The Chronic Kidney Disease Patient in the Acute Hospital Environment Laura Troidle CKD is common, affecting more than 10% of the adult US population. Hospital admissions are common among these patients and present challenges for their caregivers. In the acute hospital setting, there is often a lack of awareness of the CKD patient and the best practices developed to help this population. This can place the CKD patient at risk for medication errors such as incorrect dosage or administration of a potentially harmful or unhelpful medication. CKD patients may need procedures during a hospital stay that increase their risk of adverse events. Also, common admission practices such as placing intravenous access needs to be thoughtfully considered in this population. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: CKD, Hospital, Complications, Medications, Procedures, Morbidity
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KD is a common condition affecting greater than 10% of the US population. Adjusted admission rates for patients with CKD are significantly higher than for those without CKD. Stage 3, 4, and 5 CKD patients with a glomerular filtration rate (GFR) less than 60 mL/min have more hospitalizations than do CKD patients with higher GFRs. And the rate of death for these later stage CKD patients is higher than for those without CKD.1 Rehospitalization rates are highest for patients who are maintained on dialysis (34%) compared with the 24% CKD patients and 18% general medical patients who are rehospitalized. More recently, institutions now face financial penalties and/or may be censured for rehospitalization. Given the large percentage of patients with CKD and the increased risk of hospitalization, rehospitalization, and death and its economic impact on acute care institutions, it is important to identify potential risk factors CKD patients may confront on admission to an acute care hospital.
Provider Awareness CKD patients face potential hazards with each hospitalization. CKD is the stereotypical “elephant in the room” diagnosis. A greater knowledge about CKD patients needs to be shared among all acute hospital health care workers to lessen the risks of the nosocomial environment. Tuot and colleagues2 using the NHANES data after the National Kidney Foundation Disease Outcomes Quality Initiative (KDOQI) was established in 2002 gave a questionnaire to CKD patients asking if they were ever told by a health professional if they had failing kidneys. Only 7.4% of the patients reported awareness of having CKD. And when patients were aware of their CKD diagnosis, it did not translate into better blood pressure or glycemic control. Recently, Verhave and others3 noted that only 8% of patients with documented CKD were aware they had CKD. The unawareness is not limited to the patients. Agrawal and collegues,4 in 2008, conducted a survey of internal medicine residents and noted that half did not know that proteinuria greater than 3 months defined CKD. Onethird did not know the staging of CKD, nor that published guidelines for CKD exist. Approximately 90% of the residents chose a GFR less than 30 mL/min as the time to refer a patient to a nephrologist.
Similarly, primary care physicians need targeted education to increase awareness of CKD. Lea and others5 conducted a survey of community primary care physicians and found that they realized diabetes and hypertension were risk factors for CKD but not family history and African-American race. The lack of awareness presents an obstacle for any chance of published guidelines to benefit these patient cohorts. To address this, McBride and colleagues6 developed a CKD registry designed to promote guideline-specific care for patients with CKD by conducting interviews about CKD with medical directors of primary care clinics. The registry is new, but it is hoped it may improve management of CKD via published guidelines in a primary care setting. This perfect storm of CKD patients with significant comorbidities and risk for hospitalization creates an environment of particular concern for those caring for them. Medication errors, potentially harmful procedures, avoidance of possible preventative strategies, inattention to best practices, and poor outpatient follow-up are examples of adverse events that threaten the hospitalized CKD patient.
Medications and the Hospitalized CKD Patient Drug-associated complications are common among all hospitalized patients, and especially, those with CKD. Drug-associated nephropathy accounts for 18% to 27% of episodes of acute kidney injury (AKI) in the hospital.7 Many classes of medications, from antibiotics to antacids—from cardiac medications to chemotherapy agents and other therapeutics, are at the disposal of hospital staff to use in the treatment of the presenting illness. Patients with CKD are at increased risk for complications from these medications including AKI and hepatic toxicity, gastrointestinal illness, and neurologic sequela among many other complications. From Metabolism Associates, Yale New Haven Hospital, Avantus Renal Care, New Haven Home Dialysis, CT. Financial Disclosure: The author declares that there are no relevant financial interests. Address correspondence to Laura Troidle, PA, Metabolism Associates, 136 Sherman Avenue, New Haven, CT 06510. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.05.004
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Because a multitude of medications may pose a risk for CKD patients, it is critical that clinicians are aware of the patient's GFR and how the drug is metabolized and eliminated. Many medications that depend on clearance of the drug or its metabolites in the kidney require dose reductions. It is beyond the scope of this article to discuss all the available agents and their precautions; however, there are several common medications among hospitalized patients that need to be on the radar of the clinicians caring for CKD patients. These include medications that affect blood flow in the kidney and/or GFR (nonsteroidal antiinflammatory drugs [NSAIDS], angiotensin-converting enzyme inhibitors [ACE-I], and angiotensin receptor blockers [ARB]) medications that are toxic to the kidney (antibiotics, contrast), medications that have additional systemic toxicity (gadolinium, antibiotics, pain medications), and medications that have decreased efficacy in CKD (diuretics).
