Methods of assessing small solute removal on PD Dialytic Kt/V urea Since urea clearance is the basis of assessment of HD ade- quacy, there was interest in providing a comparable meas - urement for PD. In HD urea clearance is expressed as the Kt/V for urea per dialysis sessi on. For PD, urea clearance is also expressed as Kt/V, but with values quoted as Kt/V per we ek. Kt is the clearance of solute removed in time t, and is determined from 24 h dialyzate collections. In the expression Kt/V, clearance, Kt, is normalized for body size by division by V, the volume of total body water, which is the volume of distribution of urea. Unlike in HD, in PD the volume V is estimated separately from Kt and biochemical measurements. In clinical prac- tice, V is calculated from equations estimating V from anthropometric and de mographic variables (Appendix). These equations have been developed by regression against t otal body water measured by dilution techniques. The most commonly used equation is that of Watson and Watson. One limitation of anthropometric equations is that there is a degree of inaccuracy in the estimation of total body water in individuals. Also, obesity results in overestimation of V as fat is largely anhydrous, but increasing the weight term of the equa tions will increase estimated V. This leads to underestimation of Kt/V in obese individuals . A further limitation of normalization of clearances to V is that patients with low body w eight resulting from wasting and malnutrition will have lower values for V and thus higher Kt/V. For these patients the optimum clearance required will be greater than that suggested from these calculations. It has been suggested that V should be calculated from ideal weig ht in malnourished patients. mean predialysis serum 2M levels but not dialyzer 2M clearances were associated with al l cause mortality the relative risk of death was 1.11 per 10 mg/L rise in the 2M concentr ation above a reference value of 27 mg/L after adjusting for residual renal function and pr estudy years on dialysis. The apparent disparity between the prognostic effects of serum 2M levels and 2M dialyze r clearances is most likely due to the limited mass removal of 2M in high ef \201 - cien cy dialysis. This is due to intercompartmental transfer resistance of high molecular weight solutes within the patient during HD which results in rebound of serum 2M levels at the end of therapy. In future, 2M levels may also be used to assess the adequacy of dialysis by serving as an indicator of patient outcome and as a surrogate marker of middle molecule removal. Adequacy of peritoneal dialysis Small solute clearances As already alluded to, blood levels of retained solutes are unreliable measures of the ef \201 ciency of dialysis, and the cl earance of small solutes is determined instead. In PD, clearances of urea and creatinine ar e routinely meas- ured. In HD the intermittent nature of the treat ment allows calculation of clearance from the change in blood levels of urea before and after dialysis. This is not possible in PD due to the continuous nature of the therapy, so PD clearances are determine d by collection of drained dialyzate over a 24 h period, and a simultanous 24 h urine colle ction in sub- jects who are not anuric. A blood sample is also taken, which should be midwa y through the dialyzate and urine collection period, espe- cially for \202 uctuating ther apies, i.e. APD. To calculate clearances, it is necessary to know the amount of solute remo ved in 24 h periods by dialysis and by residual renal function. This requires knowledge of \202 uid volumes and their solute concentrations. For dialyzate, the drained volume of di alyzate in a 24 h period is determined and the concentrations of urea, cre- atinine and glu cose in the dialyzate are measured. For APD, the drained volume may be determined from the measurements derived from cycler machines. For CAPD, the \202 uid from all bags may be po oled, the total volume Dialytic creatinine clearance The other standard measure of dialytic clearance in PD is cre atinine clearance. This is determined by measurement of the quantity of cre- atinine remove d in a 24 h dialyzate collection and is calcu- lated in an analogous fashion to urinary cre atinine clearance for measurement of the GFR. It is usually expressed in liters per week an d normalized to 1.73 m2 body surface area (L/1.73 m2/week). Body surface area is determined by anthropometric equa- tions (the formula of DuBois is commonly used). Glucose interferes with some assays for creatinine estima- tion. High dialyzate glucose concentrations may re sult in R. MACTIER AND G. WOODROW 522 spuriously high dialyzate concentrations of creatinine and overestimation of creatinine cle arance. It is important to determine the effect of dialyzate glucose in your local laborato ry, and to measure glucose concen- tration in the collected dialyzate