Review of dialysate calcium concentration in hemodialysis

Hemodialysis International 2006; 10:326–337 Review of dialysate calcium concentration in Nigel TOUSSAINT, Patrick COONEY, Peter G. KERR Department of Nephrology, Monash Medical Centre, Clayton, Vic., Australia AbstractThe dialysate calcium (Ca) concentration for hemodialysis (HD) patients can be adjusted to managemore optimally the body’s Ca and phosphate balance, and thus improve bone metabolism as well asreduce accelerated arteriosclerosis and cardiovascular mortality. The appropriate dialysate Ca con-centration allowing this balance should be prescribed to each individual patient depending on amultitude of variable factors relating to Ca load. A lower dialysate Ca concentration of 1.25 to1.3 mmol/L will permit the use of vitamin D supplements and Ca-based phosphate binders in clinicalpractice, with much less risk of Ca loading and resultant hypercalcemia and calcification. Low Cabaths are useful in the setting of adynamic bone disease where an increase in bone turnover is re-quired. However, low Ca levels in the dialysate may also predispose to cardiac arrhythmias andhemodynamically unstable dialysis sessions with intradialytic hypotension. Higher Ca dialysate isuseful to sustain normal serum Ca levels where patients are not taking Ca-based binders or if Casupplements are not able to normalize serum levels. Suppression of hyperparathyroidism is alsoeffective with dialysate Ca of 1.75 mmol/L, but hypercalcemia, metastatic calcification, and over-suppression of parathyroid hormone are risks. Dialysate Ca of 1.5 mmol/L may be a compromisebetween bone protection and reduction in cardiovascular risk for conventional HD and is a commonconcentration used throughout the world. The increase in longer, more frequent dialysis such asshort-daily and nocturnal HD, however, provides another challenge with regard to optimal dialysateCa levels and higher levels of 1.75 mmol/L are probably indicated in this setting. Difficulties in de-termining the ideal dialysate Ca occur because of the complex pathophysiology of bone and mineralmetabolism in HD patients and there needs to be a balance between dialysis prescription and othertreatment modalities. To optimize management of the abnormal Ca balance, other aspects of thisdisorder need to be more fully clarified and, with evolving medications for phosphate control andtreatment of secondary hyperparathyroidism, as well as the emergence of a multitude of differentHD regimes, further studies are required to make definitive recommendations. At present, we needto maintain flexibility with HD treatments and so dialysate Ca needs to be individualized to meet thespecific requirements of patients by optimizing management of renal bone disease and simultane-ously reducing metastatic calcification and cardiovascular disease.
Key words: Dialysate calcium, hemodialysis, calcium balance, vascular calcification, mineral me-tabolism, calcium  phosphate product Correspondence to: P. G. Kerr, Department of Nephrology, Monash Medical Centre, 246 Clayton Rd, Clayton, Vic. 3168,Australia.
E-mail: r 2006 The Authors. Journal compilation r 2006 International Society for Hemodialysis drop-in clinics. All clinics are followed by a discussion of the patients seen, with all attendees at the clinic (con- sultants, registrars, and residents)—this usually takes upto an hour. There is a weekly department meeting with The training pathway for medical specialties in Australia presentations of renal histology, scientific work, or other is governed by the Royal Australasian College of Physi- nephrology topics and there is a second weekly journal cians (covering Australia and New Zealand). After a club. The hospital has a weekly general medicine meeting compulsory intern year, trainees typically enter ‘‘basic as well (similar to a grand round). In addition, all ad- training’ that incorporates exposure to all medical spe- vanced trainees must complete a ‘‘project’’ in each year of cialties and general medicine. This occurs predominantly training—this is usually a small clinical research topic, in teaching hospitals with some secondment to smaller suburban and rural hospitals. Basic training takes 3 years, The department also has 5 nephrology PhD students wherein trainees progress through working as a resident who have completed their advanced training but who doctor (similar to a House Officer) to registrar level where have elected to pursue research. Three are involved in they supervise residents. In the third year of this training, laboratory research (glomerulonephritis, diabetes, and there are 2 examinations. Firstly, there is the written exam peritoneal membrane pathobiology) and 2 in clinical re- (multiple choice format), which incorporates clinical sci- search (dialysis nutrition and vascular disease). The De- ences and clinical medicine in all internal medical disci- partment is currently involved in 23 clinical trials and has plines. If successful at this examination, candidates may an active basic science laboratory, including 14 scientists.
then sit a clinical examination, which has a format of longand short cases extending over a whole day (2 long cases and 4 short cases)—again, cases are drawn from all as-pects of internal medicine.