of aminoglycosides opens the door for both nephrotoxicity and vestibulotoxicity.8 Trimethoprim-sulfamethoxazole is another common antimicrobial agent that has been associated with life-threatening hyperkalemia and an elevation in serum creatinine level.9 Perazella monitored the charts of 105 patients given standard-dose trimethoprim-sulfamethoxazole and found that 62.5% of the patients developed a serum potassium greater than 5.0 mmol/L. Furthermore, patients with a serum creatinine more than 1.2 mg/dL had a significantly higher peak potassium than did patients with a lower serum creatinine. Although many clinicians may be unaware of best practice for the benefit of CKD patients, they most assuredly know about contrast-induced nephropathy (CIN) that has received a great deal of attention within the medical community. KDIGO has specific guidelines regarding CIN.10 There also exists an international Consensus Working Panel with published guidelines to help reduce the risk of its development.11 CIN occurs in about 10% of patients who receive intraveMedications Affecting Kidney Blood Flow or nous contrast in the outpatient setting and is associated with significant risk for AKI and death.12 Given these perGFR centages, the search for the Holy Grail to prevent CIN has NSAIDS are common, effective, and inexpensive pain reensued. The percentage of CIN is decreasing in the inlievers. However, NSAIDS interfere with kidney blood patient setting, from about flow. Under normal condi15% to approximately 7% in tions, when kidney blood CLINICAL SUMMARY 2008.13 flow is compromised, the There are several known renal medulla and cortex - CKD is a common disorder affecting greater than 10% of the risks for the development of synthesize prostaglandins US population and admissions to the acute care hospital are CIN with pre-existing CKD, to dilate the afferent arteriole frequent among these patients. especially secondary to diato bring about greater kidbetes mellitus.14 In 1 study, ney blood flow. Patients - Lack of awareness about the CKD patient contributes to greater than 50% of patients with CKD are more sensitive morbidity. with a creatinine greater to changes in kidney blood - Medications used and procedures performed during acute than 2.0 mg/dL had a rise in flow because of nephrosclehospital stay present possible threats for the CKD patient. creatinine after exposure to rosis and effects of the uncontrast.15 Other risk factors derlying kidney ailment. include congestive heart failThus, most nephrology cliniure, dehydration, increased dose of contrast, concurrent cians caution against the use of this class of medications for use of nephrotoxic agents, and multiple myeloma.16 patients with CKD. Contrast may be necessary for appropriate diagnosis of No one is going to deny the usefulness of ACEIs and an underlying disease state. For these patients, there are ARBs in patients with CKD. Most patients, especially steps that can be taken to limit the risk of the exposure. Volthose with proteinuria, are maintained on either medicaume expansion, rather than dehydration, is important tion, or both, for cardioprotective effects or to limit proteinbefore contrast exposure. Isotonic fluid—saline or bicaruria that is associated with CKD progression. Under a low bonate—is more effective than hypotonic fluid.17 blood flow state, as in dehydration or congestive heart failAchieving good urine output (.150 cm3/h) suggests ure, the efferent arteriole constricts to enhance kidney adequate hydration. blood flow. In addition, prostaglandins dilate the afferent There are many medications used to lessen the risk of arteriole, thus enhancing the GFR. Both ACEIs and ARBs CIN with N-acetylcysteine (NAC), the most common. disable the efferent arteriole's ability to vasoconstrict, Multiple conflicting reports exist about the benefit of and the GFR cannot be altered. Thus, the use of these medNAC from several meta-analyses.11 However, volume ications may need to be tabled until the underlying condiexpansion with sodium bicarbonate and NAC did tion impairing kidney blood flow improves. improve over the use of NAC alone.18 Additionally, ascorMedications With Kidney Toxicity bic acid, at a dose of 3 g orally the night before and 2 g Aminoglycosides and trimethoprim-sulfamethoxazole are orally twice a day after the contrast, has been shown to lessen the risk of CIN.19 particular antimicrobial agents that carry kidney toxicity. Aminoglycosides are broad-spectrum agents that are Medications With Other Toxicities powerful against gram-negative infection and are readily Some medications have no direct affect on kidney function available and cost effective, and a single dose may be life but may lead to the development of other serious side saving. It is worth mentioning, now, that continued use
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effects. Nephrogenic systemic fibrosis has been reported among stage 3 or greater CKD patients exposed to gadolinium-based contrast used during magnetic resonance imaging.20 The rare dermatologic disorder is characterized by deposition of collagen within skin, muscle, joints, and various organs.21 Gadolinium is suspected of causing the fibrotic disease based on its effect on fibroblast synthesis and excess production of hyaluronan and collagen.22 There exist many varieties of gadolinium, and although all promote fibroblast production, N-methylglucamine gadolinium and gadolinium trichlorite produce maximal fibroblast stimulation at lower concentration than other types of gadolinium. Nephrogenic systemic fibrosis can be associated with increased morbidity, pain, and death. Thus, gadoliniumbased contrast material is typically avoided among ESRD patients. If deemed necessary, most institutions have protocols aimed at rapidly eliminating the gadolinium from the patient by lengthy frequent HD. However, such avoidance of gadolinium and aggressive protocols may not be necessary for patients with CKD stages 1 and 2.23 Antimicrobial agents may also have systemic toxicity associated with their use among patients with CKD. Cephalosporin, carbapenem, penicillin, and quinolone use can lead to neurotoxic side effects including myoclonus, asterixis, seizures, and coma. Zhang and colleagues24 reviewed the records of both hemodialysis and peritoneal dialysis