Primary Care: Clinics in Office Practice 2008 pptx

dial-Table 1 National Kidney Foundation stages of chronic kidney disease Chronic kidney disease is defined as either kidney damage or GFR less than 60 mL per minute per 1.73 m2for greater

Accord-to the fact that patients with CKD will soon far outnumber trained ogists in the US.

nephrol-This dilemma can be solved only by a collaborative approach betweenprimary care providers and nephrologists

We, as nephrologists, are well aware that the primary care providers cupy a unique and vital role in this team approach (Table 1) Primary careproviders are at the forefront of this war against CKD They are in a posi-tion to be the first to identify and screen patients at risk for CKD, eg, thosewith diabetes, hypertension, etc They also are providers of long-term careand management of these patients

oc-Nephrologists and nephrology teams contribute to this collaborative cess by being involved in the earlier stages of CKD, perhaps at the time ofdiagnosis, and also by providing assessments of patientsÕ conditions andstrategic guides to overall management[1] An example of this is the admin-istration of erythropoietin, a proven and effective treatment strategy that isnot available in many primary care establishments[1] To be effective, how-ever, our ultimate goal, as primary care providers and nephrologists alike, is

pro-to be able pro-to educate and empower patients so that they will be able pro-to takecharge of their disease

0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc All rights reserved.

35 (2008) xi–xiii

As guest editor of two issues on ‘‘Kidney Diseases and Hypertension,’’

I feel privileged with a unique opportunity to contribute to this goal I havecarefully chosen the different topics that I feel are of great interest to ourcolleagues involved in primary care practice

The first issue deals with the typical topics faced by primary care viders, such as common fluid and electrolyte disorders, as well as acid-baseproblems These articles discuss the diseases with predominant involve-ment of renal pathophysiology, such as glomerular and tubulointerstitialdiseases, and common systemic diseases, such as diabetic nephropathy,systemic lupus erythematosus, congestive heart failure, etc The varioustreatment modalities and approaches are also rendered towards the end

pro-of each article

An article discussing the new classification of chronic kidney disease andthe various complications that may arise secondary to it is also included.The last two articles deal with common upper and lower urinary tract prob-lems, such as infections and stones

The second issue focuses on the various treatment strategies, namely nal replacement therapy or dialysis and renal transplantation Hypertension,

re-a common problem encountered in the outpre-atient setting re-and re-also the ond most common cause of CKD, is discussed in greater detail

sec-Over the past decades, with so many advances in technology, as shown byour new understanding of the various disease processes and pathophysiol-ogies, there has been a very noticeable increase in representation of the ge-riatric population in those afflicted by renal disease processes, the so-called

‘‘gerontologizing of nephrology.’’ I believe that a discussion on this newtrend is appropriate, and so it is presented in the last article

I would like to take this opportunity to thank my fellow authors who laborated with me on this project All of the authors were asked to give

col-a specific discussion relcol-ated to kidney disecol-ases col-and hypertension, whiletaking into consideration that our target audience would be the primary careproviders whom we collaborate with on a regular basis

I am hopeful that primary care providers will find the information vided in this text quite useful in their practice of daily medicine As medicine

pro-is ever-changing and developing, future studies will be publpro-ished that mayeither differ or provide updates to the recommendations presented herein

I encourage readers to stay updated with the medical literature and to use

it in their practices as they deliver healthcare

Edgar V Lerma, MD, FACP, FASN, FAHA

Section of NephrologyDepartment of MedicineUniversity of Illinois at Chicago

College of Medicine

820 S Wood StreetChicago, IL 60612-4325Associates in Nephrology, SC

210 South Desplaines Street

Chicago, IL 60661E-mail address: edgarvlermamd@pol.net

Reference

[1] Schoolwerth A The Scope of the cardio-CKD-anemia triad Taking control of chronic ney disease: beyond the kidney Presented at the ANNA Meeting Orlando, May 25, 2002.

kid-Treatment Options for End Stage

Renal Disease

Paul W Crawford, MD, FACPa,b,* ,

a

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

b

Evergreen Park Dialysis Unit, 9730 S Western Avenue, Suite 326,

Evergreen Park, IL 60805, USA

c Section of Nephrology, Department of Medicine, University of Illinois at Chicago College

of Medicine, 820 S Wood Street, Chicago, IL 60612-4325, USA

d Associates in Nephrology, SC, 210 South Desplaines Street, Chicago, IL 60661, USA

Currently, more than 480,000 United States citizens are receiving dialysis

[1] More than 314,000 are receiving hemodialysis, more than 25,000 are ceiving peritoneal dialysis, and another 143,000 have had transplants [1].Significantly, 16.8% of the population has chronic kidney disease (CKD)

re-[2] The latest National Health and Nutrition Study revealed an increasingincidence of kidney disease among aging baby boomers, as the incidence

of diabetes mellitus and hypertension rises Because of this trend, a greaterproportion of a primary care physician’s practice will involve patients withCKD, and consequently, end stage renal disease (ESRD) or CKD patientsreceiving dialysis[3]

Unfortunately, far too many of these CKD patients are referred to

a nephrologist very late More often than not, the opportunity for secondarypreventive intervention, with the goal of avoiding renal replacement ther-apy, is lost[4]

When should a patient with CKD be referred to a nephrologist?

The National Kidney Foundation Kidney Disease Outcomes Quality tiative (KDOQI) guidelines recommend a referral to a nephrologist whenthe glomerular filtration rate (GFR) is less than 30 mL per minute per1.73 m2[5] A more aggressive approach is to encourage referral when the

Ini-* Corresponding author Evergreen Park Dialysis Unit, 9730 S Western Ave., Suite 326, Evergreen Park, IL 60805.

E-mail address: pwcmd@yahoo.com (P.W Crawford).

0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc All rights reserved.

35 (2008) 407–432

GFR is less than 60 mL per minute per 1.73 m2 As a cautionary note, a sultation when the GFR is greater than 60 is warranted in the presence ofrapidly declining GFR with or without hematuria or proteinuria.

con-Late referral to the nephrologist is considered by most clinicians to be

‘‘when management pf patients with chronic kidney disease could have beensignificantly improved by earlier contact with the nephrology team,’’ and sur-prisingly, it is extremely common in the United States In most cases, it is whenone is referred within 3 months or less before start of dialysis therapy[6].With an early referral, the patient and family are given the advantage of par-ticipating in educational classes concerning CKD, as well as of receiving one-on-one counseling with a multidisciplinary kidney care team, including a nursepractitioner, physician, dietitian, and social worker These team interventions(informed selection of dialysis modality, timely placement of appropriate dial-ysis access, as well as preemptive transplant) are paramount in helping the pa-tient and family overcome many of the fears and myths associated withdialysis, as well as to arm them with skills needed to cope with the CKD, itscomplications, or ESRD diagnosis and treatment[7] Similarly, other benefitsassociated with early referral include nonemergent initiation of dialysis, lowermorbidity and improved rehabilitation, less frequent and shorter hospitalstays, lower cost, and improved survival[8] Moreover, many CKD patientsare able to remain stable (within the same CKD stage), or improve CKD stagewith aggressive intervention The National Kidney Foundation classifiesCKD stages into stages 1 through 5, as illustrated inTable 1

Unfortunately, many patients with ESRD have been threatened with ysis by primary care providers or family members Though well intentioned,the use of the threat of dialysis as a tool for motivating compliance with pre-scribed treatments and medications ultimately results in a patient who fearsthe treatment (dialysis) more than the disease (ESRD), with all the accompa-nying complications All too often, this leads to patients with CKD Stage 5 re-fusing renal replacement therapy for a prolonged time (more than a year insome cases) or even never consenting to this life-saving treatment

dial-Table 1

National Kidney Foundation stages of chronic kidney disease

Chronic kidney disease is defined as either kidney damage or GFR less than 60 mL per minute per 1.73 m2for greater than or equal to 3 months Kidney damage is defined as pathologic abnor- malities or markers of damage, including abnormalities in blood or urine tests or imaging studies From National Kidney Foundation KDOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification Am J Kidney Dis 2002;39(2 Suppl 1):S46; with permission.

