1003-1012.

32. Streetman DS, Nafziger AN, Destache CJ, et al. Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs. Pharmacotherapy 2001; 21:443-451.

33. Pannu N, Nadim M. An overview of drug-induced acute kidney injury. Crit Care Med 2008;36:S216-S223.

34. Deray G. Amphotericin B nephrotoxicity. J Antimicrob Chemother 2002;49:37-41.

35. Saliba F, Dupont B. Renal impairment and Amphotericin B formulations in patients with invasive fungal infections. Med Mycol 2008;46: 97-112.

36. Wingard JR, White MH, Anaissie E, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clin Infect Dis 2000;31:1155-1163.

37. Weisbord SD, Palevsky PM. Radiocontrast-induced acute renal failure. J Intensive Care Med 2005;20:63-75.

38. McCullough PA, Soman SS. Contrast-induced nephropathy. Crit Care Clin 2005;21:261-280.

39. Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: A randomized trial. Kidney Int 1995;47:254-261.

40. Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide on acute decreases in renal function by radiocontrast agents. N Engl J Med 1994;331:1416-1420.

41. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: Randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Int Med 2002;162:329-336.

42. Trivedi HS, Moore H, Nasr S, et al. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron 2003;93:C29-C34.

43. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: A randomized controlled trial. JAMA 2004;291:2328-2334.

44. Brar SS, Shen AY, Jorgensen MB, et al. Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephro-pathy in patients undergoing coronary angiography. JAMA 2008;300: 1038-1046.

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46. Stone GW, McCullough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy. JAMA 2003;290: 2284-2291.

47. De Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: Long-term consequences and challenges for the future. Am J Kidney Dis 2000;35:333-346.

48. Perazella MA. Drug-induced renal failure: Update on new medications and unique mechanisms of nephrotoxicity. Am J Med Sci 2003;325: 349-362.

49. Brater DC. Effects of nonsteroidal antiinflammatory drugs on renal function; focus on cyclooxygenase-2—selective inhibition. Am J Med 1999;107:S65-S70.

50. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephropathy. Am J Kidney Dis 2005;45:804-817.

26 Chronic and End-Stage Kidney Disease

Kristine S. Schonder

LEARNING OBJECTIVES

Upon completion of the chapter, the reader will be able to:

1. List the risk factors for development and progression of chronic kidney disease (CKD).

2. Explain the mechanisms associated with progression of CKD.

3. Outline the desired outcomes for treatment of CKD.

4. Develop a therapeutic approach to slow progression of CKD, including lifestyle modifications and pharmacologic therapies.

5. Identify specific consequences associated with CKD.

6. Design an appropriate therapeutic approach for specific consequences associated with CKD.

7. Recommend an appropriate monitoring plan to assess the effectiveness of pharma-cotherapy for CKD and specific consequences.

8. Educate patients with CKD about the disease state, the specific consequences, lifestyle modifications, and pharmacologic therapies used for treatment of CKD.

KEY CONCEPTS

O Chronic kidney disease (CKD) is a progressive disease that eventually leads to kidney failure (end-stage kidney disease [ESKD]).

© Early detection and treatment of CKD are fundamental factors in minimizing morbidity and mortality associated with CKD.

Declining kidney function disrupts the homeostasis of the systems regulated by the kidney, leading to fluid and electrolyte imbalances, anemia, and metabolic bone disease.

o Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers decrease protein excretion and are the drugs of choice for hypertension in patients with CKD.

O The most common complication of CKD is anemia, which is caused by a decline in erythropoietin production by the kidneys and can lead to cardiovascular disease

The goal of anemia management in CKD is to maintain hemoglobin levels between 11 g/dL (110 g/L or 6.8 mmol/L) and 12 g/dL (120 g/L or 7.4 mmol/ L), which generally requires a combination of erythropoiesis-stimulating agents (ESAs) and iron supplements.

© Bone and mineral metabolism disorders stem from disruptions in calcium, phosphorus, and vitamin D homeostasis through the interaction with the parathyroid hormone.

The management of secondary hyperparathyroidism (sHPT) involves correction of serum calcium and phosphorus levels, and decreasing parathyroid hormone secretion.

Patient education and planning for dialysis should begin at stage 4 CKD, before ESKD is reached, to allow for time to establish appropriate access for dialysis.