patients receiving these antibiotics and noted that older age, a history of a nervous system disorder, hypoalbuminemia, and use of multiple antibiotics were risk factors for the development of neurotoxicity and that inappropriate doses of antibiotics were used in all cases. Most of the symptoms improved after recognition of the side effect and prompt cessation of the antibiotic therapy. Medications used to relieve pain in patients with CKD are also implicated with systemic toxicities among patients with CKD. Gabapentin is a common, nonopioid analgesic recommended as a first step in the management of pain25 However, there are considerations for CKD patients. Zand and others26 looked at gabapentin levels based on the estimated GFR and found clinically toxic levels among patients with all degrees of reduced GFR and among patients with ESRD. Morphine is another common analgesic encountered by CKD patients admitted to an acute care hospital. However, data exist arguing against the use of morphine in patients with advanced CKD (stage 3 or greater).27 Morphine and its metabolites, morphine-6-glucuronide (M6G) and morphine-3-glucuromide, are each excreted by the kidney. However, the M6G metabolite accumulates in CKD and leads to CNS toxicity with CNS respiratory depression. Naloxone reversal of M6G-induced respiratory depression occurs significantly slower than reversal of the morphine effect on respiratory depression making morphine an unsafe opioid for CKD patients.28 Fentanyl, hydromorphone, and methadone do not have these effects in CKD patients and are preferred as alternative opioid analgesics for patients with CKD.25
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Medications With Reduced Efficacy in CKD Diuretics are frequently used during hospitalizations. Approximately 90% of patients admitted to a hospital with heart failure receive a loop diuretic during the hospital stay.29 Both underdosage and overdosage of these valuable heart failure therapies contribute greatly to prolonged hospital stay and morbidity. The National Kidney Foundation has specific guidelines regarding the use of diuretics in CKD.30 There are advantages of the different classes of diuretics based on GFR. Thiazide diuretics are not as effective as loop diuretics in patients with a GFR less than 30 cm3/min. Thus, it is important to recognize the CKD patient to efficiently use the best practice in diuretic management. Thiazide diuretics inhibit the Na1-Cl2 cotransport system of the distal tubule to decrease tubular Na1 reabsorption that, in turn, increases Na1 excretion and lessens extracellular fluid volume expansion and, thus, lowers systemic blood pressure. Thiazides may be useful for patients with a GFR greater than 30 cm3/min. Absorption is based on the thiazide used with metolazone generally preferred over other thiazide diuretics among patients with CKD. Loop diuretics inhibit the Na1-K1-2Cl2 cotransport system in the thick ascending limb of the loop of Henle to increase Na1 excretion and lower extracellular fluid volume.31 Loop diuretics are effective for all levels of CKD. Bumetanide and torsemide are almost completely absorbed, whereas furosemide absorption can be as low as 10%. It is equally important to know the outpatient diuretic dose history of the patient with CKD. CKD patients may be tolerant to lower doses of diuretics because of the distal tubule's response to hold on to extra Na1 that is lost from the loop diuretic. Adding a thiazide with the loop diuretic may overcome some of this tolerance. Others develop diuretic resistance because their inherent Na1 is too high or the patient has another reason for increased tubular absorption of Na1 such as that occurs in cirrhosis, nephrotic syndrome, or heart failure.
Medications and CKD Summary What can be done to curtail the use of inappropriate medications, whether it is nephrotoxic medications or erroneous dosing practices? Erler and colleagues32 estimated the GFR of 404 patients from 44 general medical centers in Germany and showed that in doing so, and involving the pharmacist, the percentage of patients receiving inappropriately high doses of medications was reduced. McCoy and others33 compared the use of a clinical pharmacist who used a Web-based surveillance tool to monitor orders vs the use of an automated surveillance tool and found an equal benefit for both arms.
Atheroemboli Any intervention involving atherosclerotic blood vessels opens the gate for an atheroembolic event, which poses a particularly significant threat for the CKD patient. The phenomenon is defined as a shower of small particles of cholesterol plaque that become loose either during an
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invasive procedure such as angiography or surgery or become spontaneously dislodged as that may occur in a patient on anticoagulant therapy. The cholesterol emboli then circulate before finally becoming lodged within the microvasculature. When the shower invades the microvasculature of the kidney, atheroembolic kidney disease is said to have occurred. Scolari and others34 tracked 354 episodes of atheroembolic kidney disease over a 2-year follow-up period. A total of 90% of the patients had evidence of cardiovascular disease, 60% were older than 70 years, and 83% of the patients had evidence of CKD. During the 2-year follow-up, 33% required dialysis and 29% died. The risk of dialysis and death dropped by 50% among patients receiving statins. Thus, it is important to thoughtfully consider the risk of atheroemboli as a complication when scheduling CKD patients, especially an elderly CKD patient with atherosclerotic disease, for an invasive procedure. Risk-benefit analysis of any procedure is particularly important. The addition of statin therapy may reduce the risk for CKD patients in which the procedure is absolutely necessary.
admitted to an acute care hospital. AKI complicates about 20% of all hospitalizations.40 Approximately 30% of patients with AKI have pre-existing CKD.41 Affected patients may return to their previous level of CKD after hospitalization, progress to a worsened stage of CKD or progress to ESRD. One such study noted that up to 15% of patients with CKD develop AKI progress to ESRD.42 Thus, it is critically important for the proper care of a CKD patient during a hospitalization.