It is ironic that, given our current armamentarium, our success in ing comorbidities associated with CKD Stage 5, such as anemia, hyperten-sion, metabolic acidosis, and secondary hyperparathyroidism withhyperphosphatemia leads our patients to question whether dialysis canimprove their quality of life With diligent management of these comorbid-ities, patients no longer need suffer from symptoms of fatigue, weakness,loss of mental alertness, lethargy, severe pruritus, recurrent chronic heartfailure, shortness of breath, and inability to perform activities of daily living(ADLs) Instead, they are able to work, walk miles on a treadmill, golf,bowl, swim, dance and perform all ADLs without difficulty, despite having

manag-a GFR of less thmanag-an 15 mL per minute

Indications for renal replacement therapy

ESRD is always a diagnosis of exclusion; it is only after all exams haveruled out all reversible causes for renal failure that a diagnosis of ESRDshould be made No assumptions can be made in the work-up A compre-hensive, meticulous work-up includes an extensive history and physical,laboratory exams, renal ultrasound, chest X-Ray, and CT scan and MRIwhen indicated Previous medical records must be reviewed

The National Kidney Foundation’s Kidney Disease Outcomes QualityInitiative guidelines define CKD as:

1 Kidney damage for greater than or equal to 3 months, as defined bystructural or functional abnormalities of the kidney, with or withoutdecreased GFR and manifest by either:

Pathologic abnormalities; or

Markers of kidney damage, including abnormalities in the tion of blood or urine, or abnormalities in imaging tests

composi-2 GFR less than 60 mL per minute per 1.73 m2for greater than or equal

to 3 months, with or without kidney damage (Table 2)[9]

Table 2

KDOQI criteria for initiation of renal replacement therapy

Criteria for initiation of renal replacement therapy

Patients with symptomatic severe left ventricular

dysfunction, symptomatic uremia, uncontrollable

hyperkalemia or metabolic acidosis

15–20 mL/min

According to KDOQI guidelines, hemodialysis is also indicated when theGFR has not yet decreased to or below 15 mL per minute per 1.73 m2, in thepresence of [9]:

Intractable extracellular fluid volume overload

Otherwise unexplained decline in functioning or wellbeing

Gastrointestinal dysfunction (eg, nausea, vomiting, diarrhea,gastroduodenitis)

Weight loss or other evidence of malnutrition

Hypertension

After the diagnosis of ESRD is determined, a decision concerning themost appropriate mode of renal replacement for the patient must bemade The various modes of dialysis must be very carefully discussed withpatients and families as a life saving treatment for those with ESRD who,without this opportunity to receive treatment, will die prematurely of uremiccomplications If the primary care provider is unable to dedicate the time forthis often very lengthy, emotional discussion, then it is best left to thenephrology team

Options for renal replacement therapy for ESRD

Kidney Transplantation

a Deceased donor

b Living donor

Peritoneal Dialysis

a Continuous ambulatory peritoneal dialysis (CAPD)

b Continuous cycler peritoneal dialysis (CCPD)

c Nocturnal intermittent peritoneal dialysis (NIPD)

iii Nocturnal home HD

iv Nocturnal in-center HD (not widely available)

b Daily home HD (day or nocturnal)

c Day or nocturnal 8–10 hour HD

Variations of the above referenced renal replacement therapies are beingattempted in an effort to improve outcomes, such as reduction of morbidity,mortality, and hospitalization days, in accordance with current ongoingdemonstration projects.

Goals of renal replacement therapy include:

Prolongation of life

Reversal of symptoms of uremia

Return the patient to their prior lifestyle/activities of daily livingMaintenance of a positive nitrogen balance and an adequate energyintake

Minimization of patient inconvenience

Maximization of quality of life

Selection of renal replacement therapy mode

The nephrologist has great influence over the patient’s selection of toneal versus hemodialysis The nephrologist’s preferences are greatlydependent upon their training, orientation, and practice location A signif-icant percentage of Nephrology Fellows come into practice with no priorexperience in peritoneal dialysis Subsequently, these nephrologists aremuch less likely influence a patient to choose peritoneal dialysis because

peri-of a lack peri-of confidence in their ability to successfully manage peritonealdialysis patients and staff

Lack of experienced and adequately trained staff can be, and often is,

a major deterrent to a nephrologist recommending CAPD, even whenthey believe this to be the best option for the patient Fear of insecure,inexperienced staff can also make an already apprehensive and fearfulnew ESRD patient even more anxious and reluctant to take on the respon-sibility of self-care (Table 3)

Table 3

Considerations when determining mode of renal replacement therapy

Access Desired: arteriovenous

(AV) fistula Alternate: catheter

Tenckhoff catheter; no

AV access

Tenckhoff catheter; no

AV access Frequency/duration 3 times per week/4 hrs

capacity

Not a factor Partner is

recommended

Partner is recommended

In 1946, Gordon Murray created a dialyzerda coil design on steel framedand used his invention on a patient in acute renal failure, performing the firstsuccessful dialysis in North America.

Many patients start dialysis with the perception that their kidneys aregoing to recover and that dialysis is ‘‘only temporary.’’ This is despite coun-seling to the contrary by multiple care providers that their kidney disease isirreversible and that they will need renal replacement therapy for the rest oftheir life Such denial is common in patients starting renal replacement ther-apy and is to be expected for the first 6 to 12 months of dialysis This is trueeven for the patient who has received early, in depth education about theneed for renal replacement therapy

Early identification of patients requiring AV access

Patients in CKD Stage 4 should have vein mapping with ultrasound Aftermapping has identified that the patient has adequate size vessels for the crea-tion of a native AV fistula, a surgical referral for creation of an AV fistulashould be made Only a native AV fistula should be placed The decision toplace any other form of access should be reviewed with the nephrologyteam, patient, and family Some surgeons believe an AV graft using artificialveins (PTFE) are also fistulas However, the nephrologists must not relegatethe decision of appropriate AV access placement to the vascular surgeon

The selection and order of preference for placement of AV fistula are

a wrist (radial-cephalic) primary AV fistula or and elbow (brachial-cephalic)primary AV fistula If unable to establish AV access with the preceedingmethods, then use an artificial vein graft of synthetic material or a trans-posed brachial-basilic vein fistula

Typical longevity of an AV fistula is 80% over a 3-year period as pared with 50% over 3 years for an AV-PTFE graft

com-Location of an AV graft should be determined by the anatomic size ofvessels, as shown by vein mapping, the surgeon’s skills, and the anticipatedduration of dialysis, as noted in the KDOQI guidelines After an AV fistula

is placed, a period of 4 to 16 weeks is required until adequate venousenlargement and thickening of vessel walls results in a fistula suitable forcannulation (Figs 1and2)

The implications, potential complications, and risks associated with eter placement must be weighed carefully to avoid increased morbidity andmortality Unfortunately, there are instances wherein the patient may re-quire hemodialysis on a rather emergent manner, such as in cases of acutepoinsonings or intoxications, acute renal failure with uremic signs andsymptoms at presentation, or in situations where the patient has not beenadequately prepared for hemodialysis, such that no AV access has beenplaced In these situations, the use of double lumen, noncuffed, nontun-neled, short (9 cm–13 cm) hemodialysis catheters have been the preferredmethod for vascular access Such catheters can be inserted into the jugular,subclavian, or femoral veins, via a modified Seldinger guidewire technique.Because they are noncuffed, they are considered temporary and they can beinserted at the bedside under sterile conditions Radiologic imaging guid-ance is not commonly required during their placements The subclavianroute is discouraged because of increased risk of subclavian stenosis andthrombosis For femorally inserted catheters, a length of 18 cm or less is rec-ommended to minimize recirculation

cath-Fig 1 Primary radiocephalic arteriovenous fistula A side-to-side anastomosis becomes a tional artery side-to-venous-end anastomosis by ligation of the distal venous limb close to the

func-AV anastomosis (L1) or more distally (L2) Abbreviations: A, radial artery; V, cephalic chial vein (From Feehally J, Johnson R Comprehensive Clinical Nephrology, 2nd Edition New York: Mosby, an imprint of Elsevier; 2003 p 930; with permission.)

antebra-Internal jugular catheters can be left in place for 2 to 3 weeks, while oral catheters should be removed after one use in ambulatory patients, or

fem-3 to 7 days in those who are bed-ridden The most common complicationsthat arise from such catheters are infections

At times, such temporary catheters have to be changed to the less genic, permanent, cuffed catheters that can be used for longer periods, such as

thrombo-up to 6 months For these purposes, the double lumen silastic/silicone, cuffedcatheters are used Because of their larger size, fluoroscopy is usually requiredfor placement The majority of such catheters are loss to bacteremia Throm-bosis, stenosis, and infection of the catheters are also common complications

In comparing AV fistulas or grafts to catheters, the latter usually require

an increase in hemodialysis duration of treatment by approximately 20% toachieve equivalent urea removal with the former[10] In fact, using ultra-sound dilution techniques, there is an estimated 20% to 30% decrease inblood flow (based on blood pump reading) when using a catheter asopposed to an AV access

Hemodialysis basics

The basic unit of an artificial kidney is a semipermeable membrane made

up of several thousand hollow fibers with a surface area of from 0.5 m2to

Fig 2 Arteriovenous polytetrafluoroethylene graft in the forearm (From Feehally J, Johnson R Comprehensive Clinical Nephrology, 2nd Edition New York: Mosby, an imprint of Elsevier;

2003 p 931; with permission.)