As mentioned, Monash Medical Centre cares for about Once successful at the examinations, candidates com- 485 dialysis patients, including 135 patients on perito- plete the 3 years of basic training and enter ‘‘advanced neal dialysis (PD), and there are about 70 to 90 new di- training.’’ This is usually discipline specific—in the case alysis patients entering the program each year. Dialysis in point, in nephrology. Advanced training spans a further education for advanced trainees occurs at a variety of lev- 3 years and incorporates at least 2 clinical years as a Ne- els, including treating in-hospital patients and ambulato- phrology Registrar but may include a third elective year, ry care patients. Peritoneal dialysis is offered as CAPD and either in another specialty or in research. Many candi- APD; hemodialysis (HD) is offered as satellite and home dates overlap a PhD year at this point. There are no exit (in-center tends to be a transit zone only). Home HD examinations but there are annual reports on progress, includes conventional and nocturnal dialysis, and the submitted to a Specialist Advisory Committee that is dis- department currently has 31 patients on nocturnal HD.
The registrar covering dialysis at any one time is re- At Monash Medical Centre, we run a large program by sponsible for ambulatory management of outpatient HD Australian standards. The Nephrology Department cares and PD patients. As with all nephrology units in Mel- for 485 dialysis patients and over 500 transplant patients, bourne, training in ambulatory dialysis for the advanced including kidney–pancreas transplantation. There are 3 trainee at Monash Medical Centre occurs throughout the clinical registrars who rotate through care of the inpatient duration of the 3 years of clinical practice as a registrar, ward, dialysis, and transplantation (transplant patients and is integral to the overall efficiency of HD patient care are cared for by the Physicians in Australia). There are in the department. There is one co-ordinated dialysis out- usually about 25 to 30 inpatients at any one time but re- patient clinic per week with regular attendance by Con- nal biopsies and many surgical procedures are performed sultants and registrars, as well as allied health staff in- as day cases. We perform around 300 renal biopsies per cluding a dietician, social worker, and dialysis educators.
year (native and transplant), and there are about 40 to 45 There are 20 to 25 HD inpatients at any one time cared transplants per year (including 8–10 kidney-pancreas).
for by the ward registrar, but with good clinical practice Educational activities include formal rounding with the most management of patients will occur in the commu- consultant 3 times/week, separately in general nephro- nity with regular out-patient review. In-patient HD logy and transplantation, and attendance at a dialysis training involves regular ward rounds with the consult- clinic weekly and a glomerulonephritis clinic weekly.
ant, and direct communication with dialysis nursing staff There are 2 formal transplant clinics weekly, plus daily and between registrars. There would typically be about Hemodialysis International 2006; 10:326–337 10 to 15 acute HD patient admissions per month, and centration was used as this most closely matched normal review of patients in the intensive care setting, especially serum ionized Ca. It was soon discovered that higher of those requiring support with hemofiltration, is also levels of Ca were required to sustain serum Ca levels and crucial to optimal training of advanced trainees at Monash to increase Ca load, therefore preventing hypocalcemia The administration of active vitamin D (calcitriol) in the 1970s eliminated the need for the dialysate to im- prove Ca load and a higher dialysate Ca concentration,with a net flux of Ca into the patient, was not required.
With the introduction of Ca-based phosphate binders in A 54-year-old male has been managed with HD for 3 years.
the late 1980s, in association with calcitriol use, hyper- His dialysis parameters include—4 hr, 3 times/week, using calcemia became a more common potential problem, and a 1.6 m2 polysulfone high-flux dialyzer, achieving a spKt/V a lower Ca dialysate was re-introduced. Slatapolsky et al., of 1.5. He has always struggled with phosphate control.