Summary CKD patients represent 10% of the adult US Population. Admissions to an acute care hospital are common among these patients contributing to the morbidity and mortality CKD patients face. Properly identifying the CKD patient within the acute hospital setting is critical. Problembased learning examples for residents in training may be preferable to conference lectures. Then, using best practice guidelines and optimizing all hospital staff, including pharmacists and nutritionists, may lessen the risk these patients face.
Vein Preservation Venous access and phlebotomy are almost certain events for hospitalized patients and are not complication exempt. For patients with CKD, the complications may negatively affect future plans for dialysis access. Complications of venous access and phlebotomy include infection, phlebitis, venous stenosis, and thrombosis and can occur early after an intravenous catheter is placed.35 A native arteriovenous fistula (AVF) is the preferred form of vascular access for patients choosing HD as their kidney replacement modality.36 Other forms of vascular access, the arteriovenous graft, and the central venous catheter are each associated with higher morbidity and mortality and more hospitalizations.37 Patients starting HD with a catheter have a higher rate of mortality in the first 90 days of hemodialysis therapy than those starting with an AVF.38 It is important to maintain vein health by avoiding unnecessary vein use and to consider timely vascular access placement to avoid the central venous catheter or the peripherally inserted central catheter. Admissions to an acute care hospital increase with later stage CKD. The reality is that CKD patients are subject to frequent phlebotomy and intravenous catheters, including central venous catheters, at a time when veins need to be preserved. Or, a CKD patient may be prepared with an AVF only to risk the sphygmomanometer or a needle stick that threatens the function of the AVF. It is important for members of the patient care team, from the phlebotomists to the nurses to the residents and other clinicians, to recognize the CKD patient trying to preserve native veins. One such intervention, the “Medic Alert” bracelet, has been developed for CKD patients, who are in stage 3 or later, to wear.39 The bracelet identifies the extremity where the AVF is planned to be placed.
Acute Kidney Injury Among Patients With CKD It is critically important that all these risks and preventative strategies be taken into account for the CKD patient who is
References 1. US Renal Data System. USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2012. 2. Tuot DS, Plantinga LC, Hsu C, Powe N. Is awareness of chronic kidney disease associated with evidence-based guideline-concordant outcomes? Am J Nephrol. 2012;35:191-197. 3. Verhave JC, Troyanov S, Mongeau F, et al. Prevalence, awareness, and management of CKD and cardiovascular risk factors in publicly funded health care. Clin J Amer Soc Nephrol. 2014;9(4):713-719. 4. Agrawal V, Ghosh AK, Barnes AM, McCullogh PA. Awareness and knowledge of clinical practice guidelines for CKD among internal medicine residents: a national online survey. Am J Kid Dis. 2008;52:1061-1069. 5. Lea JP, McClellan WM, Meicher C, et al. CKD Risk Factors reported by Prim Care physicians: do Guidel make a difference?. 2006;47: 72-77. 6. McBride D, Dohan D, Hendley MA, Powe NR, Tuot DS. Developing a CKD registry in primary care: provider attitudes and input. Am J Kid Dis. 2013;63:577-583. 7. Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991;324:377-384. 8. Black FO, Pesznecker S, Stallings V. Permanent gentamicin vestibulotoxicity. Otol Neurotol. 2004;25:559-569. 9. Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med. 1996;124:316-320. 10. KDIGO 2012: clinical practice guidelines for the evaluation and management of chronic kidney disease. Kid Int Suppl. 2013;3:1-150. 11. Stacul F, Adam A, Becker CR, et al. Strategies to reduce the risk of contrast-induced nephropathy. Am J Cardiol. 2006;98:59K-77K. 12. Mitchell AM, Jones AE, Tumlin JA, Kline JA. Incidence of contrastinduced nephropathy after contrast-enhanced computed tomography in the out-patient setting. Clin J Am Soc Nephrol. 2009;5:4-9. 13. McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol. 2008;51:1419-1428. 14. Parfrey PS, Griffiths SM, Barrett BJ, et al. Contrast-material induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study. N Engl J Med. 1989;320:143-149.