2.0 m2 Arranged in parallel, these fibers provide separation of the tient’s blood and dialysate fluid Blood from the patient circulates throughthe dialyser and is returned to the patient with the assistance of a pumpand tubing Dialysate makes just a single pass through the dialyzer(Fig 3A).

pa-There are several types of extracorporeal therapy: hemodialysis, tration, hemodiafiltration, and hemoperfusion For the purpose of manage-ment of chronic renal failure in the outpatient setting, this discussion will belimited to that of hemodialysis

hemofil-There are several variants of hemodialysis These include:

Conventional hemodialysis, which uses a conventional low flux (smallpore size) membrane The primary mechanism of solute removal isdiffusion

High efficiency hemodialysis, which uses a low flux membrane withhigher efficiency for removal of small solutes (eg, use a large surfacearea membrane)

High flux hemodialysis, which uses a high flux (large pore size) membranethat is more efficient in removing large solutes

Hemodialysis machines have several key components (Fig 3B), such as:Blood pumpddelivers blood to the artificial kidney at a constant rate ofapproximately 500 mL per minute

Monitorsdensures pressure inside blood circuit is not excessive.Detectordmonitors leakage of red blood cells from the blood circuitrycomponent into the dialysate compartment

Air detector/shut off devicedprevents air from entering the patient.Dialysate pumpddelivers dialysate to the artificial kidney

A proportioning systemdassures proper dilution of the dialysateconcentrate

Heaterdwarms the dialysate to approximately body temperature.Ultrafiltration controllerdprecisely regulates fluid removal

Conductivity monitordchecks dialysate ion concentrations (Fig 4).With all the above devices, the artificial kidney can safely and reliablyexchange water and solute in the physiologic ranges necessary to maintainchemical homeostasis as well as hemodynamic stability

Water transport and solute clearance

Ultrafiltration coefficients are used to measure effectiveness of watertransport across the dialysis membrane Ultrafiltration coefficients are usu-ally 2 mL to 5 mL per hour per mm Hg, with conventional membranes and

15 mL to 60 mL per hour per mm Hg with high flux membranes[11] Stablepatients may tolerate 5-L ultrafiltration or fluid removal over the 4-hourdialysis treatment, with close monitoring of vital signs

Mass transfer coefficient (Ko) and membrane surface area (A) determinesolute transport of dialysis membranes, expressed as mass transfer-areacoefficient KoAas molecular size increases and diffusive clearance of solutesdecreases Therefore, small molecules, such as urea, are readily cleared atrates much higher than normal glomerulus of the kidney However, 4 hours

of dialysis 3 times per week cannot replace 24 hours, 7 days-a-week of ance at the rate of 168 hours per week

clear-Dialysate composition

Dialysate sodium at or above plasma sodium prevents hemolysis fromabrupt decrease in plasma sodium Potassium often is kept low to decreaseplasma potassium Bicarbonate concentrate is usually high to correct acido-sis Today, acetate is seldom used in the United States because of problemswith transient hypoxemia, metabolic acidosis, intradialytic hypotension, andcardiac arrhythmia Calcium concentration in dialysate may vary depending

on individual needs of the patient Magnesium is usually low for ESRDpatients who tend to be hypermagnesemic For all patients, to avoid hypo-glycemia, the glucose in the bicarbonate bath is usually kept at 200 mg/dL

Complications of hemodialysis

Hemodialysis today is a relatively safe procedure; however, tions do occur

complica-Hypotension

The most common complication of hemodialysis is hypotension This can

be either intradialytic or after dialysis

Etiology of hypotension

Dialysis-related hypotension is attributed to changes in body volume.Both the amount of fluid removed and the rapidity of the removal fromthe intravascular space can affect the development of hypotension, as can

Fig 3A Diagram of a hemodialysis circuit Labels point to blood removed for cleansing, arterial pressure monitor, blood pump, heparin pump to prevent clotting, dialyzer, inflow pres- sure monitor, air detector clamp, venous pressure monitor, air trap and air detector, and clean blood returned to body (From the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Treatment Methods for Kidney Failure Hemodialysis (KU-152) Available

at http://kidney.niddk.nih.gov/kudiseases/pubs/choosingtreatment/index.htm ) Fig 3B Blood circuit for hemodialysis (a) The blood circuit (b) The pressure profile in the blood circuit with an arteriovenous fistula as the vascular access (From Feehally J, Johnson R Comprehen- sive Clinical Nephrology, 2nd Edition New York: Mosby, an imprint of Elsevier; 2003 p 955 with permission.)

=

changes in serum osmolality and sympathetic tone Patients taking oralantihypertensive medication before dialysis can experience intradialytichypotension In addition, patients eating while being dialyzed can experi-ence hypotension secondary to splanchnic pooling.

Management of intradialytic and post dialysis hypotension

Treatment of hypotension may include:

Normal saline infusion

Recumbency

Discontinuing ultrafiltration

Increasing dry weight

Decreasing the temperature of the dialysate

Fig 4 Design of a modern hollow-fiber dialyzer (From Feehally J, Johnson R Comprehensive Clinical Nephrology, 2nd Edition New York: Mosby, an imprint of Elsevier; 2003 p 953; with permission.)

Sodium modeling during hemodialysis

Isolated ultrafiltration

Withhold antihypertensive medications before dialysis

Midodrine, an oral selective a1-agonist has been used in some cases withsatisfactory results The use of salt-poor albumin has been shown not todemonstrate any advantage over normal saline infusion, and may actually

be more costly

Hypertension

Hypertension during or immediately after dialysis is another commoncomplication, and it is primarily volume-dependent in its etiology Thereare patients, with so-called ‘‘dialysis-resistant hypertension,’’ whose bloodpressures remain elevated despite adequate fluid removal Such patientstend to have underlying long-standing hypertension and often have excessiveinterdialytic weight gains They may have a hyperactive renin angiotensinsystem in response to fluid removal[12]

Use of erythropoietin has also been associated with a 20% to 30% dence of new onset of hypertension, or exacerbation

inci-Cardiac arrhythmia

Cardiac arrhythmias can occur in any patient, but are most often seen inpatients on multiple cardiac medications and when a low K bath is beingused The numbers of patients with cardiovascular disease and arrhythmiadeveloping ESRD are continuing to rise and warrant close attention[13]

Arrhythmia prevention

Preventive measures may entail use of bicarbonate dialysate with closemonitoring of the potassium and calcium levels in the patient’s serumand the dialysate The use of zero potassium dialysate is arrhymogenic initself and should not be used, especially if the patient is on maintenancedigoxin

Steal syndrome

Steal syndrome is commonly seen in patients with radiocephalic venous fistulas or grafts, where blood flow to the involved hand is divertedand diminished These patients should be evaluated for signs and symptoms

arterio-of ischemia, such as subjective coldness and paresthesia, objective reduction

in skin temperature, or intact sensory or motor functions Neurologicchanges and muscle wasting tend to occur in severe cases

Mild ischemia can be treated with analgesics or by wearing a glove Thosethat do not respond to conservative measures may require surgical interven-tion with banding or access correction or even ligation

Muscle cramps

Muscle cramps are common when a patient drops below their dry weight

or when they undergo ultrafiltration that is too rapid Peripheral arterialdisease (PAD) is common in kidney patients with CKD and can producemuscle cramps[14] As expected, they tend to occur toward the latter part

of the dialysis session, tending to involve the lower extremities, mostcommonly This is also the reason for a significant proportion of patientsdiscontinuing dialysis treatment session prematurely

Muscle cramp management

Large intradialytic weight gain can be avoided with fluid restrictions

of 1,000 cc to 1,500 cc plus urine volume per 24 hours, a task thatrequires extreme self-discipline for some patients whose thirst center isoveractive

In the past, quinine sulfate, given 2-hours before dialysis, was favored bymany physicians The United States Food and Drug Administration cur-rently regards quinine sulfate as both unsafe and ineffective for prevention

of muscle cramps Oxazepam has been used by some physicians with varyingrates of success The value of sodium modeling in relieving muscle crampshas been shown in at least one study[15]

Evaluation for PAD with Ankle Brachial Index (ABI) may indicate ence of PAD that requires further treatment and evaluation

pres-Restless leg syndrome

Patients usually complain of crawling sensations on both lower ties, which seem to occur during periods of inactivity (while the patient issleeping or seated) Sometimes it is perceived as pain Prompt relief is usu-ally obtained by moving the legs, hence, the term ‘‘restless legs.’’ Manypatients have difficulty sleeping and can have a poor quality of life Use

extremi-of certain antidepressants (eg, tricyclic antidepressants, selective serotoninreuptake inhibitors, and lithium) can exacerbate the symptom Restlessleg syndrome has to be differentiated from peripheral neuropathy, whichtends to be more constant and is not relieved by movement