in 1986, reported on HD patients receiving Ca carbonate Owing to regulatory restrictions, sevelemar hydrochloride as phosphate binders in association with dialysis contain- is unavailable. His phosphate control includes calcium ing 1.75 mmol/L Ca dialysate revealing the complication carbonate, 2 tablets 3 times daily with meals, and alumi- of hypercalcemia.4 A repeat analysis of patients reported num hydroxide, 1 tablet 3 times daily with meals. He also in 1989, with lower Ca dialysate (1.25 mmol/L) and as- takes calcitriol 0.25 mcg daily. His serum calcium is sociated Ca carbonate administration, at an average dose 2.6 mmol/L, phosphate 2.1 mmol/L, intact parathyroid of 10.5 g/day, demonstrated no hypercalcemia.5 The ben- hormone (iPTH) level is 53 pmol/L, and albumin is 38 g/ efits of low Ca dialysate in association with Ca-containing L. One is concerned about his iPTH level and would like to binders and also with calcitriol have also been confirmed increase his calcium carbonate to 9 tablets daily but are in many early studies, with the active vitamin D compo- nent effective in treating patients with secondary hyper- What options in the dialysate calcium concentration are avail- able? What is the ‘‘correct’’ dialysate calcium? However, the more recent introduction of non-Ca, nonaluminum-based phosphate binders, noncalcemic vi-tamin D analogues, as well as the emergence of calcimi- metic agents into clinical practice improving managementof mineral metabolism, have made the current choice of dialysate Ca even more difficult, and also more crucial.
Using the appropriate dialysate calcium (Ca) concentrationin HD patients has important management implications with regard to the prevention of renal bone disease and also, more importantly, the reduction of vascular calcifi- Patients with end-stage kidney disease (ESKD) have a cation. Manipulations of the dialysate Ca concentration disruption in systemic Ca and phosphate homeostasis. As enable alterations in Ca load as dialysate Ca impacts on a result of limited excretion of phosphate, diminished serum Ca, phosphate, and parathyroid hormone (PTH) hydroxylation of 25-hydroxyvitamin D to calcitriol (1,25- and, most likely, soft tissue calcification. Concentrations in dihydroxyvitamin D) and resulting hypocalcemia, there is the dialysate can be customized depending on the current an effect on bone, the gut, and the parathyroid glands.
and targeted serum Ca levels as well as the desire to main- Hypersecretion of PTH is initially appropriate by increas- tain hemodynamic stability during dialysis.1 ing Ca phosphate release from bone and enhancing uri- nary phosphate excretion (via a decrease in proximalreabsorption). PTH can, in early stages, correct both the Dialysate in general, with its electrolyte and acid-base hypocalcemia and the hyperphosphatemia. With declin- components, has evolved specifically and scientifically ing kidney function, worsening phosphate retention is through studies to provide the best outcome measures for intimately related to the common development of sec- patients on HD, but the optimal dialysate Ca concentra- ondary HPT. The latter is a major cause for concern be- tion is yet to be delineated.2 When dialysis was initially cause the high circulating levels of PTH play an important introduced in the 1960s, 1.25 mmol/L dialysate Ca con- role in the development of renal osteodystrophy and pos- Hemodialysis International 2006; 10:326–337 sibly in other uremic complications as well. Increased levels of PTH are also closely associated with cardiovas-cular disease in dialysis patients.
Worldwide use of dialysate Ca varies throughout different Current management of mineral metabolism in ESKD in- countries. The most recent clinical practice guidelines by volves the control of hyperphosphatemia and the use of ac- the National Kidney Foundation (New York, United tive vitamin D compounds to suppress PTH, with an aim to States) Kidney Disease Outcome Quality Initiative (K/ obtain normalization of serum Ca and phosphate. Phosphate DOQI) guidelines recommend a dialysate Ca concentra- control in dialysis patients is difficult and management relies tion of 1.25 mmol/L rather than 1.5 mmol/L to avoid on dietary restriction, the use of phosphate binders, many of excess Ca load and prevent vascular calcification,2 where- which are Ca-based, and dialysis.8 Dialysis has limited abil- as in Japan and Australia a dialysate of 1.5 mmol/L is ity for phosphate control although phosphate removal by common. There is no