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15. Thompson JR, Henrich WL. Nephrotoxic agents and their effects. In: Jacobson HR, Striker GE, Klahr S, eds. The Principles and Practice of Nephrology. St Louis, MO: Mosby; 1995:788-796. 16. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol. 2000;11:177-182. 17. 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 Intern Med. 2002;162:329-336. 18. Briguori C, Airoldi F, D’Andrea D, et al. Renal insufficiency following contrast media administration trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation. 2007;115:12111217. 19. Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation. 2004;110:2837-2842. 20. Introcaso CE, Hivnor C, Cowper S, Weith VP. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: a case series of nine patients and review of the literature. Int J Dermatol. 2007;46: 447-452. 21. Kuo PH, Kanal E, Abu-Alfa A, Cowper SE. Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology. 2007;242:647-649. 22. Penfield JG, Reilly RF. Nephrogenic systemic fibrosis risk: is there a difference between gadolinium-based contrast agents? Semin Dial. 2008;21:129-134. 23. Chrysochou C, Power A, Shurrab AE, et al. Low risk for nephrogenic systemic fibrosis in nondialysis patients who have chronic kidney disease and are investigated with gadolinium-enhanced magnetic resonance imaging. Clin J Am Soc Nephrol. 2010;5:484-489. 24. Zhang J, Huang C, Li H, et al. Antibiotic-induced neurotoxicity in dialysis patients: a retrospective study. Ren Fail. 2013;35:901-905. 25. Barakzoy AS, Moss AH. Efficacy of the World Health Organization analgesic ladder to treat pain in ESRD. J Amer Soc Nephrol. 2006;17:3198-3203. 26. Zand L, McKian KP, Qian Q. Gabapentin toxicity in patients with CKD: a preventable cause of morbidity. Am J Med. 2011;123:367-373. 27. Murtagh FE, Chai MO, Donohoe P, Edmonds PM, Higgins IJ. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother. 2007;21:5-16. 28. Olofsen E, vanDorp E, Teppema L, et al. Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory
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depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study. Anesthesiology. 2010;12: 1417-1427. Peacock WF, Costanzo MR, DeMarco T, et al. Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE registry. Cardiology. 2009;113:12-19. National Kidney Foundation. KDOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43:S1-S290. Brater DC. Update in diuretic therapy: clinical pharmacology. Semin Nephrol. 2011;31:483-494. Erler A, Beyer M, Petersen JJ, et al. How to improve drug dosing for patients with renal impairment in primary care-a cluster-randomized controlled trial. BMC Fam Pract. 2012;13:91-99. McCoy AB, Cox ZL, Neal EB, et al. Real-time pharmacy surveillance and clinical decision support to reduce adverse drug events in acute kidney injury. Appl Clin Inform. 2012;3:221-238. Scolari F, Ravani P, Gaggi R, et al. The challenge of diagnosing atheroembolic renal disease. Circulation. 2007;116:298-304. Xiang DZ, Verbeken EK, Van Lommel ATL, et al. Composition and formation of the sleeve enveloping a central venous catheter. J Vasc Surg. 1998;28:260-271. Besarab A, Brouwer D. Improving arteriovenous fistula construction: Fistula first initiative. Hemodial Int. 2004;8:199-206. Vassalotti JA, Jennings WC, Beathard GA, et al. Fistula first breakthrough initiative: targeting catheter last in fistula first. Semin Dial. 2012;25:303-310. Perl J, Wald R, McFarlane P, et al. Hemodialysis vascular access modifies the association between dialysis modality and survival. J Am Soc Nephrol. 2011;22:1113-1121. Vachharajani T. Medical alert bracelet: an effective way to preserve veins for future dialysis vascular access in patients with chronic kidney disease. Medscape J Med. 2009;11:1. Ali T, Khan I, Simpson W, et al. Incidence and outcomes in acute kidney injury: A comprehensive population-based study. J Am Soc Nephrol. 2007;18:1292-1298. Khosla N, Soroko SB, Chertow GM, et al. Program to Improve Care in Acute Renal Disease (PICARD). Preexisting chronic kidney disease: A potential for improved outcomes from acute kidney injury. Clin J Am Soc Nephrol. 2009;4:1914-1919. Lo LJ, Go AS, Chertow GM, et al. Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease. Kidney Int. 2009;76:893-899.
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KD is a common condition affecting greater than 10% of the US population. Adjusted admission rates for patients with CKD are significantly higher than for those without CKD. Stage 3, 4, and 5 CKD patients with a glomerular filtration rate (GFR) less than 60 mL/min have more hospitalizations than do CKD patients with higher GFRs. And the rate of death for these later stage CKD patients is higher than for those without CKD.1 Rehospitalization rates are highest for patients who are maintained on dialysis (34%) compared with the 24% CKD patients and 18% general medical patients who are rehospitalized. More recently, institutions now face financial penalties and/or may be censured for rehospitalization. Given the large percentage of patients with CKD and the increased risk of hospitalization, rehospitalization, and death and its economic impact on acute care institutions, it is important to identify potential risk factors CKD patients may confront on admission to an acute care hospital.
Provider Awareness CKD patients face potential hazards with each hospitalization. CKD is the stereotypical “elephant in the room” diagnosis. A greater knowledge about CKD patients needs to be shared among all acute hospital health care workers to lessen the risks of the nosocomial environment. Tuot and colleagues2 using the NHANES data after the National Kidney Foundation Disease Outcomes Quality Initiative (KDOQI) was established in 2002 gave a questionnaire to CKD patients asking if they were ever told by a health professional if they had failing kidneys. Only 7.4% of the patients reported awareness of having CKD. And when patients were aware of their CKD diagnosis, it did not translate into better blood pressure or glycemic control. Recently, Verhave and others3 noted that only 8% of patients with documented CKD were aware they had CKD. The unawareness is not limited to the patients. Agrawal and collegues,4 in 2008, conducted a survey of internal medicine residents and noted that half did not know that proteinuria greater than 3 months defined CKD. Onethird did not know the staging of CKD, nor that published guidelines for CKD exist. Approximately 90% of the residents chose a GFR less than 30 mL/min as the time to refer a patient to a nephrologist.