Gabapentin has been shown to be effective and can also help with theinsomnia Recently, ropinirole, a dopamine agonist approved for use in Par-kinson’s disease, has shown to be a promising agent [16]

Disequilibrium syndrome

This syndrome may occur when too much fluid is removed over too short

a time period Disequilibrium syndrome may manifest as a range of toms, including headache, nausea, vomiting, altered mental status, seizure,coma, and death

symp-Disequilibrium syndrome management

Fortunately, disequilibrium syndrome is much less common in patientswho are referred to a nephrologist for timely initiation of dialysis Earlyreferral coupled with improved technology has made this syndrome muchrarer than in the past

Anaphylaxis

Anaphylactic reactions may manifest with burning or heat over the accesssite or throughout the body, chest or abdominal pain, difficulty breathing,hypotension or hypertension, fever, chills, pruritis, emesis, urticaria, flush-ing, and even cardiopulmonary arrest The typical onset of symptoms isusually within the first 5 minutes of initiating dialysis, although it may bedelayed by up to 20 minutes

Fortunately, improved technology has decreased the incidence andfrequency of anaphylactic reactions to the dialysis membrane Modernmembranes are much more biocompatible Using bicarbonate dialysisrather than acetate dialysis has also decreased the occurrence of anaphy-laxis Thorough rinsing of the dialyzer before use, helping to remove anynoxious materials or contaminants that became attached to the membraneduring manufacturing, has also reduced the occurrence of anaphylaxis.Eliminating the reuse of dialyzers prevents patient exposure to contami-nation of membranes by chemicals used during sterilization and repro-cessing and reduces the risk of anaphylaxis caused by sensitivity to thesechemicals

Postdialysis syndrome

An ill-defined, washed-out feeling or malaise during or after hemodialysis

is seen in approximately one third of patients[17] It has been attributed toseveral factors: decreased cardiac output, peripheral vascular disease,depression, deconditioning, electrolyte abnormalities, hypotension, andmyopathy, among others

Infectious complications

Patients with ESRD primarily die from cardiovascular events However,infections are the second most common cause of death[18,19] Temporarydialysis catheters are the source for most infections AV fistulas carry theleast risk of infection Staphylococcus aureus and Staphylococcus epidermidisare the bacterial culprits most frequently found Frequent infection control

in services and follow-up training to staff are required policy for all dialysisunits, whether hemodialysis or peritoneal dialysis units

Hepatitis B was prevalent in the 1970s Currently Hepatitis C is moreprevalent and increasing risk for liver failure and cirrhosis in ESRD

patients Unfortunately, the mode of transmission is not yet established.Screening for Hepatitis B is mandatory and patients presenting or develop-ing this condition require isolation.

Vaccination for Hepatitis B, Flu, and pneumonia are offered to ate patients Patients are considered candidates for the vaccines unless a spe-cific contraindication, such as established antibody levels for Hepatitis B, ispresent (Table 4)

appropri-Role of water treatment in hemodialysis complications

Water treatment is the most critical component of hemodialysis nately, it is also the most monitored, regulated, and precisely accurate seg-ment of dialysis Purification of water from municipalities is critical because

Fortu-of inherent levels Fortu-of contaminants, as well as hardness that varies fromlocation and water source Inadequate removal of calcium, aluminum, bac-teria, chloramine, and other water components that may be either naturallyoccurring or as a result of contamination can lead to deadly consequences.There is no room for error in proportioning systems whose function is tomaintain proper osmolality, electrolyte content, and pH balance Improper

Table 4

Vaccination table for patients with ESRD

Vaccine Recommended May use if otherwise indicated Contraindicated

temperature range can lead to hemolysis Air leak detectors ensure againstair embolism that can arise from a defective blood circuit.

Peritoneal dialysis

Peritoneal dialysis is the author’s first choice for renal replacement apy for a patient with ESRD if a kidney transplant is not possible or avail-able Peritoneal dialysis was initially used only to treat patients who were inacute kidney failure Typically used exclusively in intensive care units (ICU),

ther-a hther-ard plther-astic cther-atheter wther-as plther-aced into the peritonether-al cther-avity, ther-allowing theinfusion of peritoneal dialysis fluid The dialysis fluid was supplied in 2-literglass bottles The ICU nurse would perform exchanges every 1 to 2 hours,documenting hourly volume of intake and output, and calculating a positive

or negative fluid balance This was a very laborious task for nursing staff,often requiring a one-to-one patient-to-staff ratio (hardly available intoday’s nursing shortage era)

By the mid-1970s, continuous ambulatory peritoneal dialysis was duced Currently, more than 25,000 patients with ESRD are on peritonealdialysis

intro-Fundamentals of peritoneal dialysis

Peritoneal dialysis involves an exchange of solutes and fluids across theperitoneal membrane, which serves as the dialysis surface, via diffusionand convective transport regulate solute movement Urea, creatinine, andpotassium move into the peritoneal cavity dialysate across the peritonealmembrane, while bicarbonate and calcium move in the opposite direction.The concentration gradient between dialysate and blood facilitates smallmolecule movement Convection is also responsible for solute movementacross the peritoneal membrane Patients perform the exchanges at home

on a daily basis and have follow-up at the dialysis center or home therapycenter twice monthly Peritoneal dialysis patients are typically seen by thenephrologist once a month and by the staff twice a month for social, dietary,and financial needs Monthly laboratory work is required at a minimum;more frequent laboratory work may be required (Fig 5)

A high concentration of glucose in the peritoneal dialysis fluid is used assolute driving fluid removal, creating an osmotic gradient for ultrafiltration

of fluid, and providing a dwell time that is not prolonged Crucial to tive exchanges and fluid removal are peritoneal blood flow, dialysatevolume, and the integrity of the peritoneal membrane (Table 5)

effec-The peritoneal dialysis catheter is inserted by a surgeon or nephrologist

as an out-patient procedure Most catheters are double-cuffed, curled tipTenckhoff catheters Other types of catheters are available, but they areinfrequently used

Fig 5 Diagram of a patient receiving peritoneal dialysis Dialysis solution in a plastic bag drips through the catheter into the abdominal cavity CAPD is the most common form of peritoneal dialysis (From the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Kidney Failure: Choosing a Treatment That’s Right for You (KU-50) Available at: http:// kidney.niddk.nih.gov/kudiseases/pubs/choosingtreatment/index.htm )

Table 5

Peritoneal dialysate fluid composition

Peritoneal dialysate fluid composition

Continuous ambulatory peritoneal dialysis

CAPD uses 9 L to 10 L of peritoneal dialysis fluid per day, usually in 2-L

to 3-L bags Four to six exchanges are typically performed over a period of

24 hours The peritoneal dialysis fluid is infused into the peritoneal cavityvia catheter The fluid remains in the cavity for 4 to 6 hours, is then drainedout, removing water and solutes, including urea and creatinine The number

of exchanges and the volume of the peritoneal dialysis fluid bags are mined by patient size, peritoneal membrane permeability, and residual kid-ney function (Fig 6)

deter-Automated continuous cycling peritoneal dialysis

While the mechanism of dialysis is the same, patients on CCPD use

a cycler A cycler is a small bedside device that is programmed to setvolumes of infusion, dwell times and drain times After programming, thedevice automatically performs exchanges while the patient is either asleep

or resting Because the process is automated, the patient is able to rest out interruption, with the exception of an alarm that sounds as a result of

with-a problem detected by the cycler (Fig 7)

Fig 6 Flush-before-fill strategy used with Y transfer sets (A) A small volume of fresh dialysis solution is drained directly into the drainage container (either before or just after drainage of the abdomen) This washes away any bacteria that may have been introduced in the limb of the

Y leading to the new bag at the time of connection (B) Fresh solution is introduced through the rinsed connector (From NIH Publication No 01-4688, May 2001 Available at: http://www intelihealth.com/IH/ihtIH/WSIHW000/23,847/25,944/273,441.html?d¼dmtContent#works )

Benefits of self care using CAPD or CCPD

Residual renal function preservation

Better quality of life

Lower morbidity and mortality

Adequacy of peritoneal dialysis is measured through determination ofKT/V where K equals urea clearance, T equals per unit time, and V equalstotal body water The combination of creatinine clearance of peritoneumand residual renal function should reach a weekly KT/V of 2 Failure toachieve the guideline level of 2 may result in uremic symptoms, decreasedprotein intake, and increased mortality (Table 6)

Complications of peritoneal dialysis

Peritonitis is the most common complication of peritoneal dialysis Thiscomplication is usually discovered when the patient reports a cloudy drain-age bag A diagnosis of peritonitis is confirmed through a positive gramstain, cell count, and sensitivity culture, as well as signs and symptoms ofperitoneal inflammation Empiric treatment is started to treat gram-positive

or gram-negative organisms by instillation of intraperitoneal antibiotics

Objective criteria for rationing dialysis?