recommendation for dialysate Ca in HD is very much a time-dependent process.9 the European Best Practice Guidelines (EBPG). The first Aluminum hydroxide was initially thought to be the Dialysis Outcomes and Practice Patterns Study (DOPPS) ideal phosphate binder, especially being the most cost involved 307 HD centers with participants from Japan, effective; however, it has largely been abandoned because United States, and Europe, and revealed that the average of the risks of aluminum toxicity with osteomalacia and dialysate Ca concentration was 1.45 mmol/L, 60% of encephalopathy.10 If aluminum-based binders are need- patients exceeding the K/DOQI recommendation.19 ed, certain guidelines recommend against their use for Lower dialysate Ca in general was more predominantly longer than 4 weeks.2 Ca carbonate and Ca acetate sub- used in the United States. Interestingly, from the DOPPS sequently replaced aluminum hydroxide as the most data there was a significantly increased all-cause (but commonly used phosphate binders but their use is asso- not cardiovascular) mortality risk associated with a higher ciated with hypercalcemia, especially in association with the use of vitamin D metabolites or higher dialysate Ca Despite all studies so far, recommendations worldwide concentrations.11 Although patients were previously di- are based mostly on opinion, with mortality and morbid- alyzed against 1.5 or 1.75 mmol/L Ca baths to prevent Ca ity data currently lacking, to answer the question of depletion, as mentioned with the widespread use of Ca- which dialysate Ca is the safest and most effective. Rec- salts, as phosphate binders, reduced Ca dialysate became ommendations from Locatelli et al., based on a consensus standard. More physiological dialysate with a lower Ca of from the third ‘‘Accord Workshop,’’ held in Paris in 2000 1.25 mmol/L allowed for increased intestinal Ca absorp- and published in 2002, suggested that the dialysate Ca tion with Ca-based medication, without a positive dialysis content should be 1.5 to 1.75 mmol/L, with 1.5 mmol/L Ca balance and resultant hypercalcemia.12,13 preferred in patients taking Ca supplements or vitamin D With this change, however, there is an association with analogues to avoid a positive Ca balance.20 The consensus worsening secondary HPT, as a result of negative dialysis recommended a dialysate Ca concentration of 1.75 mmol/ Ca balances, and the use of Ca-containing binders is L if patients were not on these medications, and it sug- perhaps only more likely to accelerate the process of Ca gested that 1.25 mmol/L should be avoided for prolonged deposition and vascular calcification.12,14–17 Also, a lower periods due to risks of aggravating secondary HPT.
dialysate Ca has not been shown to produce positive effects Given the interplay between dialysate Ca concentra- in a study of health-related quality-of-life parameters.17 tions and medication administration with regard to serum The more recent introduction of Ca-free binders, with Ca and phosphate control, changes in the practice of a decrease in the overall intestinal Ca absorption, phosphate binder prescription are important in providing now alters the balance toward an overall negative Ca load the optimal Ca dialysate concentration. More than 80% of with the potential to stimulate PTH production. There- all dialysis patients are managed with phosphate binders, fore, a trend toward the use of higher concentrations Ca-based agents previously being the most predominant of dialysate Ca has been recommended to avoid Ca worldwide;19 however, the most recent DOPPS data depletion and 1.5 mmol/L Ca bath has subsequently (2002–2004) revealed that 25.9% of patients were tak- become more accepted for the majority of HD patients.
ing the Ca-free binder sevelamer, compared with 0.1% of This level seems to be suitable because the moderately patients using sevelamer during the initial observation negative dialysis balances can be easily counterbalanced period (1996–2001).21 Phosphate binder usage differs by the administration of mild doses of Ca-containing across countries, with currently over half of patients in binders, if necessary, in order to ensure a neutral total the United States and some Western European countries being managed with non-Ca-based binders, although Ca Hemodialysis International 2006; 10:326–337 acetate may still be more cost effective.10 In some coun- tries, non-Ca-based phosphate binders such as sevelamer and lanthanum are not readily available due to regulatoryand cost issues.