Similarly, primary care physicians need targeted education to increase awareness of CKD. Lea and others5 conducted a survey of community primary care physicians and found that they realized diabetes and hypertension were risk factors for CKD but not family history and African-American race. The lack of awareness presents an obstacle for any chance of published guidelines to benefit these patient cohorts. To address this, McBride and colleagues6 developed a CKD registry designed to promote guideline-specific care for patients with CKD by conducting interviews about CKD with medical directors of primary care clinics. The registry is new, but it is hoped it may improve management of CKD via published guidelines in a primary care setting. This perfect storm of CKD patients with significant comorbidities and risk for hospitalization creates an environment of particular concern for those caring for them. Medication errors, potentially harmful procedures, avoidance of possible preventative strategies, inattention to best practices, and poor outpatient follow-up are examples of adverse events that threaten the hospitalized CKD patient.
Medications and the Hospitalized CKD Patient Drug-associated complications are common among all hospitalized patients, and especially, those with CKD. Drug-associated nephropathy accounts for 18% to 27% of episodes of acute kidney injury (AKI) in the hospital.7 Many classes of medications, from antibiotics to antacids—from cardiac medications to chemotherapy agents and other therapeutics, are at the disposal of hospital staff to use in the treatment of the presenting illness. Patients with CKD are at increased risk for complications from these medications including AKI and hepatic toxicity, gastrointestinal illness, and neurologic sequela among many other complications. From Metabolism Associates, Yale New Haven Hospital, Avantus Renal Care, New Haven Home Dialysis, CT. Financial Disclosure: The author declares that there are no relevant financial interests. Address correspondence to Laura Troidle, PA, Metabolism Associates, 136 Sherman Avenue, New Haven, CT 06510. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.05.004
Advances in Chronic Kidney Disease, Vol 21, No 4 (July), 2014: pp 355-359
355
356
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Because a multitude of medications may pose a risk for CKD patients, it is critical that clinicians are aware of the patient's GFR and how the drug is metabolized and eliminated. Many medications that depend on clearance of the drug or its metabolites in the kidney require dose reductions. It is beyond the scope of this article to discuss all the available agents and their precautions; however, there are several common medications among hospitalized patients that need to be on the radar of the clinicians caring for CKD patients. These include medications that affect blood flow in the kidney and/or GFR (nonsteroidal antiinflammatory drugs [NSAIDS], angiotensin-converting enzyme inhibitors [ACE-I], and angiotensin receptor blockers [ARB]) medications that are toxic to the kidney (antibiotics, contrast), medications that have additional systemic toxicity (gadolinium, antibiotics, pain medications), and medications that have decreased efficacy in CKD (diuretics).
of aminoglycosides opens the door for both nephrotoxicity and vestibulotoxicity.8 Trimethoprim-sulfamethoxazole is another common antimicrobial agent that has been associated with life-threatening hyperkalemia and an elevation in serum creatinine level.9 Perazella monitored the charts of 105 patients given standard-dose trimethoprim-sulfamethoxazole and found that 62.5% of the patients developed a serum potassium greater than 5.0 mmol/L. Furthermore, patients with a serum creatinine more than 1.2 mg/dL had a significantly higher peak potassium than did patients with a lower serum creatinine. Although many clinicians may be unaware of best practice for the benefit of CKD patients, they most assuredly know about contrast-induced nephropathy (CIN) that has received a great deal of attention within the medical community. KDIGO has specific guidelines regarding CIN.10 There also exists an international Consensus Working Panel with published guidelines to help reduce the risk of its development.11 CIN occurs in about 10% of patients who receive intraveMedications Affecting Kidney Blood Flow or nous contrast in the outpatient setting and is associated with significant risk for AKI and death.12 Given these perGFR centages, the search for the Holy Grail to prevent CIN has NSAIDS are common, effective, and inexpensive pain reensued. The percentage of CIN is decreasing in the inlievers. However, NSAIDS interfere with kidney blood patient setting, from about flow. Under normal condi15% to approximately 7% in tions, when kidney blood CLINICAL SUMMARY 2008.13 flow is compromised, the There are several known renal medulla and cortex - CKD is a common disorder affecting greater than 10% of the risks for the development of synthesize prostaglandins US population and admissions to the acute care hospital are CIN with pre-existing CKD, to dilate the afferent arteriole frequent among these patients. especially secondary to diato bring about greater kidbetes mellitus.14 In 1 study, ney blood flow. Patients - Lack of awareness about the CKD patient contributes to greater than 50% of patients with CKD are more sensitive morbidity. with a creatinine greater to changes in kidney blood - Medications used and procedures performed during acute than 2.0 mg/dL had a rise in flow because of nephrosclehospital stay present possible threats for the CKD patient. creatinine after exposure to rosis and effects of the uncontrast.15 Other risk factors derlying kidney ailment. include congestive heart failThus, most nephrology cliniure, dehydration, increased dose of contrast, concurrent cians caution against the use of this class of medications for use of nephrotoxic agents, and multiple myeloma.16 patients with CKD. Contrast may be necessary for appropriate diagnosis of No one is going to deny the usefulness of ACEIs and an underlying disease state. For these patients, there are ARBs in patients with CKD. Most patients, especially steps that can be taken to limit the risk of the exposure. Volthose with proteinuria, are maintained on either medicaume expansion, rather than dehydration, is important tion, or both, for cardioprotective effects or to limit proteinbefore contrast exposure. Isotonic fluid—saline or bicaruria that is associated with CKD progression. Under a low bonate—is more effective than hypotonic fluid.17 blood flow state, as in dehydration or congestive heart failAchieving