In the early days of dialysis in the United States, dialysis was only offered

at university teaching centers It was considered a high risk, experimental,but life saving procedure Dialysis was only offered to those with ESRDwho were accepted by the ‘‘God Committees’’ as eligible for dialysis Crite-ria were very limiting; for example, patients had to be under the age of

55 and could not be diabetic I will never forget having to inform a year-old father of two children that the committee voted he was not eligiblefor dialysis Never again do I wish to see a committee decide who may betreated and who is essentially given a death sentence Yet some 35 yearslater, this pendulum of death appears to be resurfacing in the medical

55-Fig 7 Example of a system used for cycler-assisted peritoneal dialysis Solution is heated fore use and weighed after use The last bag of solution may have a different concentration to last throughout the day (From NIH Publication No 01-4688, May 2001 Available at: http:// www.intelihealth.com/IH/ihtIH/WSIHW000/23,847/25,944/273,441.html?d¼dmtContent# works )

be-=

community, as use of medical resources based on costs is becoming moreprevalent.

The role of the medical field is to ‘‘do no harm.’’ To accomplish thishealth care providers must always weigh benefits against the risk for anyprocedure, including dialysis and transplant For patients who cannot main-tain adequate perfusion of vital organs secondary to hypotension resultingfrom hemodialysis, the risk of dialysis outweighs the benefits In a patientfor whom previous abdominal surgery has resulted in multiple adhesionsobstructing inflow and drainage of peritoneal dialysis fluid, or for thosewho develop sclerosing peritonitis, the risk of peritoneal dialysis outweighsthe benefits

Dialysis, even when benefits outweigh the risk, is contraindicated if thepatient cannot understand the procedure and give informed consent, and

do not have family or a guardian who can do so on their behalf Otherpatients perceive, even when the benefit is evident to the physician, thatthe procedure is torturous and not beneficial to them Those patients shouldnot be coerced to undergo dialysis, despite the ultimately grave outcome.The author is not a proponent of socialized medicine systems that refusedialysis to patients over a certain age, or that deny dialysis to patients withcertain diseases, or that block access to dialysis based on ability to pay fortreatment, or that refuse treatment based on race, gender or ethnic group.Ultimately, the decision of who should or should not receive dialysis must

be made by an informed, educated patient and family, in conjunction withthe medical care team that includes the nephrologist, primary care physi-cian, nurses, social workers, and spiritual leader

Kidney transplantation

Much literature has been published attesting to the survival benefits ofpatients who have undergone renal transplantation as compared with those

Table 6

Common laboratory parameters measured in patients receiving dialysis

on dialysis Comparisons on rates of mortality have been made betweenthose patients who are on the waiting list (for renal transplant) and thosewho are already transplant recipients From these studies, the question arose

of whether transplantation of these patients before initiation of dialysis emptive transplantation) would translate into significantly improvedoutcomes

(pre-Several studies published recently [20–23], show significantly improvedpatient and allograft survival in those with preemptive transplants asopposed to those who were on dialysis for a period of time before transplan-tation There have been lower rates of delayed graft function or acuterejection episodes (biopsy-confirmed) associated with preemptive transplan-tation Interestingly, preemptive transplant recipients have better socioeco-nomic and demographic features[24] that were also correlated with betteroutcomes Examples of these include younger age, white race, higher degree

Box 1 Initial evaluation of the potential renal transplant

recipient

Complete history and physical examination (includes detailedsurgical and psychosocial history)

Blood type, complete blood count, blood urea nitrogen,

creatinine, electrolytes, calcium, phosphorous, albumin, liverfunction tests, prothrombin time, and partial thromboplastintime

Serologic testing for HIV, cytomegalovirus, varicella virus, herpessimplex virus, Epstein Barr virus, hepatitis virus A, B, and C,rapid plasma reagin, and fluorescent treponemal antibodyUrinalysis and urine or bladder-wash culture

Purified protein derivitive

Chest X-ray and electrocardiogram

In men: testicular examination and, in those over the age of 50,measurement of prostate specific antigen and a digital rectalexamination

In women: breast examination and, in those over the age of 40,mammography The age for mammography should be

lowered to 35 if there is a history of breast cancer in the

premenopausal years in a first-degree relative

HLA antigen typing and a panel reactive antibody assay to detectfor previous sensitization

of education, and employment They also had fewer HLA antigenmismatches.

It is therefore reasonable to recommend possibly avoiding dialysis withearly preemptive transplantation in certain situations This should be con-sidered, especially in younger individuals with very minimal comorbidities,

if at all

The role of hemodialysis versus peritoneal dialysis as before-transplantdialysis modality in predicting outcomes remains controversial Studieshave also shown that successful renal transplantation significantly improvesquality of life and decreases the risk of mortality as compared with mainte-nance dialysis However, because of the donor organ shortage, there is anever increasing number of candidates waiting on the transplant list, andwait times are also increasing Some groups are trying to find ways to alle-viate this donor shortage, such as specialists in xenotransplantation, propo-nents of paired-exchange transplantation, as well as good Samaritan oraltruistic transplantation The Consensus Conference[25](United Networkfor Organ Sharing) currently recommends that adult candidates for renaltransplant should have progressive renal disease and a GFR less than

18 mL per minute for them to be placed on the cadaveric renal transplantwaiting list The evaluation of both potential renal transplant donor andrecipient tends to be tedious and exhaustive (Box 1)

Before a patient is accepted for renal transplantation, one has to take intoconsideration, certain contraindications (Box 2) Advanced age, history of

Box 2 Contraindications to renal transplantation

Proven habitual medical noncompliance

HIV infection (Although most centers exclude patients whoare HIV positive; in certain cases, those considered to havewell-controlled HIV infection are still eligible for solid

organ transplantation)

Absolute

Untreated current infection

Active malignancy with short life expectancy

Chronic illness with life expectancy of less than 1 year

Poorly controlled psychosis

Active substance abuse

previous transplantation, as well as underlying kidney disease diagnosis, arenot contraindications to renal transplantation Certain renal diseases, such

as focal segmental glomerulosclerosis and IgA nephropathy, have highrecurrence rates in the transplanted organ, yet are not considered ascontraindications

Unfortunately, there is still a large proportion of patients who arereferred for actual renal transplantation who are eventually excluded.Reasons for exclusion are varied, and include medical contraindication,patient decision, obesity, death, and insurance or financial reasons [26].The most common medical reasons were heart disease, malignancy, andnoncompliance

References

[1] U.S Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD); 2007 [2] Saydah S, Eberhardt M, Rios-Burrows, et al Prevalence of Chronic Kidney Disease and Associated Risk FactorsdUS 1999–2004 MWR 2007;56(8):161–5.

[3] Wetterhall SF, Olson DR, DeStefano F, et al Trends in diabetes and diabetic complications, 1980–1987 Diabetes Care 1992;15:960–7 [Abstract].

[4] Levin A Consequences of later referral on patient outcomes Nephrol Dial Transplant 2000; 15(Suppl 3):8–13.

[5] National Kidney Foundation K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification Part 4 Definition and Classification

of Stages of Chronic Kidney Disease Available at: http://www.kidney.org/Professionals/ Kdoqi/guidelines_ckd/p4_class_g2.htm Accessed July 22, 2008.

[6] Stevens LA, Levey AS Chronic kidney disease: staging and principles of management In: Greenberg A, editor Primer on kidney diseases 4th edition Philadelphia: National Kidney Foundation; 2005 p 461.

[7] Crawford PW Changing Trends in Referral Source of ESRD Patients in a Nephrology tice Between 1995 and 2005 [Abstract] Presented at the National Kidney Foundation 2006 Spring Clinical Meeting Chicago, April 19–23, 2006.

Prac-[8] Kausz AT, Pereira BJ Late referral to nephrologists of patients with chronic kidney disease In: Rose BD, editor UpToDate Wellesley (MA): UpToDate; 2008.

[9] National Kidney Foundation NKF K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations 2006 Updates Available at: http://www.kidney.org/ Professionals/kdoqi/guideline_upHD_PD_VA/hd_rec1.htm Accessed July 22, 2008 [10] Schwab SJ Acute hemodialysis vascular access In: Rose BD, editor UpToDate Waltham (MA): UpToDate; 2008.

[11] Cheung AK Hemodialysis and hemofiltration In: Greenberg A, editor Primer on kidney diseases 4th edition Philadelphia: National Kidney Foundation; 2005 p 467.