The leading cause of mortality in patients with ESKD iscardiovascular disease.32,33 Compared with the generalpopulation, dialysis patients have a 3- to 30-fold increase in mortality, depending on the age group examined.33 The diffusion of Ca in HD depends on the Ca gradient This excess in mortality compared with the general pop- between the serum concentration and the dialysate ulation is not explained by the presence of traditional concentration. Studies have shown that when the dialy- cardiovascular risk factors, and a large component of the sate Ca is greater than 1.5 mmol/L, there is an expected vascular calcification is likely due to the chemical prob- gain in Ca.11,22,23 Losses by convective transport, lem of Ca and phosphate excess. Precipitation of Ca and however, can exceed the amount of Ca gained by diffu- phosphate may be responsible for much of the medial sion22 so ultrafiltration is also an important factor in the arterial calcification and the Ca  phosphate product overall Ca balance. Ca mass balance studies have dem- (Ca  P) is an independent risk factor for vascular calci- onstrated that generally, providing the patient is norm- fication and cardiovascular death.34 It has also been dem- ocalcemic, a dialysate Ca concentration of 1.75 mmol/L onstrated that phosphate levels are linearly and produces a positive Ca balance and a negative balance independently associated with all-cause and cardiovascu- is obtained with a dialysate Ca of 1.25 mmol/L.23–25 lar mortality in dialysis and predialysis patients.34 Dialysate free of Ca has been shown in one early human Vascular calcification is not, however, as simple as ‘‘Ca study to produce symptomatic hypocalcemia within the loading’’ with passive precipitation of Ca and phosphate first 60 min of dialysis for chronic HD patients 26 when one or more of these minerals are in excess. It is and hypotension can also result from inadvertent use of now recognized that this extra-osseous calcification in ESKD is an active process involving vascular smooth Ca ions are extremely important in the contractile muscle cell transformation to osteoblast-like cells with process of both vascular smooth muscle cells and cardi- elevated phosphate levels and other as yet unidentified ac myocytes and changes can have significant effects on uremic toxins inducing this differentiation. Only once hemodynamics.28 Whether this effect is a result of chang- mineralization is initiated will alterations in Ca and es in myocardial contractility or mediated through vas- phosphate balance accelerate this process via multiple cular reactivity is unclear. Serum ionized Ca increases mechanisms.35–37 In recent years, several mechanisms during sessions with dialysate Ca of 1.5 and 1.75 mmol/L have been identified to explain vascular calcification in- and decreases to the lower limits of normal after HD with cluding loss of inhibition, induction of bone formation, 1.25 mmol/L. Van Kuijk et al., reported that with the circulating nucleational complexes, and cell death.
lower dialysate Ca concentration, there is a significantly An elevated Ca  P combination is likely to be a pre- larger decline in blood pressure compared with higher dominant risk factor and Ca alone may also be problem- dialysate Ca in patients with normal cardiac function.29 atic because, in general, a positive Ca balance may This is perhaps related to decreased left ventricular con- promote or accelerate soft-tissue and vascular calcifica- tractility using the lower dialysate Ca. Stable blood pres- tion even in the absence of hypercalcemia.38 During con- sure is also achieved with the use of higher dialysate Ca in ventional HD, a positive Ca balance and a concomitant those patients with impaired cardiac function.30 inflammatory state probably act as co-factors in the HD with a dialysate Ca bath of 1.75 mmol/L therefore seems to be a possible strategy for improving hemody- Studies using electron-beam computed tomography namic stability in patients, especially for those with (EBCT) have accurately and quantitatively assessed coro- cardiac impairment.31 This therapy, however, is limited nary artery calcification with total calcification scores by the concerns of developing hypercalcemia with result- proven to be strongly predictive of coronary artery athe- ant excessive Ca loads exacerbating vascular calcification.
rosclerosis and of major future adverse cardiac events in The recent introduction of calcimimetics, as well as the general population.40,41 In those patients with ESKD, the widespread use of Ca-free phosphate binders, may calcification scores are also markedly increased, especially provide the opportunity to use a higher dialysate Ca con- at a younger age, and progress more rapidly, although the centration without the effect of predisposing cardiovas- prognostic significance of EBCT in this population has only recently been investigated.16,42–45 Hemodialysis International 2006; 10:326–337 The presence and extent of vascular calcification in cluded that the effect of serum Ca on blood pressure was ESKD is consistently linked to an increased risk of death.
through left ventricular (LV) stroke volume and output.
Modalities for determining the degree of calcification, in- It has been postulated that an increase in serum-ion- cluding plain radiography,45 ultrasound,46 and EBCT,44 ized Ca during HD could also potentially lead to impaired have all correlated greater calcification with poorer prog- LV relaxation. However, using a dialysate Ca concentra- nosis and shown that vascular calcification is a strong and tion of 1.75 mmol/L one study showed that perhaps this independent predictor of cardiovascular and all-cause was not necessarily the case, revealing no change in Dop- mortality in HD patients. The administration of Ca-con- pler measures of LV diastolic function with an increase in taining phosphate binders is associated with progressive serum Ca after 1 hr of HD without ultrafiltration.55 In- coronary calcification but correlation between dialysate stead, changes in these LV parameters were thought more Ca levels and EBCT is yet to be determined.