good urine output (.150 cm3/h) suggests ure, the efferent arteriole constricts to enhance kidney adequate hydration. blood flow. In addition, prostaglandins dilate the afferent There are many medications used to lessen the risk of arteriole, thus enhancing the GFR. Both ACEIs and ARBs CIN with N-acetylcysteine (NAC), the most common. disable the efferent arteriole's ability to vasoconstrict, Multiple conflicting reports exist about the benefit of and the GFR cannot be altered. Thus, the use of these medNAC from several meta-analyses.11 However, volume ications may need to be tabled until the underlying condiexpansion with sodium bicarbonate and NAC did tion impairing kidney blood flow improves. improve over the use of NAC alone.18 Additionally, ascorMedications With Kidney Toxicity bic acid, at a dose of 3 g orally the night before and 2 g Aminoglycosides and trimethoprim-sulfamethoxazole are orally twice a day after the contrast, has been shown to lessen the risk of CIN.19 particular antimicrobial agents that carry kidney toxicity. Aminoglycosides are broad-spectrum agents that are Medications With Other Toxicities powerful against gram-negative infection and are readily Some medications have no direct affect on kidney function available and cost effective, and a single dose may be life but may lead to the development of other serious side saving. It is worth mentioning, now, that continued use
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effects. Nephrogenic systemic fibrosis has been reported among stage 3 or greater CKD patients exposed to gadolinium-based contrast used during magnetic resonance imaging.20 The rare dermatologic disorder is characterized by deposition of collagen within skin, muscle, joints, and various organs.21 Gadolinium is suspected of causing the fibrotic disease based on its effect on fibroblast synthesis and excess production of hyaluronan and collagen.22 There exist many varieties of gadolinium, and although all promote fibroblast production, N-methylglucamine gadolinium and gadolinium trichlorite produce maximal fibroblast stimulation at lower concentration than other types of gadolinium. Nephrogenic systemic fibrosis can be associated with increased morbidity, pain, and death. Thus, gadoliniumbased contrast material is typically avoided among ESRD patients. If deemed necessary, most institutions have protocols aimed at rapidly eliminating the gadolinium from the patient by lengthy frequent HD. However, such avoidance of gadolinium and aggressive protocols may not be necessary for patients with CKD stages 1 and 2.23 Antimicrobial agents may also have systemic toxicity associated with their use among patients with CKD. Cephalosporin, carbapenem, penicillin, and quinolone use can lead to neurotoxic side effects including myoclonus, asterixis, seizures, and coma. Zhang and colleagues24 reviewed the records of both hemodialysis and peritoneal dialysis patients receiving these antibiotics and noted that older age, a history of a nervous system disorder, hypoalbuminemia, and use of multiple antibiotics were risk factors for the development of neurotoxicity and that inappropriate doses of antibiotics were used in all cases. Most of the symptoms improved after recognition of the side effect and prompt cessation of the antibiotic therapy. Medications used to relieve pain in patients with CKD are also implicated with systemic toxicities among patients with CKD. Gabapentin is a common, nonopioid analgesic recommended as a first step in the management of pain25 However, there are considerations for CKD patients. Zand and others26 looked at gabapentin levels based on the estimated GFR and found clinically toxic levels among patients with all degrees of reduced GFR and among patients with ESRD. Morphine is another common analgesic encountered by CKD patients admitted to an acute care hospital. However, data exist arguing against the use of morphine in patients with advanced CKD (stage 3 or greater).27 Morphine and its metabolites, morphine-6-glucuronide (M6G) and morphine-3-glucuromide, are each excreted by the kidney. However, the M6G metabolite accumulates in CKD and leads to CNS toxicity with CNS respiratory depression. Naloxone reversal of M6G-induced respiratory depression occurs significantly slower than reversal of the morphine effect on respiratory depression making morphine an unsafe opioid for CKD patients.28 Fentanyl, hydromorphone, and methadone do not have these effects in CKD patients and are preferred as alternative opioid analgesics for patients with CKD.25
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Medications With Reduced Efficacy in CKD Diuretics are frequently used during hospitalizations. Approximately 90% of patients admitted to a hospital with heart failure receive a loop diuretic during the hospital stay.29 Both underdosage and overdosage of these valuable heart failure therapies contribute greatly to prolonged hospital stay and morbidity. The National Kidney Foundation has specific guidelines regarding the use of diuretics in CKD.30 There are advantages of the different classes of diuretics based on GFR. Thiazide diuretics are not as effective as loop diuretics in patients with a GFR less than 30 cm3/min. Thus, it is important to recognize the CKD patient to efficiently use the best practice in diuretic management. Thiazide diuretics inhibit the Na1-Cl2 cotransport system of the distal tubule to decrease tubular Na1 reabsorption that, in turn, increases Na1 excretion and lessens extracellular fluid volume expansion and, thus, lowers systemic blood pressure. Thiazides may be useful for patients with a GFR greater than 30 cm3/min. Absorption is based on the thiazide used with metolazone generally preferred over other thiazide diuretics among patients with CKD. Loop diuretics inhibit the Na1-K1-2Cl2 cotransport system in the thick ascending limb of the loop of Henle to increase Na1 excretion and lower extracellular fluid volume.31 Loop diuretics are effective for all levels of CKD. Bumetanide and torsemide are almost completely absorbed, whereas furosemide absorption can be as low as 10%. It is equally important to know the outpatient diuretic dose history of the patient with CKD. CKD patients may be tolerant to lower doses of diuretics because of the distal tubule's response to hold on to extra Na1 that is lost from the loop diuretic. Adding a thiazide with the loop diuretic may overcome some of this tolerance. Others develop diuretic resistance because their inherent Na1 is too high or the patient has another reason for increased tubular absorption of Na1 such as that occurs in cirrhosis, nephrotic syndrome, or heart failure.