[12] Rahman M, Dixit A, Donley V, et al Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients Am J Kidney Dis 1999;33:498–506 [13] Keith DS, Nichols GA, Gullion CM, et al Longitudinal follow-up and outcomes among

a population with chronic kidney disease in a large managed care organization Arch Intern Med 2004;164:659–63.

[14] Jaar BG, Plantinga LC, Astor BC, et al Novel and traditional cardiovascular risk factors for peripheral arterial disease in incident-dialysis patients Adv Chronic Kidney Dis 2007;14:304–13 [15] Sandowski RH, Allred EN, Jabs K Sodium modeling ameliorates intradialytic and interdia- lytic symptoms in young hemodialysis patients J Am Soc Nephrol 1993;4:1192–8.

[16] Pellecchia MT, Vitale C, Sabatini M, et al Ropinirole as a treatment of restless legs drome in patients on chronic hemodialysis: an open randomized crossover trial versus levo- dopa sustained release Clin Neuropharmacol 2004;27:178–81.

syn-[17] Parfrey PS, Vavasour HM, Henry S, et al Clinical features and severity of nonspecific toms in dialysis patients Nephron 1998;50:121–8.

symp-[18] Bloembergen WE, Stannard DC, Port FK, et al Relationship of dose of hemodialysis and cause-specific mortality Kidney Int 1996;50:557–65 [Medline].

[19] US Renal Data System: USRDS 2000 Annual Data Report: Atlas of End-Stage Renal ease in the United States Bethesda, MD, National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2000.

Dis-[20] Kasiske BL, Snyder JJ, Matas AJ, et al Preemptive kidney transplantation: the advantaged and the disadvantaged J Am Soc Nephrol 2002;13:1358–64.

[21] Meier-Kriesche HU, Port FK, Ojo AO, et al Effect of waiting time on renal transplant come Kidney Int 2000;58:1311–7.

out-[22] Mange KC, Joffe MM, Feldman HI Effect of use or non-use of long-term dialysis on the subsequent survival of renal transplants from living donors N Engl J Med 2001;344:726–31 [23] Gill JS, Tonelli M, Johnson N, et al Why do preemptive kidney transplant recipients have an allograft survival advantage? Transplantation 2004;78:873–9.

[24] Butkus DE, Dottes AL, Meydrech EF, et al Effect of poverty and other socioeconomic ables on renal allograft survival Transplantation 2001;72:261–6.

vari-[25] Consensus conference on standardized listing criteria for renal transplant candidates plantation 1998;66:962–7.

Trans-[26] Holley JL, Monaghan J, Byer B, et al An examination of the renal transplant evaluation cess focusing on cost and the reasons for patient exclusion Am J Kidney Dis 1998;32(4): 567–74.

pro-Management of the Kidney

Transplant Recipient

Aparna Padiyar, MDa,b, Fadi H Akoum, MDa,b,

Donald E Hricik, MDa,b,*

a

Division of Nephrology, Department of Medicine, Case Western Reserve University,

Cleveland, OH, USA

b University Hospitals Case Medical Center, 11100 Euclid Avenue, Room 8124

Lakeside Building, Cleveland, OH 44106, USA

Recent trends in kidney transplantation

During the past two decades, remarkable strides have been made to crease the success of kidney transplantation and to prolong the lives of pa-tients with end-stage renal disease General advances in medical science,including improvements in surgical techniques and the development of effec-tive antimicrobial agents, undoubtedly have played a role in this successstory However, the current success of kidney transplantation has been re-lated more directly to an improved understanding of the immunobiology

in-of allograft rejection and the development in-of immunosuppressive drugs pable of preventing and treating rejection Today, the incidence of acute re-jection experienced during the first posttransplantation year is less than20%, and 1-year graft survival rate exceeds 90% at most centers As a con-sequence of improved graft and patient outcomes, kidney transplantationhas become the renal replacement therapy of choice for patients with end-stage renal disease, offering a survival advantage over dialysis irrespective

ca-of age, ethnicity, or underlying kidney disease[1]

Long-term graft and patient survival rates also have improved in recentyears, but as many as 30% of transplanted kidneys continue to fail within

5 years of transplantation Currently, the most common causes ofgraft loss after the first posttransplant year are: 1) ‘‘chronic allograft

This work was supported, in part, by funding from the Leonard Rosenberg Research Foundation.

* Corresponding author University Hospitals Case Medical Center, 11100 Euclid Avenue, Room 8124 Lakeside Building, Cleveland, OH 44106.

E-mail address: dhricik@aol.com (D.E Hricik).

0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc All rights reserved.

35 (2008) 433–450

nephropathy,’’ a common but poorly understood entity that likely has bothimmune and non-immune causes (see below); and 2) death with a function-ing graft It is possible that death with a functioning graft is related directly

to the toxicities of the very immunosuppressants that have yielded such pressive short-term outcomes The available maintenance drugs variablycontribute to the risks of cardiovascular disease, infection, and malignancy,which are the main causes of late mortality in transplant recipients[2,3] Inthe field of kidney transplantation, the focus of patient management hasshifted from short- to long-term management issues, including strategies

im-to reduce long-term exposure im-to im-toxic immunosuppressants This has come especially relevant with the advancing age of the kidney transplant re-cipient population

be-Although transplantation offers a survival advantage and improved ity of life for most patients with end-stage kidney disease, a continued dis-parity between the supply of allografts from deceased donors and thedemand for these organs by a growing population of transplantation candi-dates has led to a continued increase in the size of the waiting list and inwaiting times Death of patients on the kidney waiting list is becomingmore common[4] The net shortage of deceased donor kidneys has forcedthe transplantation community to extend the criteria for acceptable donors,including use of donors after cardiac death[5] The shortage of deceased do-nors has also fueled a recent increase in the use of living related and livingunrelated donors as well as related efforts to expand the living donor poolvia desensitization protocols, nondirected donations, and living donor ex-change programs

qual-Role of the primary care physician

As patients live longer with functioning allografts, the number of lent solid organ transplant recipients will continue to increase, making itlikely that a vast majority of primary care physicians ultimately will be ex-posed to recipients of kidney and other solid organ allografts The growingnumber of transplant recipients has resulted in a paradigm shift in attitudesregarding long-term patient management issues at many transplantationcenters In an earlier era, many centers were keen on providing both primaryand tertiary care to their relatively small populations of successful trans-plant recipients Growth in the volume of transplantation patients has notbeen paralleled by comparable growth in resources (professional personnel,space, administrative infrastructure) required to provide comprehensive care

preva-to all patients Both posttransplantation care and the regular re-evaluation

of patients on ever-growing waiting lists require more time and space thanever In addition, regulatory agencies are increasingly demanding medicalfollow-up of living kidney donors, posing even further demands for re-sources at transplantation centers

In this setting, the transplantation community increasingly will look toprimary care physicians to play a role in the long-term management of kid-ney transplant recipients and possibly in the long-term follow-up of livingkidney donors The primary care physician should be aware of commonmedical problems confronting kidney transplant recipients, have some rudi-mentary knowledge of immunosuppressive medications and their interac-tions with other drugs, and, most importantly, develop a good sense forwhen it is appropriate to refer a transplantation patient back to the trans-plantation center.

Common complications of kidney transplantation

Cardiovascular disease

Patients with end-stage renal disease (ESRD) experience rates of vascular morbidity and mortality 10 to 20 fold greater then that of thegeneral population Kidney transplantation clearly mollifies this risk Trans-plant recipients have repeatedly been shown to enjoy a persistent survivaladvantage compared with waitlisted ESRD patients, evident by 3 monthspost transplantation This survival advantage is in a large part due to a re-duction in cardiovascular risk accompanying the improved renal functionthat an allograft provides However, cardiovascular morbidity and mortal-ity still remain prevalent in the posttransplantation population, accountingfor 25% to 40% of patient deaths [6–8] The various causes of long-termmortality in kidney transplant recipients are shown inFig 1

cardio-Data from the United States Renal cardio-Data System (USRDS) estimate theincidence of cardiovascular disease in kidney transplant recipients to betwice that of the general population[7] Not surprisingly, a history of car-diovascular disease before transplantation is a major risk factor for post-transplantation cardiovascular morbidity Hypertension, hyperlipidemia,and diabetes are widespread in this patient population and contribute toposttransplantation cardiac risk Many transplant recipients have stage II