so that an appropriat e correction to dialyzate creatinine concentration can be made. Conversely, in anuric patients, it is more dif \201 cult to achieve clearance targets for creatinine clearance than Kt/V urea by increasing dialysis dose. Kt/V urea or creatinine clearance? The relative merits of urea and creatinine clearances ha ve been debated and are unclear. Neither is superior in performance in re \202 ecting othe r fea- tures of uremia or predicting outcomes. The two measures may vary discordantly in di fferent clini- cal situations. Important factors leading to differences between urea and cr eatinine clearances include PD modality and prescrip- tion, membrane transportation type an d presence of residual renal function. Residual renal function urea and creatinine clearance Residual renal function can make a si gni \201 cant contribution to small solute clearances in PD. Renal clearances of urea and creatinine are measured from 24 h urine collections and values may be added to dialytic cle arances to give total clearances. Renal urea clearances are measured from 24 h urine urea a nd blood urea concentrations and expressed as residual renal Kt/V urea using similar calcul ations to dialytic Kt/V. Creatinine is an imperfect measure of renal function due to tubula r secretion. This leads to overestimation of renal function, which is proportionally greate r with lower clear- ances and especially so for residual renal clearance in patients on dia lysis. To correct for this, \200\230residual renal creatinine clearance \200\231 is calcul ated as the mean of creatinine and urea clearances, as urea is passively reabsorbed in the tubules leading to underestimation of actual renal clearance. Minimum and target dialysis dose in PD There has been huge interest in de \201 ning optima l measures of dialysis, to allow objective determination of ideal dialysis prescription, wi th the aim of reducing the high morbidity and mortality of patients on dialysis, while avoi ding unnec- essarily intrusive dialysis regimes that would reduce patient quality of life w ithout any clinical bene \201 t. Various guidelines have been produced by national and int ernational organizations over time and have been rewrit- ten as advances in the evidence ba se relating to aspects of clearance and patient outcomes have been made. Initial guidelines focused exclusively on small solute clear- ance measurements and were based on the \202 awed assump- tion that control of uremic toxicity is related to total small solute clearanc e, and that clearance of molecules such as urea and creatinine has equivalent impact on out come, whether by dialysis or residual renal function. Total small solute clearances Total small solute clearances are calculated by adding dia- l ytic and residual renal clearances together. However, they are not truly interchangeable. R esidual renal function is an important determinant of sur- vival, whereas dialytic clearanc es beyond a minimum target are not. There is also a proportionally different contribution o f residual renal function and dialysis to urea and creatinine clearances. Even with correct ion of renal creatinine clearance by cal- culation as a mean of creatinine and urea clearan ces, resid- ual renal function contributes a greater proportion of total creatinine clearan ce than total Kt/V urea. Patients with signi \201 cant residual renal function have a rela - tively greater creatinine clearance than Kt/V urea. 1997 NKF DOQI guidelines and the CANUSA study These early guidelines were based on outcomes of obser- vational studies. The largest and m ost in \202 uential was the CANUSA study. This was a large observational study of PD patie nts in Canada and USA. The original publication of this study showed that decreases in tota l Kt/V urea and total creatinine clearance were associated with a decline in nutrition and increased mortality. This was the basis of the in \202 uential 1997 NKF DOQI guidelines fo r minimum small solute clearances in PD. These were a minimum weekly Kt/V of 2.0 and creati nine clearance of 60 L/1.73 m2/week for CAPD. Because of the intermittent nature of APD, it was decided on the basis of opinion that targets should be even higher for APD than CAPD t o counter theoretical increased tox- icity from higher peak solute concentrations. These ta rgets were often challenging to achieve, especially in larger or anuric patients, raising c oncerns as to whether PD could provide adequate treatment for such patients. Paradoxically, data (including some from the CANUSA study) showed that patients with lower peritoneal mem - brane transportation status, in whom it was most dif \201 cult to achieve the highest cl earance values, actually had a better survival than higher transporters. In other words, pa tients whose transportation status conferred a survival bene \201 t on PD were most likely to fail PD due to inadequate clearances. Table 