<E> Dialysis involves the removal of metabolic waste products and excess fluids and electrolytes by diffusion and ultrafiltration from the bloodstream across a semipermeable membrane into an external dialysate solution.

The kidney is made up of approximately 2 million nephrons that are responsible for filtering, reabsorb-ing and excreting solutes and water. As the number of functioning nephrons declines, the primary functions of the kidney that are affected include:

• Production and secretion of erythropoietin

• Activation of vitamin D

• Regulation of fluid and electrolyte balance

• Regulation of acid-base balance

Chronic kidney disease (CKD), also known as chronic kidney insufficiency, progressive kidney disease, or nephropathy, is defined as the presence of kidney damage or decreased glomerular filtration rate (GFR) for 3 months or more.1 Generally, CKD is a progressive decline in kidney function (a decline in the number of functioning nephrons) that occurs over a period of several months to years. A decline in kidney function that occurs more rapidly, over a period of days to weeks, is known as acute kidney injury (AKI), which is discussed in Chapter 25. The decline in kidney function in CKD is often irreversible. Therefore, measures to treat CKD are aimed at slowing the progression to end-stage kidney disease (ESKD).

EPIDEMIOLOGY AND ETIOLOGY

The National Kidney Foundation (NKF) developed a classification system for CKD (Table 26-1).1 The staging system defines the stages of CKD based on GFR level, but also accounts for evidence of kidney damage in the absence of changes in GFR, as in stage 1 CKD. The GFR is calculated using the abbreviated Modification of Diet in Renal Disease study equation:

GFR = 186 x (SCr)-1194 x (age)-0 214 x (0.742 if female) x (1.21 if African American)

Based on the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006, the prevalence of CKD in the United States is 16%, corresponding to more than 31 million people. This number is increased from 12.8% reported with the previous NHANES report from 1988 to 1994, which is attributed to the increased prevalence of diabetes and hypertension, and the aging population.

Q CKD is a progressive disease that eventually leads to ESKD. The prevalence of ESKD has increased more than fivefold since 1980 to more than 500,000 people in 2006 with nearly 111,000 new cases of ESKD diagnosed in 2006. The prevalence of ESKD is related to ethnicity, affecting 3.6 times more African Americans and 1.8

times more Native Americans as Caucasians. Table 26-1 NKF-K/DOQI Classification for CKD

90° or higher"

60-39 30-59 15-29

Less than 15 (includes patients on dialysis)

GFR, glomerular filtration rate; NKF^K/DOQl, National Kidney Foundation-Dialysis Outcome Quality Initiative.

aCKD can be present with a normal or near normal GFR if other markers of kidney disease are present, such as proteinuria, hematuria, biopsy results showing kidney damage, or anatomic abnormalities (e.g., cysts).

This is likely because these ethnicities have increased risk and prevalence of the causes of CKD, including diabetes mellitus (DM) and hypertension, and other vascular diseases.1

Because of the progressive nature of CKD, determination of risk factors for CKD is difficult. Risk factors identified for CKD are classified into three categories (Table 26-2):

• Susceptibility factors, which are associated with an increased risk of developing CKD, but are not directly proven to cause CKD. These factors are generally not modifiable by pharmacologic therapy or lifestyle modifications.

• Initiation factors, which directly cause CKD. These factors are modifiable by pharmacologic therapy.

• Progression factors, which result in a faster decline in kidney function and cause worsening of CKD. These factors may also be modified by pharmacologic therapy or lifestyle modifications to slow the progression of CKD.

Susceptibility Factors

Susceptibility factors can be readily used to develop screening programs for CKD. For example, older patients, those with low kidney mass or birth weight, and those with a family history of kidney disease should be routinely screened for CKD. Minority and low socioeconomic communities may be targets for more widespread CKD screening programs. Other factors, such as hyperlipidemia, are not directly proven to cause CKD, but can be modified by drug therapies.