to III chronic kidney disease (CKD) (based upon the National Kidney

Foundation [NKF] classification schema), and CKD is a well-establishedrisk factor for cardiovascular disease Moreover, corticosteroids, calcineurininhibitors (CNIs), and target of rapamycin (TOR) inhibitors each have dis-tinctive side effects that individually play a role in cardiovascular risk.Traditional risk factors (age, smoking, blood pressure, gender, total andhigh density cholesterol as accounted for in the Framingham risk score) donot fully account for the accelerated rates of cardiovascular disease seen inkidney transplant recipients [6,7] Nontraditional factors such as level ofallograft function, proteinuria, abnormal calcium and phosphorus meta-bolism, hypertriglyceridemia, hyperhomocysteinemia, anemia, systemicinflammation and oxidative stress also play a significant role Weight-gainpost-transplantation, averaging about 3 kg in the first year, is commonand may contribute to cardiovascular risk Multiple episodes of acute rejec-tion have been associated with the development of post-transplantation car-diovascular disease, possibly reflecting inflammation associated with therejection episode or treatment with high doses of immunosuppressants.Immunosuppressive drugs can affect both traditional and nontraditionalrisk factors[6] Corticosteroids exert hypertensive and dyslipidemic effects,increase insulin resistance, and contribute to posttransplantation obesity.Adverse effects of CNIs (cyclosporine and tacrolimus) include hypertension,dyslipidemia, renal insufficiency and the development of new-onset diabetes.The TOR inhibitors cause of hyperlipidemia, proteinuria, anemia, and hy-perglycemia Although the effects of TOR inhibitors on homocysteine areunknown, these agents have been associated with increased levels of inflam-matory markers, including C-reactive protein.

Diabetes mellitus

New onset of diabetes mellitus (NODAT) is considered a serious adverseevent after transplantation and confers increased risks of cardiovascularmorbidity, impaired long-term graft function, and decreased patient survival

[6,9,10] In a patient population already at substantially high risk for vascular disease, pre-existing diabetes or NODAT increases the relative riskfor ischemic heart disease over 2.5 fold compared with non-diabetic trans-plant recipients According to USRDS data, NODAT is independently as-sociated with a 60% greater risk of graft loss and an almost 90% greatermortality Emerging evidence suggests that microvascular complicationssuch as neuropathy, nephropathy, and retinopathy are accelerated in pa-tients with NODAT, resulting in a significant increase not only in diseaseburden but also in health care cost

cardio-The incidence of NODAT increases continuously with time plantation, and recent data suggest that the absolute incidence has risenover the last decade [6,9,10], possibly reflecting the epidemic of obesity.The incidence can vary between 2% and 50% the first 3 years after trans-plantation, depending upon the population studied and how diabetes

posttrans-mellitus is defined Well-established non-modifiable risk factors include creased age, family history of diabetes mellitus, African American or His-panic ethnicity, and hepatitis C infection Lifestyle modification mayinfluence risk factors such as body weight and hyperlipidemia Commonlyused immunosuppressive agents also substantially contribute to the develop-ment of NODAT Corticosteroids are well known to cause peripheral insu-lin resistance CNIs, especially tacrolimus, have been associated withimpaired glucose metabolism, causing both decreased insulin productionand increased insulin resistance Newer data suggest that sirolimus, an agentoften used as an alternative to CNIs, is also diabetogenic, possibly causingapoptosis of beta cells.

in-Hypertension

Management of hypertension poses a challenge in the kidney transplantrecipient Considering that an elevation in either systolic or diastolic bloodpressure is an independent risk factor for allograft failure and increased mor-tality, it stands to reason that hypertension should be treated aggressively.However, almost 90% of transplant recipients are affected and up to onethird do not have optimal control[6] Surprisingly, there are no large, pro-spective, randomized controlled studies that demonstrate improved long-term outcomes by decreasing blood pressure in kidney transplant recipients.Likewise, the optimal target blood pressure for kidney transplant recipients isnot well defined The Kidney/Dialysis Outcomes Quality Initiative (K/DOQI) clinical practice guidelines, the European Best Practice Guideline(EBPG) and the American Society of Transplantation (AST) have recom-mended different targets for blood pressure control (K/DOQI targets130/80 mmHg; EBPG targets less than 130/85 mmHg in patients withoutproteinuria and less than 125/75 mmHg in proteinuric patients; AST targetsless than 140/90 mmHg.) Additionally, a number of studies indicate thathypertension is underdiagnosed by office blood pressure measurement inthis patient population, and that ambulatory blood pressure monitoringmay be a more sensitive tool The causes of posttransplantation hypertensionare diverse (Table 1)

In the general population, individuals who fail to exhibit the normal turnal decrease in blood pressure (ie, ‘‘nondippers’’) have been found to be

noc-at increased risk for left ventricular hypertrophy and adverse cardiovascularoutcomes Additionally, persistent non-dipping status may be associatedwith a faster rate in decline of GFR and increased proteinuria in patientswith CKD Immediately following kidney transplantation, nocturnal hyper-tension (‘‘nondipping’’) is common and associated with use of CNIs [11].Over the long term, the nocturnal blood pressure profile improves in a signif-icant number of patients (up to 30% in some series) The mechanisms bywhich CNIs blunt the normal nocturnal ‘‘dipping’’ status of blood pressureare unclear

Hyperlipidemia occurs in approximately 60% to 80% of kidney plant recipients and results from a multitude of factors [6] Both pretrans-plantation dyslipidemia and posttransplantation immunosuppressioncontribute Additionally obesity, hyperglycemia, insulin resistance, protein-uria, and treatment with beta-blockers or with diuretics all play a role.The mechanisms by which immunosuppressive agents cause dyslipidemiaare largely unknown Cyclosporine, and to a lesser extent tacrolimus, nega-tively impact the serum lipid profile The TOR inhibitor sirolimus is wellknown to cause profound elevations in total cholesterol, low-density lipo-protein (LDL) cholesterol, and triglycerides in a dose-dependent manner.However, despite an increase in Framingham risk score associated with ad-verse serum lipid profiles, cardiovascular event rates in patients taking siro-limus have been lower than expected [12,13] The reason for this apparentparadox is unclear, but it could be related to intrinsic anti-atherogenic prop-erties of the TOR inhibitors Corticosteroids inhibit lipoprotein lipase andenhance HMG CO-A and free fatty acid synthase, ultimately resulting inclinically apparent hyperlipidemia even at the small doses used for mainte-nance immunosuppression

trans-A number of small clinical trials and retrospective analyses have lated posttransplantation dyslipidemia with long-term allograft dysfunctionand loss, particularly among males Moreover, the Assessment of Lescol inRenal Transplantation Study (ALERT), the largest study of its kind, sug-gested some benefit to lowering cholesterol levels in kidney transplant recipients

corre-[14] ALERT was a multicenter, randomized, double blind, placebo-controlled

Chronic allograft nephropathy

Recurrent or de novo kidney disease

Ischemia reperfusion injury

Renal artery stenosis

In the native kidneys

In the transplanted kidney

Persistent parenchymal disease in native kidneys

Immunosuppressive medications

Corticosteroids

Increase renal sodium absorption

Volume expansion

Calcineurin inhibitors (cyclosporine O tacrolimus)

Renal arteriolar vasoconstriction

Sympathetic nervous stimulation

Increased renal sodium absorption

study of 2102 renal transplant recipients who were randomized to tin (n¼ 1050) or placebo (n ¼ 1052), and followed for 5 to 6 years Thestudy initially failed to show a statistically significant difference in the pri-mary composite endpoint (ie, occurrence of a major cardiac adverse event,namely cardiac death, nonfatal myocardial infarction, or coronary interven-tion) However, a trend toward a decreased incidence of myocardial infarc-tion and sudden death was observed in the fluvastatin group during the earlystudy period and persisted to achieve statistical significance in post hoc anal-yses[15].

fluvasta-The NKF K/DOQI clinical practice guidelines for posttransplantationhyperlipidemia are based largely upon the National Cholesterol EducationProgram (NCEP) III guidelines used in the general population NKF K/DOQI mandates evaluation for dyslipidemia in kidney transplant recipients

at baseline, 2 to 3 months after a change in treatment, and at least annuallythereafter Recommended targets are an LDL cholesterol of less then 100mg/dL, non-high density lipoprotein of less then 130 mg/dL, and triglycer-ide level of less then 150 mg/dL Interestingly, NCEP III advocates LDL re-duction to a goal less than 70 mg/dL in patients in the general population athigh cardiac risk It is unclear if such a strategy is warranted in kidney trans-plant recipients, who have event rates approximately twice that of the gen-eral population

Malignancy

As part of their role in preventing rejection, immunosuppressive agentsimpair the normal immune response Whether by directly damagingDNA, interfering with DNA repair mechanisms, or disturbing immunosur-veillance for neoplastic or virally infected cells, immunosuppression in partaccounts for the cancer risk seen in kidney transplant recipients Preexistentrisk factors, such as the ‘‘uremic milieu’’ of ESRD or treatment with dialysisalso may play a role It is therefore not surprising that the incidence of can-cer is greater in kidney transplant recipients than in the general population.The most common cancer posttransplantation is nonmelanoma skin can-cer, with an almost 20-fold increased incidence in kidney transplant recipi-ents as compared with the general population [15] The incidence ofcancers linked to viral infections are also increased after kidney transplanta-tion and include Epstein-Barr virus (EBV)-associated non-Hodgkin’s lym-phoma and human herpes virus 8-associated Kaposi’s sarcoma Whetherother cancers occur at increased rates is more controversial Recent largeregistry analyses in the United States, Canada, and Australia reveal an in-creased risk of several neoplasms after kidney transplantation, many withmore than a two to three fold increase compared with the general popula-tion[16–18] The majority of these cancers are of known or suspected viralorigin For example, human papilloma virus has been associated with can-cers of the tongue, mouth, vulva, vagina, and penis and may be an etiologic

agent in some cancers of the eye, lip, salivary gland, and esophagus titis B and C are linked to liver cancer.