13.5.3 Recommended small solute clearance targets in PD Organization Recommendations Minimum total Kt/V urea of 1.7 and minimum target creatinine clearance of 45 L/1.73 m2/week (required only for APD and not CAPD) ISPD guidelines for solute and \202 uid removal in adults (2006) NKF K/DOQI Guidelines (2006) Minimum total Kt/V urea of 1.7 Renal Association (UK) Guidelines (2007) Minimum total Kt/V urea of 1.7 or minimum target creatinine clearance of 50 L/1.73 m2/week Minimum total Kt/V urea of 1.7 and minimum target creatinine clearance of 45 L/1.73 m2/week (required only for APD and not CAPD) European Best Practice Guidelines for PD (2005) CHAPTER 13.5 Adequacy of dialysis 523 CAPD Increasing clearance on CAPD is often achieved by increas- ing exchange volumes. The u se of large volumes does increase the risk of hernias and \202 uid leaks and because of t he increase in intra-abdom- inal pressure may even have an adverse effect on ultra \201 l- tration. It is important to ensure that adequate ultra \201 ltration is achieved to ensur e \202 uid balance is maintained and because clearance depends on the volume of dialyzate that is drained. Clearances on CAPD may also be increased by increasing the number of exch anges per day. CAPD is well-suited to lower transportation status patients as longer dwell times allow greater equilibration of solutes between blood and dialyzate. This led to revisions of some guidelines to account for transportation status, with lower c learance targets required by lower transporters. Reanalysis of the CANUSA study data showed that the effect of clearance on outcomes was explained by variation in residual renal func tion, with no effect of dialytic clear- ance alone. More recent trial evidence for target dialysis dose in PD Two large randomized controlled t rials from Mexico (ADEMEX trial) and from Hong Kong have compared out- comes in patients ra ndomized to PD regimes achieving dif- ferent small solute clearances. Both studies demonstr ated that prescribing dialysis regimens prospectively to achieve clearances greater than th e lower clearance groups did not improve survival and that survival was again dependent on residual renal function. Based on these data, more modest minimum small solute clearance ta rgets have been produced, on the basis that there is no bene \201 t in routinely increasin g dialysis to achieve higher clearances than those achieved in the low clearance groups in these two trials (Table 13.5.3). It is important to appreciate that these are minimum clear - ance targets. It is still acknowledged that lower clearances are likely to result in a si gni \201 cant risk of complications. It is appropriate to increase the dialysis prescripti on in sub- jects who demonstrate features of uremia such as anorexia or malnutrition despit e achieving the minimum small sol- ute targets. Dialysis prescriptions should not routinely be reduced in those with clearances greater than these targets. Most guidelines now routin ely state that adequacy of treat- ment extends beyond small solute clearances to include: \200 \200 APD APD presents more permutations for treatment modi \201 ca- tion in individual patients . Nightly cycles can be altered in number, duration and vol- ume of exchange over a wide ra nge, which impacts on both clearance and ultra \201 ltration. Increasing cycle volumes inc reases clearance and larger volumes are tolerated by the patient in the supine position in bed at night. The number of exchanges may also be increased to increase total dialyzate vol ume, which often means reduc- ing individual cycle duration if the overnight treatment time is constant. However, increasing the number of cycles also increases the number of gaps be tween cycles during which the \202 uid volume in the peritoneum is reduced or absent and less dialysis occurs. Thus increasing the cycle number and thereby the total dialyzate volu me may not always increase clearance, and may even reduce it, especially with lower transpo rter status. Overnight APD regimens are adjusted according to mem- brane transportation sta tus. With higher transportation status, more rapid equilibration of solutes between the blo od and dialyzate results in greater bene \201 t of increasing the cycle number to increase the total drained volume. This will also aid ultra \201 ltration. In lower transporters, time of dialysis, and thus the effect of lost time between cycles, becomes more important. In lower transportation state patients it is preferable to prescribe fewer, longer dwells. With nightly dialysis, clearance is best optimized by maximizing dwell volumes rather than number. Daytime exchange(s) are very important in APD. As the long duration allows full equ ilibration of small solutes, they make a proportionally greater contribution to clearance p er liter of dialyzate than nightly cycles. Most patients will have at least a single daytim