Hyperlipidemia

Patients with CKD have a higher prevalence of dyslipidemia compared to the general population. The dyslipidemia in CKD is manifested as an elevation in total cholesterol (TC) levels, low-density lipoprotein cholesterol (LDL-C) levels, triglycerides, and lipoprotein(a) levels, and decreases in high-density lipoprotein cholesterol (HDL-C) levels. The prevalence within the CKD population appears to be related somewhat to the degree of proteinuria. In nephrotic syndrome, with urine protein excretion rates that exceed 3 g/24 hour, almost all patients have some degree of dyslipidemia.4 Mounting evidence suggests that hyperlipidemia can promote kidney injury and subsequent progression of CKD. The mechanism is similar to that of atherosclerosis, whereby lipid deposition causes activation of macrophages and monocytes, which secrete growth factors that stimulate cell proliferation and oxidation of lipoproteins. These lead to endothelial dysfunction, cellular injury, and fibrosis in the kidney.5

Table 26-2 Risk Factors Associated With CKD

Susceptibility

• Reduced kidney mass

• Low birth weight

• Racial/ethnic minority

• Family history of kidney disease

• Low income or education

• Systemic inflammation

• Dyslipidemia Initiation

• Diabetes mellitus

• Hypertension

• Autoimmune disease

• Polycystic kidney disease

• Drug toxicity

• Urinary tract abnormalities (infections, obstruction, stones) Progression

• Hyperglycemia: Poor blood glucose control (in patients with diabetes)

• Hypertension: Elevated blood pressure

• Proteinuria

• Tobacco smoking

Initiation Factors

The three most common causes of CKD in the United States are DM, hypertension, and glomerulonephritis. Together these account for about 75% of the cases of CKD (37% for diabetes, 24% for hypertension, and 14% for glomerulonephritis).6 These are discussed in further detail below.

Diabetes

DM is the most common cause of CKD, causing 43% of all ESKD, which is increased from 13% in 1980.6 The risk of developing diabetic kidney disease (DKD) associated with DM is closely linked to hyperglycemia and is similar for both type 1 and type 2,

although it is slightly higher in patients with type 2 DM. An estimated 3% of patients with DM will develop ESKD, which is 12 times greater than those without DM.8

Hypertension

The second most common cause of CKD is hypertension.6 It is more difficult to determine the true risk of developing CKD in patients with hypertension because the two are so closely linked, with CKD also being a cause of hypertension. The prevalence of hypertension is correlated with the degree of kidney dysfunction (decreased GFR) with 40% of patients with CKD stage 1, 55% of patients with CKD stage 2, and over 75% of patients with CKD stage 3 presenting with hypertension.1 The risk of devel-

oping ESKD is linked to both systolic and diastolic blood pressure.9 A blood pressure greater than 210/120 mm Hg is associated with a 22% increased relative risk of developing ESKD, compared with a blood pressure less than 120/80 mm Hg.9

Glomerulonephritis

The etiologic and pathophysiologic features of glomerular diseases vary with the specific disease, making it difficult to extrapolate the risk for progression of CKD in patients affected by glomerular diseases. Certain glomerular diseases are known to rapidly progress to ESKD, while others progress more slowly or may be reversible.

Progression Factors

Progression factors can be used as predictors of CKD. The most important predictors of CKD include proteinuria, elevated blood pressure, hyperglycemia, and tobacco smoking.

Proteinuria

The presence of protein in the urine is a marker of glomerular and tubular dysfunction and is recognized as an independent risk factor for the progression of CKD. 0 Furthermore, the degree of proteinuria correlates with the risk for progression of CKD. An increase of 1 g of protein excretion per day is associated with a fivefold increase in the risk of progression of CKD, regardless of the cause of CKD.11 The mechanisms by which proteinuria potentiates CKD are discussed later. Microalbuminuria (greater than 30 mg albumin excreted per day) is also linked with vascular injury and increased cardiovascular mortality.

Elevated Blood Pressure

Systemic blood pressure correlates with glomerular pressure and elevations in both systemic blood pressure and glomerular pressure contribute to glomerular damage. The rate of GFR decline is related to elevated systolic blood pressure and mean arterial pressure. The decline in GFR is estimated to be 14 mL/min per year with a systolic blood pressure of 180 mm Hg. Conversely, the decline in GFR decreases to 2 mL/min

per year with a systolic blood pressure of 135 mm Hg. Elevated Blood Glucose

The reaction between glucose and protein in the blood produces advanced glycation end products (AGEs), which are metabolized in the proximal tubules. Hyperglycemia increases the synthesis of AGEs in patients with diabetes and the corresponding increase in metabolism is suspected to be a cause of DKD.14