Serum-ionized Ca levels are a determinant of vasoconstric- All patients with ESKD will have renal bone disease by the tion; therefore, alterations in dialysate Ca concentration time they require dialysis. On dialysis, this does not im- may impact on arterial compliance. One study looking at prove but progresses and in HD patients renal bone disease the effect of treatment with lower dialysate Ca revealed is a serious complication that can result in fractures, bone favorable changes in blood pressure and arterial compli- pain, and extraosseous calcification. Several different fac- ance as well as a reduction in serum aldosterone levels tors contribute to bone disease and a spectrum exists from (a marker of vasoactivity).47 However, cardiac arrhythmias high bone turnover disease, related to secondary HPT, to are also more likely to occur in HD patients with lower low bone turnover disease due to osteomalacia or ady- dialysate Ca associated with the potential for worsening of namic bone disease, the latter a result of aluminum toxicity or more commonly overtreatment of HPT with vitamin D.
Intradialytic hypotension remains a problem in HD Clinically, the distinction between these pathological and the etiology is multifactorial. As outlined earlier, one diagnoses is often based on the serum PTH level. Para- predisposition has been low dialysate Ca and one study, thyroid hormone levels of less than 11 pmol/L (100 pg/ where HD patients underwent alternate dialysis with 1.25 mL) are suggestive of adynamic bone disease and levels and 1.75 mmol/L dialysate Ca, revealed a minor but sta- greater than 33 pmol/L (300 pg/mL) are indicative of tistically significant reduction in mean blood pressure overstimulating PTH and high turnover bone disease. Di- with the use of the lower Ca bath.50 Manipulations have alysate Ca has been shown to consistently correlate in- shown to improve efficacy with this regard by using high- versely with PTH and therefore higher Ca dialysate will er Ca dialysate.51,52 More hemodynamically stable dialy- suppress HPT and lower Ca levels will improve turnover sis sessions, without intradialytic hypotension, may be achieved with a dialysate Ca of 1.75 mmol/L and result in The diagnostic value of serum PTH levels to predict subsequent improved morbidity. For patients with cardi- accurately the nature of renal bone disease, however, is ac impairment and reduced life-span, the benefits of re- debatable. Levels between 11 pmol/L (100 pg/ml) and duction in dialysis events could be weighed against the 55 pmol/L (500 pg/ml) are probably insufficiently sensi- potential long-term effects of a higher dialysate Ca con- tive or specific to diagnose either low or high turnover centration with increases in vascular calcification that bone disease.2 The K/DOQI guidelines suggest that if a may not affect life expectancy. Increasing the magnesium patient with ESKD and serum levels of intact PTH be- dialysate concentration to 0.75 mmol/L may also be of tween 11 and 55 pmol/L develops unexplained hyper- benefit for a lower (1.25 mmol/L) dialysate Ca to reduce calcemia, bone pain, or an increase in bone alkaline the incidence of intradialytic hypotension.53 phosphatase (ALP) activity, a bone biopsy can be useful.
Blood pressure may be altered by changes in Ca either The bone biopsy will allow more accurate assessment of through alterations in systemic vascular resistance or the rate of bone formation and bone mineralization and changes in cardiac output, or both. A study of 8 HD pa- tients with variable dialysate Ca from 0.5 to 2.5 mmol/L For patients with adynamic bone disease (low or low- showed changes in blood pressure with alterations in Ca normal bone turnover), the use of lower dialysate may be levels.54 Higher Ca dialysate augmented cardiac output beneficial. These patients are at a higher risk of cardio- while leaving vascular resistance unchanged, so it was con- vascular mortality and often have high Ca  P as a result Hemodialysis International 2006; 10:326–337 Table 1 Potential advantages and disadvantages of different dialysate calcium concentrations of high serum Ca levels.56 In one prospective study of HD of alternate 1.25 and 1.75 mmol/L dialysate Ca (2 hr each), patients with biochemical markers suggestive of adynam- there was a significant reduction in intra-dialytic events, ic bone disease, dialysate Ca was reduced from 1.75 to described to be related to an increase in cardiac output with 1.25 mmol/L in patients to assess bone metabolism.57 an ionized Ca-induced increase in myocardial contractility.