e dwell. Clearances may be signi \201 cantly increased by adding an additional second dayt ime dwell (optimized cycling perito- neal dialysis (OCPD)). Due to the slower diffusion of larger creatinine mole cules than the smaller urea molecule, creatinine is less easily remo ved by short nightly APD cycles. Thus dialytic clear- ances of creatinine may be proportion ally lower than urea for patients on APD compared with those on CAPD. \202 uid balance control; other electrolyte control (e.g. acidosis and bone bio- chemistr y); nutrition; anemia; patient symptoms; quality of life and rehabilitation. \200 \200 \200 All of these should be considered and not neglected by focusing simply on solute clearances . PD prescription and small solute clearances Every dialysis prescription needs to be written and adjusted on an individual patient basis. Factors that determine small solute clearance include: \200 \200 \200 \200 volume of dialysis \202 uid; length of dialysis dwell times; peritoneal membrane transpor tation status; eventual drained dialyzate volume. A higher transportation state is associated with more rapid dif- fusion of solutes and ofte n makes it easier to achieve clear- ance targets. However, a higher transportation state is also associated with less good ultra \201 ltration and when this results in lower eventua l drained volume this can adversely affect clearances. A higher transportation state is ass ociated with poorer \202 uid removal and, despite higher small solute clearances, in many studies it is associated with greater mortality than a lower transportation state. R. MACTIER AND G. WOODROW 524 Changes in PD prescription can be guided by prescription- modeling computer programs that p redict the effect of a change in dialysis prescription in a patient where data such as tran sportation status are known. It is important to repeat clearance measurements in patients s oon after any prescription changes to determine their actual effect. Episodes of dehydration have been observed to be associ- ated with loss of residual functio n and so whilst overhydra- tion is a serious problem, dehydration resulting from overaggres sive \202 uid removal should also be avoided. Preservation of residual renal function has been shown with ACEIs and ARBs and these agents should be consid- ered in patients who sti ll have residual renal function. PD prescription and larger solute clearances Although the focus of blood tests and dialytic clearance measurements has been on small molecules, it is likely that many manifestations and adverse effects of renal failure are due to the retention of larger solutes. The diffus ion of these substances is slower than urea and creatinine and increasingly so with increas ing molecular size. Thus clearance of these molecules does not change in pro- portion with smaller solutes on changing the dialysis pre- scription. When equilibration is very slow, m easures that increase small solute clearance such as increasing exchange number and volumes will have a much lesser effect on the clear- ance of large molecules. For large molecules clearance is more dependent on the duration of dialysis. This is important since some regim ens, such as NIPD which has a long \200\230dry \200\231 period without dialyzate present i n the peritoneal cavity, may produce small solute clear- ances equivalent to CCPD, but have inferior removal of important larger molecules due to the lesser time of dialysis. Other aspects of adequacy in PD A philosophy of optimizing care in PD has developed to enco mpass not only optimizing small solute clearances but also to consider multiple aspects of treatment and patient well-being. Nutrition Reduced appetite and nutrient intake may result from inad- equate dialysis and be an important re \202 ection of uremic toxicity. This may contribute to malnutrition which is asso- ciated with an increased risk of morbidity and mortality. The nutritional state m ay be assessed by dietary history and physical examination. Urea is the major breakdown pro duct of protein metabo- lism. If a patient is in neutral protein balance, excreted nitrogen in the form of urea is equal to the nitrogen of protein intake. Urea values from dialysate and urine collections can be used not only to assess small solute clearance but also to ca lculate protein intake. This is called the protein equivalent of total nitrogen appearance (PNA). It is normalized to body weight as nPNA. Normalization in malnourished patients with low body weight may lead to relatively high nPNA values. This may result in a failure to d iagnose inadequate protein intake in malnourished patients. There is debate as to whether P NA should be normalized to ideal body weight or the subject \200\231s premorbid body weight . Care should be taken in interpreting nPNA in patients with weight loss. Another limitatio n of nPNA is the underlying assumption of neutral nitrogen