Tobacco Smoking

Smoking is an independent risk factor for the development of microalbuminuria in primary hypertension. In patients with CKD, smoking is also an independent and dose-dependent risk factor for development of CKD and microalbuminuria, and progression to ESKD.15 The risk is more pronounced in men compared to women (odds ratio [OR] 3.59), independent of other risk factors.15 Smoking increases the risk for progression to ESKD in patients with CKD from any cause, and can increase the risk as much as 10-fold, compared to nonsmokers.15

The effects of smoking on the kidney are multifactorial and occur in both healthy individuals and those with CKD. Smoking induces intimal thickening and hyperplasia of the glomerulus, and raises systemic blood pressure.15 Similar effects were seen with chewing tobacco. These effects are related to the amount of nicotine exposure.15

PATHOPHYSIOLOGY

A number of factors can cause initial damage to the kidney. The resulting sequelae, however, follow a common pathway that promotes progression of CKD and results in irreversible damage leading to ESKD (Fig. 26-1).

The initial damage to the kidney can result from any of the initiation factors listed in Table 26-2. Regardless of the cause, however, the damage results in a decrease in the number of functioning nephrons. The remaining nephrons hypertrophy to increase glomerular filtration and tubular function, both reabsorption and secretion, in attempt to compensate for the loss of kidney function. Initially, these adaptive changes preserve many of the clinical parameters of kidney function, including creatinine and electrolyte excretion. However, as time progresses, angiotensin II is required to maintain the hyperfiltration state of the functioning nephrons. Angiotensin II is a potent vasoconstrictor of both the afferent and efferent arterioles, but has a preferential effect to constrict the efferent arteriole, thereby increasing the pressure in the glomerular capillaries. Increased glomerular capillary pressure expands the pores in the glomerular basement membrane, altering the size-selective barrier and allowing proteins to be filtered through the glomerulus.16

Protein excretion through the nephron, or proteinuria, increases nephron loss through various complex mechanisms. Filtered proteins are reabsorbed in the renal tubules, which activates the tubular cells to produce inflammatory and vasoactive cytokines and triggers complement activation. 6 These cytokines cause interstitial damage and scarring in the renal tubules, leading to damage and loss of more nephrons. Ultimately, the process leads to progressive loss of nephrons to the point where the number of remaining functioning nephrons is too small to maintain clinical stability, and kidney function declines.

ASSESSMENT

Because CKD often presents without symptoms, assessment for CKD relies on appropriate screening strategies in all patients with risk factors for developing CKD (Table 26-2). Evaluation for CKD and the subsequent treatment strategies are dependent on the diagnosis, comorbid conditions, severity and complications of disease, and risk factors for the progression of CKD. Early treatment of CKD and the associated complications of CKD are the most important factors to decrease morbidity and mortality associated with CKD. However, the probability of patients not diagnosed with CKD to have an assessment of serum creatinine (SCr) or urine protein excretion ranges from 0.01 to 0.04, depending on insurance coverage.17 Screening for CKD should be performed in all people with an increased risk for developing CKD, including patients with DM, hypertension, genitourinary abnormalities, autoimmune disease, increased age, or a family history of kidney disease. The assessment for CKD should include measurement of SCr, urinalysis, blood pressure, serum electrolytes, and/or imaging studies.

FIGURE 26-1. Proposed mechanisms for progression of kidney disease. (From Joy MS, Kshirsagar A, Franceschini N. Chronic kidney disease: Progression-modifying therapies. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 749, with permission.)

FIGURE 26-1. Proposed mechanisms for progression of kidney disease. (From Joy MS, Kshirsagar A, Franceschini N. Chronic kidney disease: Progression-modifying therapies. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 749, with permission.)

The primary marker of structural kidney damage is proteinuria, even in patients with normal GFR. Clinically significant proteinuria is defined as urinary protein excretion greater than 300 mg/day or greater than 20 mcg/min in a timed urine collection. Significant proteinuria can also be determined by a spot urine dipstick greater than 30 mg/dL or a urine protein/creatinine ratio greater than 200 mg/g.1 Microalbuminuria is defined as 30 to 300 mg of albumin excreted in the urine per day or a urine albumin/creatinine ratio greater than 30 mg/day.1 The NKF recommends routine assessment of proteinuria to detect CKD. A urine dipstick positive for the presence of protein warrants quantification of proteinuria. Patients with a urine protein/creatinine ratio greater than 200 mg/g or urine albumin/creatinine ratio greater than 30 mg/g should undergo diagnostic evaluation; patients with values below these levels should be reevaluated routinely.1 Assessment of microalbuminuria

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