Hepa-Not all immunosuppressive agents are the same in terms of cancer risk.Studies in animals demonstrate that the TOR inhibitors have antineoplasticproperties, including inhibition of cell-to-cell adhesions required for meta-static growth and inhibition of tumor angiogenesis mediated by vascular en-dothelial growth factor (VEGF)[19] Furthermore, preliminary studies seem

to indicate that patients receiving TOR inhibitor-based immunosuppressionexhibit lower rates of malignancy than patients receiving other regimens.Recent reports have described regression of cutaneous Kaposi’s sarcomawith conversion to sirolimus from a cyclosporine-based regimen

Whether it is cost effective to apply the same cancer screening guidelinesused in the general population to kidney transplant recipients remains un-clear In the absence of good data, most transplantation centers follow thoseguidelines to screen for common solid tumors Ironically, there are no read-ily available population-based screening guidelines for the most commoncancers occurring in transplant recipients (ie, skin cancer, lymphoma, Kapo-si’s sarcoma, and kidney cancer), and there is a great need to develop suchguidelines[20] Particular attention should be placed on patients at highestrisk, ie, patients positive for hepatitis B and C, EBV-negative recipients oforgans from EBV-positive donors, and recipients infected with human pap-illoma virus The benefits of antiviral therapies, including vaccinations, inpreventing cancer after kidney transplantation is largely unknown Like-wise, the potential antineoplastic benefits of the TOR inhibitors require fur-ther attention in prospective studies

Bone disease

Immunosuppression (particularly from corticosteroids) and secondaryhyperparathyroidism are often acknowledged as major causes of bone dis-ease posttransplantation However, the condition is much more complex,and comprises a spectrum of metabolic alterations of bone remodeling

[6,21,22] Preexisting uremic osteodystrophy, which encompasses some bination of hyperparathyroidism, adynamic bone disease, osteomalacia,mixed bone disease, B2 microglobulin-associated amyloidosis, and diabeticosteopathy, certainly contributes Other important underlying factors arepoor renal function; hypercalcemia; hyperphospaturia and hypophosphate-mia; and alterations of vitamin D metabolism

com-The main pathologic alterations in bone remodeling in the kidney plant recipient consist of decreased bone formation and mineralization inthe face of persistent resorption Osteoblast number is decreased while apo-ptosis of osteoblasts and osteocytes is increased New evidence implicatesthe growth factor, fibroblast growth factor-23 (FGF-23, or phosphatonin),

trans-in posttransplantation hypophosphatemia[22] FGF-23 induces ria, inhibits calcitriol synthesis, and accumulates in chronic kidney disease

phosphatu-The contribution of hypophosphatemia to apoptosis of osteoblasts isunclear.

Although cyclosporine has long been associated with loss of bone mineraldensity over time, the relative effect of tacrolimus has only recently been de-scribed Both agents have been linked to high bone turnover in animal stud-ies; however, their effect in humans is unclear as they are often used inconjunction with glucocorticoids Conversely, many studies in kidney trans-plant recipients have shown a correlation between glucocorticoid cumulativedose and bone mineral density Steroids increase osteoclastic resorption, de-crease osteoblastic activity, decrease intestinal calcium absorption, and in-crease renal calcium wasting (thereby stimulating parathyroid hormonesecretion) Localized osteonecrosis is a debilitating complication that can re-sult from chronic glucocorticoid use

Clinically, transplant recipients experience a rapid decline in bone eral density in the first 6 to 12 months posttransplantation, particularly inthe lumbar spine [6,21,22] The fracture rate of approximately 3% peryear post transplantation is higher than that seen in patients with CKDstage V who are on dialysis, and up to four times higher than the rate ob-served in the general population However, the decline in bone mineral den-sity as assessed by dual x-ray absorptiometry in the transplant recipient doesnot necessarily correlate with fracture rate

min-Treatment options remain limited[6,21] The K/DOQI and EBPG ommend serial bone mineral density measurement and close monitoring

rec-of serum calcium, phosphate, and PTH concentrations The optimal level

of parathyroid hormone in kidney transplant recipients is unknown wise, there is a paucity of data regarding the efficacy of bisphosphonatesand vitamin D analogs in the treatment of posttransplantation bone disease.Given the heterogeneity of the problem, and the concern for potential over-suppression of bone turnover with agents currently available, more studiesare needed that can evaluate reduction of fracture risk Therapy should beconsidered for those at high risk, such as those with severely low bone min-eral density, history of fractures, or biopsy-proven disease

Like-Chronic allograft nephropathy

Renal allograft failure is a common cause of ESRD and accounts for up

to 30% of patients on the waiting list for transplantation[6,23] The mostcommon cause of allograft failure after the first year post transplantation

is a poorly defined entity referred to as chronic allograft nephropathy(CAN) Histopathologically, CAN is characterized by arterial intimal fibro-sis, interstitial fibrosis, and tubular atrophy without evidence of any specificetiology Glomerular capillary walls thicken with an occasional double-con-tour appearance, termed ‘‘transplant glomerulopathy.’’ Although there are

no universally accepted diagnostic criteria, CAN is generally recognized

by slowly progressive renal allograft dysfunction after 3 months

posttransplantation in the absence of active rejection, acute drug toxicity, oranother disease Clinically, azotemia, proteinuria (occasionally in the ne-phrotic range), and worsening hypertension develop, which frequentlylead to loss of the allograft.

The pathogenesis of CAN is complex and multifactorial[6,23] Both mune and nonimmune mechanisms of injury are implicated Immune-medi-ated factors include HLA mismatch, prior sensitization, prior rejection, andchronic or subclinical rejection Hypertension, glomerular hyperfiltrationand hypertrophy, diabetes, hyperlipidemia, proteinuria, smoking, and obe-sity are important modifiable nonimmunologic etiologic factors Early graftdysfunction, ischemia/reperfusion injury, CMV infection, chronic hypoxia,oxidative stress, and chronic CNI toxicity also may play a role Donor fac-tors (age, living versus deceased source, genetic factors, donor/recipient sizemismatch, and comorbidities) can contribute as well

im-Greater than 90% of allografts demonstrate histologic changes consistentwith at least mild CAN at one year post transplantation[6,23] Disease se-verity (ie, the amount of interstitial fibrosis and tubular atrophy, the pres-ence of sclerotic glomeruli and vascular change) correlates with late graftfunction and failure There is no specific treatment for CAN Rather, non-specific treatment approaches include efforts to reduce urinary protein ex-cretion, control hypertension and dyslipidemia, and maintain adequateimmunosuppression Conversion from a CNI-containing regimen to theTOR inhibitor sirolimus is associated with an improvement in short-termrenal function, but adequately powered randomized trials are needed toascertain if this strategy leads to long-term benefit [24] Similarly, interest

in CNI-free or CNI-minimization regimens to prevent the development ofCAN is growing

Infectious diseases

Infections after kidney transplantation follow a specific temporal digm [25,26] The timetable for these infections can be roughly dividedinto three distinct periods (Fig 2) The first month after transplantation isdominated by postsurgical infections including: infection of the surgicalsite, bronchopneumonia, urinary tract infection, and catheter-related infec-tions The offending organisms are generally bacteria or yeast Common in-fections during this early period include: oropharyngeal candidiasis (thrush),bacterial and fungal urinary tract infections, intravenous catheter infections,and reactivation of mucosal herpes simplex virus (HSV) (oral, pharyngeal,genital) in seropositive patients Onset of hepatitis B or C infection occa-sionally may appear in a fulminant form during this early period

para-The second period (months 2–6) harbors the opportunistic infections ditionally associated with transplantation and immunosuppression [25,26].These include cytomegalovirus (CMV) infections ranging from a flu-likesyndrome with fever, chills, myalgias and leukopenia, to the most