balance. In catabolic patients p rotein breakdown will result in increased nitrogen excretion that is in excess of intake, g iv- ing a misleadingly high estimate of protein intake in patients at risk of wasting and m alnutrition. Conversely, nPNA will underestimate protein intake in anabolic patients. Importance of preservation of residual renal function There is strong evidence to support t he relationship of residual renal function to outcome in PD. Residual renal function may be better preserved on PD than HD. There are a number of possible explanations for this inclu ding: \200 stable \202 uid status without the periods of hypotension and hypovolemia that occur in H D; the absence of the systemic in \202 ammatory changes that occur in HD due to exposure o f blood to bioincompat- ible dialysis membranes. There are several possible explanations why an equivalent amount of renal small solute clea rance appears to have greater \200\230value \200\231 than the same clearance achieved by P D: \200 Renal function may provide better clearance of larger molecules than dialysis. Remaining ki dney function may also be a marker for ongoing bene \201 cial metabolic and endocrine acti vity of the kidney that is not provided by dialysis. Residual renal function may lead to be tter preservation of \202 uid status, with evidence that later loss of residual renal fun ction on PD may be associated with \202 uid over- load and hypertension. Salt and water balance Fluid balance is a fundamental role of dialysis. Fluid excess causes hypertension, cardiac dysfunction and left ventricular hypertrophy and is likely to be a m ajor fac- tor in mortality of dialysis patients. Reduced sodium and water removal have been associated with poorer survival in a number of observational studies. European Best Practi ce Guidelines for PD have set a mini- mal ultra \201 ltration target of 1 L though other o rganizations have stated that the evidence does not provide a rationale for such a target. Whilst \202 uid overload is to be avoided there is no evidence for a bene \201 cial effe ct of achieving 1 L ultra \201 ltration in all patients on PD. Given the great clinical and prognostic importance of residual renal function, efforts shou ld be made to preserve it for as long as possible. Where possible, nephrotoxic insults, suc h as NSAID pre- scription and radiocontrast media administration, should be avoided. The ef fect of aminoglycosides, used in the management of peritonitis, on residual renal function is unclear. Evidence from studies is con \202 icting. CHAPTER 13.5 Adequacy of dialysis 525 Further reading Hemodialysis adequacy Allon M. Depner TA, Radeva M, et al. Impact of dialys is dose and membrane on infection-related hospitalization and death: Results of the HEMO st udy. J Am Soc Nephrol 2003; 14: 1863 \200\2231870. Patients with low volume ultra \201 ltration should be assessed for the presence of \202 uid overload, deteriorating peritoneal membrane function, and poor nutritional intake befo re increasing \202 uid removal. Fluid management and small solute clearances need to be c onsidered jointly when adjusting PD dialysis prescrip- tions. Beto JA, Bansal VK, Ing TS, et al. Variation in blood sample collection for determination o f haemodialysis adequacy. Am J Kidney Dis 1998; 31: 135 \200\223141. Acidosis Correction of acidosis is important as acidosis both con- tributes to malnutrition by promoting protein catabolism, and causes bone demineralization. Serum bicarbonate shoul d be maintained within the nor- mal range, with some evidence that the nutritional state ma y bene \201 t if the serum bicarbonate is maintained in the higher part of this range. Canaud B, Morena M, Cristal JP, Krieter D. Beta-2-microglobulin, a uraemic toxin with a dou ble meaning. Kidney Int 2006; 9; 1297 \200\2231299 Cheung AK, Rocco MV, Yan G, et al. Serum beta-2-microglobulin levels predict mortality in d ialysis patients: results of the HEMO study. J Am Soc Nephrol 2006; 17: 546 \200\223555. Daugirdas JT, Schneditz D. Overestimation of hemodialysis dose depends on dialysis efficien cy by regional blood flow but not by conventional two pool kinetic analysis. ASAIO J 1995; 41: M719 \200\223M724. Calcium, phosphate and parathyroid hormone Abnormal bone biochemistry has been increasingly recog- nized to be important in dialysis, not just with respect to skeletal complications, but also in the development of car- diovascular disease. Adverse cardiovascular effects in clude development of vascular calci \201 cation with cardiac, cerebral and peripheral vasc ular disease, cardiac valvular calci \201 cation, and cardiac dysfunction. The key aims of treatment are to avoid hypercalcemia, con- trol serum phosphate and to avoid an excessivel y high cal- cium \227 phosphate product. Control of serum PTH is also necessary. Daugirdas JT. Second generation logarithmic estimates of single- pool variable volume Kt/V; an analysis of error. J Am Soc Nephrol 1993; 4: 1205 \200\2231213. Depner T, Daugirdas J, Greene T, et al. Dialysis dose and the effect of gender and body siz e on outcome in the HEMO study. Kidney Int 2004; 65: 1386 \200\2231394. Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and \202 ux on mortality an d morbidity in maintenance hemodialysis patients: Primary results of the HEMO study. N Engl J Med 2002; 347: 2010 \200\2232019. Geddes CC, Traynor JP, Walbaum D, et al. A new method of post- dialysis blood urea sampling : the \200\230stop dialysate \202 ow \200\231 method. Nephrol Dial Transplant 2000; 15: 517 \200\223523. Gotch FA, Sargent JA. A mechanistic analysis of the National Cooperative Dialysis Study (NC DS). Kidney Int 1985; 28: 526 \200\223534. Lai YH, Guh JY, Chen HC, Tsai JH. Effects of dif ferent sampling methods for measurement of post dialysis blood urea nitrogen on urea kineti c modeling derived parameters in patients under- going long-term hemodialysis. ASAIO J 1995 ; 41: 211 \200\223215. Quality of life Achieving optimum quality of life for patients on PD is as important as max imizing survival and achieving biochemi- cal and other medical targets. Questionnaire asses sment tools have been developed which allow standardized determination of various physical and psychosocial aspects of the patient \200\231s well-being. Important goals of PD are to achieve optimal rehabilitation of patients with minimal intrusion of their illness and trea t- ment in their lives. Being able to continue normal social activities and employment are crucial outcomes of treat- ment. Li Z, Lew NL, Lazarus JM, Lowrie EG. Comparing the urea reduc- tion ratio and urea product as outcome-based measures of hemodialysis dose. Am J Kidney Dis 2000; 35: 598 \200\223605. Lowrie EG, Li Z, Ofsthun N, Lazarus JM. Measurement of dialyser clearance, dialysis time, a nd body size: death risk relationships among patients. Kidney Int 2004; 66: 2077 \200\22320 84. Owen WF, Lew NL, Lowrie EG, et al. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing haemodialysis. N Eng J Med 1993; 329: 10 01 \200\223 1006. When to start PD? Debate continues as to whether an \200\230early \200\231 start of PD on biochemical grounds will help to delay the complications of renal failure, or whether this simply exposes the patient to the inconvenience and potential hazards of PD unneces- sarily early. On the basis of older interpretations of adequacy studies it has been proposed that patients should start PD when renal clearance declines to the equivalent of target clear- ances for PD. This would equate to a renal creatinine clearance of 10 mL/min to match a we ekly Kt/V target of 2. This is partly based on the assumption of equivalence of renal and d ialytic clearances which, as discussed, is not nec- essarily the case. It seems reasonable therefore to start PD at signi \201 cantly lower levels of renal function, provided that t here are no features of uremia and, in particular, no features of malnu- trition or an inab ility to achieve target nutritional intake that may be attributable to renal failure. Port FK, Wolfe RA, Hulbert-Shearon TE, et al. High dialysis dose is associated with lower m ortality among women but not among men. Am J Kidney Dis 2004; 43: 1014 \200\2231023. Priester-Coary A, Daugirdas JT. A recommended technique for obtaining the post dialysis BUN. Semin Dial 1997; 10: 23 \200\22325. Schneditz D, Kaufman AM, Polaschegg HD, et al. Cardiopulmonary recirculation during hemodia lysis. Kidney Int 1992; 42: 1450 \200\2231456. Traynor JP, Geddes CC, Ferguson C, Mactier R A. Predicting 30- minute postdialysis rebound blood urea concentrations using the stop dial ysate \202 ow method. Am J Kidney Dis 2002; 39: 308 \200\223314. Traynor JP, Oun HA, McKe nzie P, et al. Assessing the utility of the stop dialysate \202 ow method in patients rec eiving haemodia \201 ltra- tion. Nephrol Dial Transplant 2005; 20: 2479 \200\2232484. Peritoneal dialysis adequacy Bargman JM, Thorpe KE, Churchill DN. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of t he CANUSA Study. J Am Soc Nephrol 2001; 12: 2158 \200\2232162. Churchill DN, Taylor DW, Keshaviah PR for the CANUSA Peritoneal Dialysis Study Group: Adequ acy of dialysis and nutrition in con- tinuous peritoneal dialysis: association with clinica l outcomes. J Am Soc Nephrol 1996; 7: 198 \200\223207. R. MACTIER AND G. WOODROW 526 European Best Practice Guidelines: European Best Practice Guidelines for Peritoneal Dialysis. Nephrol Dialysis Transplant 2005; 20(Suppl 9). http://www.ndt-educational.org/guidelines.asp Cochrane Renal Group: Paniagua R, Amato D, Vonesh E, et al. Effects of in-creased perito- neal clearances on mort ality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002; 13: 1307 \200\2231320. http://www.cochrane-renal.org/ Australia and New Zealand Dialysis and Transplant Registry: Lo WK, Ho YW, Li CS, et