Medications and CKD Summary What can be done to curtail the use of inappropriate medications, whether it is nephrotoxic medications or erroneous dosing practices? Erler and colleagues32 estimated the GFR of 404 patients from 44 general medical centers in Germany and showed that in doing so, and involving the pharmacist, the percentage of patients receiving inappropriately high doses of medications was reduced. McCoy and others33 compared the use of a clinical pharmacist who used a Web-based surveillance tool to monitor orders vs the use of an automated surveillance tool and found an equal benefit for both arms.
Atheroemboli Any intervention involving atherosclerotic blood vessels opens the gate for an atheroembolic event, which poses a particularly significant threat for the CKD patient. The phenomenon is defined as a shower of small particles of cholesterol plaque that become loose either during an
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invasive procedure such as angiography or surgery or become spontaneously dislodged as that may occur in a patient on anticoagulant therapy. The cholesterol emboli then circulate before finally becoming lodged within the microvasculature. When the shower invades the microvasculature of the kidney, atheroembolic kidney disease is said to have occurred. Scolari and others34 tracked 354 episodes of atheroembolic kidney disease over a 2-year follow-up period. A total of 90% of the patients had evidence of cardiovascular disease, 60% were older than 70 years, and 83% of the patients had evidence of CKD. During the 2-year follow-up, 33% required dialysis and 29% died. The risk of dialysis and death dropped by 50% among patients receiving statins. Thus, it is important to thoughtfully consider the risk of atheroemboli as a complication when scheduling CKD patients, especially an elderly CKD patient with atherosclerotic disease, for an invasive procedure. Risk-benefit analysis of any procedure is particularly important. The addition of statin therapy may reduce the risk for CKD patients in which the procedure is absolutely necessary.
admitted to an acute care hospital. AKI complicates about 20% of all hospitalizations.40 Approximately 30% of patients with AKI have pre-existing CKD.41 Affected patients may return to their previous level of CKD after hospitalization, progress to a worsened stage of CKD or progress to ESRD. One such study noted that up to 15% of patients with CKD develop AKI progress to ESRD.42 Thus, it is critically important for the proper care of a CKD patient during a hospitalization.
Summary CKD patients represent 10% of the adult US Population. Admissions to an acute care hospital are common among these patients contributing to the morbidity and mortality CKD patients face. Properly identifying the CKD patient within the acute hospital setting is critical. Problembased learning examples for residents in training may be preferable to conference lectures. Then, using best practice guidelines and optimizing all hospital staff, including pharmacists and nutritionists, may lessen the risk these patients face.
Vein Preservation Venous access and phlebotomy are almost certain events for hospitalized patients and are not complication exempt. For patients with CKD, the complications may negatively affect future plans for dialysis access. Complications of venous access and phlebotomy include infection, phlebitis, venous stenosis, and thrombosis and can occur early after an intravenous catheter is placed.35 A native arteriovenous fistula (AVF) is the preferred form of vascular access for patients choosing HD as their kidney replacement modality.36 Other forms of vascular access, the arteriovenous graft, and the central venous catheter are each associated with higher morbidity and mortality and more hospitalizations.37 Patients starting HD with a catheter have a higher rate of mortality in the first 90 days of hemodialysis therapy than those starting with an AVF.38 It is important to maintain vein health by avoiding unnecessary vein use and to consider timely vascular access placement to avoid the central venous catheter or the peripherally inserted central catheter. Admissions to an acute care hospital increase with later stage CKD. The reality is that CKD patients are subject to frequent phlebotomy and intravenous catheters, including central venous catheters, at a time when veins need to be preserved. Or, a CKD patient may be prepared with an AVF only to risk the sphygmomanometer or a needle stick that threatens the function of the AVF. It is important for members of the patient care team, from the phlebotomists to the nurses to the residents and other clinicians, to recognize the CKD patient trying to preserve native veins. One such intervention, the “Medic Alert” bracelet, has been developed for CKD patients, who are in stage 3 or later, to wear.39 The bracelet identifies the extremity where the AVF is planned to be placed.
Acute Kidney Injury Among Patients With CKD It is critically important that all these risks and preventative strategies be taken into account for the CKD patient who is
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