This demonstrated a significant reduction in Ca  P The authors concluded that with the use of profiling, by (5.62–3.95) and an increase in PTH. Parameters of bone individualizing the dialysate Ca concentrations used and resorption (pyridinoline) and formation (bone ALP) alternating between them, there may be an improvement were significantly increased, peaking after 12 months.
in hemodynamic stability, while simultaneously reducing Treatment with a lower dialysate Ca may therefore be potential problems with hypercalcemia.
potentially advantageous in this clinical setting to stimu- Despite only a small sample size, this study demon- strated a possible strategy to help ameliorate intradialytic Another study reviewing 67 patients, with the dialysate hypotension, a significant cause of patient morbidity, but Ca reduced from 1.5 to 1.25 mmol/L, also analyzed bone longer-term cardiovascular morbidity and mortality as metabolism and revealed an initial increase in PTH and well as effects on renal bone disease have not been analy- osteocalcin.58 In a subgroup with initially low PTH levels (o11 pmol/L), there was an improvement in adynamicbone disease. In those patients with PTH 433 pmol/L, lowering the dialysate Ca also allowed an increase in thedose of vitamin D without consequent hypercalcemia, Nocturnal hemodialysis (NHD) provides longer and po- and a subsequent reduction in PTH. Therefore, reducing tentially more frequent dialysis and has definitely been dialysate Ca allows more flexible adjustment of vitamin D proven to provide superior phosphate control compared to correct metabolic abnormalities of bone related to sec- with conventional hemodialysis (CHD),9,60 with NHD pa- tients even being able to discontinue phosphate binders.
The elimination of Ca-containing phosphate binders at the commencement of NHD has previously been shown, how-ever, to lead to a loss of up to 8 g of elemental Ca per week One possibility of utilizing the benefits of low dialysate Ca in oral intake, and so exacerbate Ca deficiency and sec- to prevent hypercalcemia but at the same time avoiding in- ondary HPT.61 Increasing the dialysate Ca concentration tra-dialytic hypotensive episodes is with the use of Ca pro- corrects this problem, with an overall net gain of Ca to the filing. In a randomized crossover trial, Kyriazis et al., patient when using a 1.75 mmol/L Ca bath.
studied 18 HD patients undertaking 4-hr dialysis with ei- The effects of daily dialysis on Ca balance may differ ther 1.25 mmol/L Ca dialysate or with 1.25 mmol/L for the depending on whether the modality is NHD or short daily first 2 hr and 1.75 mmol/L for the remaining 2 hr, followed (SDHD).61–65 The London Daily/NHD Study examined by a 4-hr session with 1.5 mmol/L bath.59 Hemodynamic the effect of dialysate Ca concentration on Ca and phos- effects were comparable between dialysis with either phate metabolism, comparing daily HD (including NHD 1.25 mmol/L or 1.5 mmol/L, with hypotension toward the and SDHD) with CHD.61 Patients on NHD were initially end of treatment sessions. With HD using the combination dialyzing against a 1.25 mmol/L Ca bath with demonstra- Hemodialysis International 2006; 10:326–337 tion of increases in ALP and PTH; predialysis serum Ca serum Ca levels and therefore this was the recommended levels became lower in patients on NHD within a month.
dialysate to reduce acceleration of bone turnover and sub- This observational study showed that increasing the di- sequent development of renal osteodystrophy. Another alysate Ca concentration in NHD prevented HPT and Japanese study of HD patients also confirmed the neces- bone disease. Those patients on CHD and SDHD still sity of a higher dialysate Ca to prevent worsening second- required phosphate binders and did not become Ca ary HPT when sevelamer is used as a phosphate binder, deficient on 1.25 mmol/L Ca dialysate. Concerns still ex- even with additional active vitamin D supplements.72 ist, though, that higher Ca baths in NHD, however, may Lanthanum carbonate is another newer phosphate potentially contribute to hypercalcemia, vascular calcifi- binder, although initial concerns with its use surround- cation, and subsequently more cardiovascular mortality.
ed the potential absorption of this element and long-term Despite the higher Ca levels with increased dialysate accumulation in tissues.73 In vitro, it has anticalcification Ca, the Ca  P is reduced on NHD because of much bet- and antiatherosclerotic properties and may be another ter phosphate control and although long-term mortality alternative to Ca-based binders but long-term studies data are not yet available, this mode of dialysis certainly provides greater improvements in well-being, cardiovas-cular outcomes, and bone metabolism.61,62,66,67 The prescription of active vitamin D is a major treatment to correct hypocalcemia and suppress PTH levels inESKD. According to the DOPPS data, 52% of patients were treated with some form of vitamin D therapy.19Calcitriol (1,25[OH]2D3) and alfacalcidol (1a[OH]2D2) Sevelamer hydrochloride is a newer phosphate binder have been predominantly used, administered by an oral containing neither Ca nor aluminum. It is useful for or an intravenous route, but concerns regarding the risks patients requiring better phosphate control and who are of hypercalcemia and hyperphosphatemia have led to also being administered vitamin D metabolites to reduce the emergence of vitamin D analogues that suppress the potential for hypercalcemia. Sevelamer has been PTH without affecting serum Ca and phosphate levels.