al. Effect of Kt/V on survival and clinical outcome in CAPD patient s in a randomized prospective study. Kidney Int 2003; 64: 649 \200\223656. http://www.anzdata.org.au/ National Institute for Clinical Excellence: Lo WK, Bargman JM, Burkart J, Krediet RT, Pollock C, Kawanishi H, Blake PG for the ISPD Ade quacy of Peritoneal Dialysis Working Group. Guideline on targets for solute and \202 uid removal in adult patients on chronic peritoneal dialysis. Peritoneal Dialysis Int 2006; 26: 520 \200\223522. http://www.nice.org.uk/ International Society of Peritoneal Dialysis: http://www.ispd.org Internet resources Renal Association Clinical Practice Guidelines: See also Hemodialysis, hemofiltration and hemodiafiltration, p. 494 Peritoneal dialysis, p. 506 Dial ysis strategies, p. 480 Medical management of dialysis patients, p. 528 http://www.renal.org/guidelines/index.html The Renal Registry: http://www.renalreg.org National Kidney Federation Dialysis Outcomes Quality Initiative: http://www.kidney.org/professionals/kdoqi/ This page intentionally left blank J.R. DE ZOYSA 528 Medical management of the dialysis patient \200 \200 Introduction Caring for the patient with end-stage renal disease (ESRD) encompasses care re lated to both renal and nonrenal dis- ease. As well as renal-speci \201 c issues such as a nemia, bone disease, nutrition, pruritis and hypertension, the nephrolo- gist will also be called upon to optimize the medical man- agement of comorbid conditions such as cardiac dis ease and diabetes, as well as focusing on primary prevention. Close co-ordination with othe r services is required. epoetin zeta; darbepoetin alpha; Mircera . The latter two ESAs have a longer half-life and may be administered monthly. The response t o all ESAs is dose dependent but the dose required to achieve the target hemoglobin varies from patient to patient. The route and frequency of administra- tion will also in \202 uen ce response. The choice of ESA, route and frequency of administration should be based on th e physician \200\231s choice and discussion with the patient. Usually for ESAs with a short half-life twice- or thrice-weekly administration is required and for those with a long hal f-life weekly to monthly treatment is required. Subcutaneous administration is associated w ith a reduced EPO requirement but may carry an increased risk of pure red cell aplasia. How ever, this side-effect is rare. In the initiation phase of treatment both iron stores and h emoglobin levels should be assessed fortnightly. Once in the maintenance phase of therapy i ron and hemoglobin levels should be monitored monthly. Iron supplementation and ESA dosing should be tailored to the individual patient \200\231s response. Management of renal anemia Many of the symptoms associated with ESRD such as fatigue, depre ssion, reduced exercise tolerance and dysp- nea are attributable to anemia. The treatment o f anemia was revolutionized by the introduction of recombinant human erythropoetin (EPO). M anagement of anemia in ESRD should also include: \200 \200 \200 \200 \200 prevention of blood loss; ensuring adequate iron stores; provision of adequate dialysis; co ntrol of hyperparathyroidism; avoidance of aluminum overload. Most anemia guidelines recommend a target hemoglobin level of >11 g/dL in ESRD. However, th erapy does carry side-effects (Table 13.6.1) and there is increasing evidence that there is little bene \201 t and possibly some risk in main- taining hemoglobin levels >13 g/dL. Resistant anemia Some ESRD patients are relatively resistant to therapy with ESAs. This sho uld be investigated in patients who fail to attain the target hemoglobin while receiving do ses of EPO >300 \200\223450 IU/kg/week. A variety a conditions may produce resistance (Tabl e 13.6.3); this is most often due to an absolute, relative or functional iron de \201 cien cy. A further escalation in the EPO dose will result in achieve- ment of the target hemoglo bin in up to 10% of patients with resistant anemia, in whom these conditions have been excl uded or treated. Iron management There is a synergistic relationship between iron and EPO therapy: EPO incre ases iron requirements by stimulating red blood cell formation while adequate iron increase s red blood cell production and reduces EPO requirements. This is especially important duri ng initial therapy when EPO is being used to correct rather than maintain hemo- globin. ESR D patients will typically require iron supplemen- tation. Historically, iron stores have be en assessed using ferritin and transferrin saturation, but it is now recognized that ESRD p atients with values in the normal range may still have both an absolute and functional iron deficiency. Several other tests have been introduced to determine iron stores (Table 13.6. 2). Typically these are assessed monthly in ESRD patients. Some PD patients will maintain h emoglobin level within the target range without EPO or supplemental iron ther- apy. Typical ly a proportion of PD patients will require oral iron supplementation, whereas most HD pati ents will require intravenous iron supplementation. Intravenous iron is available in severa l forms and is gener- ally safe. Rarely anaphylaxis may occur and careful moni- toring is r ecommended during administration. Management of renal bone disease Changes in bone and mineral metabolism appear early in CKD . Several types of lesions may be present in the ESRD patient. Typically these are thought of as disorders of high or low bone turnover (Table 13.6.4). Clinical manifestations The clinical symptoms of renal bone disease are often nonspeci \201 c and include: \200 \200 \200 \200 \200 \200 acute and chronic bone pain; pain around individual joints; muscle weakness; skeletal defor mities; pruritis; extraskeletal calci \201 cations including calciphylaxis. Treatment with erythropoiesis stimulating agents Diagnosis Double tetracycline labeling followed by bone biopsy remains the gold standard fo r the diagnosis of renal osteod- ystrophy but is not routinely performed in clinical practi ce. Conventional X-rays are frequently performed but are an insensitive test. Several erythropoiesis stimulating agents (ESAs) are com- mercially available although this varies from country to country. Available ESAs include: \200 \200 \200 epoetin alpha; epoetin beta; epoetin delta; CHAPTER 13.6 Medical management of the dialysis patient 529 Table 13.6.1 Potential bene \201 ts and risks of partial or complete correction of anemia with erythropoetin Mild bone disease Normal Improvements in: Cardiac function Quality of life Exercise capacity Cognition Sexual functi on/menses Nutrition Sleep Immune function Coagulopathy Increased risk of: Hypertension Graft thrombosis Pure red cell aplasia Seizures/encephalopa thy Cardiovascular disease (if Hb >13.5 g/dL) Osteomalacia Adynamic bone Osteitis fibrosa cystica Mixed osteodystrophy High bone turnover Low bone turnover Fig.13.6.1. The spectrum of renal bone disease. Table 13.6.2 Laboratory tests used to assess iron stores in ESR These are routinely measured in patients with CKD and ESRD and can be used to guide treatme nt. Ferritin Transferrin Transferrin saturation Serum iron Protoporphyrin Percent hypochromic r ed cells Reticulocyte hemoglobin Serum transferrin receptor Management Treatment should begin early in the course of CKD in order to prevent skeletal c hanges developing. In ESRD patients serum calcium, serum phosphate and calcium phosphate pr oduct should be assessed monthly and PTH concentration should be assessed 3-monthly. These parameters should be considered together when determining the appropriate management. Achie ving ideal targets is challenging with conventional dialysis and currently available therap ies. Table 13.6.3 Conditions associated with erythropoietin resistance in ESRD patients Absolute, relative or functional iron de \201 ciency In \202 ammation/infection Hyperpara thyroidism Aluminum overload Vitamin de \201 ciency (B12, folate) Myeloma/myelo \201 bros is/other hematological disorders Malignancy Malnutrition Patient concordance with treatment Control of serum phosphate Control of phosphate is the key to effective therapy and the ser um concentration of phosphate should be main- tained between 1.1 and 1.78 mmol/L. Initially a renal dietician should provide education and counseling about restriction of dietary int ake of phos- phate. If this is ineffective the next step is use of a phosphate binder. Vari ous agents have been used including: \200 \200 \200 \200 \200 aluminum hydroxide; magnesium salts; calcium salts; sevelemar; lanthanum carbonate. Table 13.6.4 Bone lesions in ESRD Osteitis \201 brosis cystica Characterized by very high bone turnover with marrow \201 brosis Mild bone disease Calcium salts are currently \201 rst-line therapy, although daily doses may need to be li mited due to the risk of hypercalcemia and the potential to worsen vascular calci \201 - c ation. Less severe disease characterized by an increase in the osteoid surface and high/normal bon e formation Osteomalacia Characterized by an excess of unmineralized osteoid Adynamic bone disease Control of serum calcium The serum calcium should be maintained in the range of 2.1 \200 \2232.4 mmol/L. This should be assessed using a predialysis sample in HD patients and ideal ly should be maintained at the lower range of normal unless this worsens hyperparathyroidis m. This may be achieved by oral calcium supplementation, use of calcitriol, which will incr ease both calcium and phos- phate concentrations, and by manipulating the dialyzate calcium . The ideal calcium dialyzate concentration is unclear. Characterized by low bone formation Mixed renal osteodystrophy There is both an increase in marrow \201 brosis and unmineralized osteoid Other, e.g. 2-microglobulin amyloidosis