demonstrated to stabilize cardiac calcification and reduce the rate of progression by avoiding or reducing the need (1a[OH]2D2) have been studied although none have been for Ca-based phosphate binders, therefore providing completely successful in avoiding alterations of Ca and a reduction in Ca load.68 The Dialysis Clinical Outcomes phosphate and to date have not been proved superior to Revisited (DCOR) study recently demonstrated that patients who used sevelamer experienced a 9% reduction Paricalcitol (19-nor-1,25[OH]2D2) is being more com- in risk of death from all causes relative to patients using monly used in the United States, perhaps following the Ca-based phosphate binders over a 2-year period, with retrospective report of reduced mortality in North Amer- mortality influenced by age and duration of treatment.69 ican HD patients taking paricalcitol rather than calci- However, this study did not reveal a significant survival triol.75 No trials as yet have adequately addressed the benefit for the non-Ca-based binder, failing to meet its implication of these newer vitamin D agents in relation to primary or secondary endpoints and showing no signif- icant difference in mortality or morbidity with sevelamercompared with Ca-based phosphate binders.
Interestingly, following the initial published literature revealing the advantages of sevelamer, it was emphasized The introduction of calcimimetic agents into clinical prac- by Backenroth, in a letter to the editor, that dialysate Ca tice has also had beneficial effects on serum Ca, phos- was not even included in the study.70 More recently, the phate, and Ca  P and have brought increased focus on effects of different dialysate Ca concentrations were as- the increased mortality risk associated with hyper- sessed with the use of sevelamer hydrochloride.71 With calcemia.76 Cinacalcet binds to and activates the Ca-sens- 1.37 mmol/L Ca dialysate, serum Ca levels decreased and ing receptor in the parathyroid glands, lowering the PTH levels increased significantly and with 1.25 mmol/L threshold for its activation by extra-cellular Ca and di- Ca dialysate, there was even transient hypocalcemia. The minishing PTH release. Again, similar to the initial trials group with a dialysate Ca of 1.5 mmol/L had unchanged with sevelamer, dialysate Ca was not considered with the Hemodialysis International 2006; 10:326–337 early study involving cinacalcet and therefore the optimal with LV dysfunction or frequent intra-dialytic hypotension, dialysate Ca bath to be prescribed in the setting of calci- but with reductions to 1.5 mmol/L should hypercalcemia mimetics has not been determined.77 The use of arise. Higher dialysate Ca concentrations of 1.75 mmol/L 1.75 mmol/L dialysate Ca was assessed in a small sample may also be necessary for patients whose medication list is of 7 HD patients, with administration of cinacalcet in pa- free of Ca-based binders and vitamin D supplements, as tients with severe secondary HPT showing reduction in well as for patients with marked secondary HPT and also serum PTH levels and without hypercalcemia.77 those undertaking NHD, although the long-term risk ofvascular calcification needs exploration.
Adjustment to the dialysate Ca concentration can change the overall Ca balance to maintain appropriate Recent changes in the management of mineral metabo- serum levels of Ca and phosphate and therefore reduce lism in patients with ESKD have placed more emphasis the risks of renal osteodystrophy and cardiovascular dis- on the concentration of Ca in dialysate. A dialysate Ca ease. Dialysate Ca concentration should be measured and concentration of 1.25 to 1.5 mmol/L is often the most taken into consideration in all studies analyzing serum appropriate for HD patients. The negative dialysis Ca bal- Ca, calcification, and mineral metabolism in HD patients, ance is countered by the oral administration of Ca-based and as mentioned more research is warranted to deter- phosphate binders and, if necessary, the use of vitamin D analogues for management of secondary PTH. This allowsan overall neutral total body Ca balance.78 A newer strat- egy of re-emerging aluminum-based phosphate binders insome countries and more importantly aluminum-free and With regard to the initial clinical scenario, the predom- Ca-free binders, such as sevelamer and lanthanum, world- inant aim for this patient would be for better phosphate wide, can be used for more optimal control of hyper- control and greater suppression of PTH. At the same time, phosphatemia without the excessive Ca load and the risk careful monitoring of serum calcium and Ca  P is equal- of exacerbating vascular calcification. With this strategy, it ly important to reduce the overall cardiovascular risk. If may be necessary to adjust upwards the dialysate Ca con- sevelamer is not available, a reduction in phosphate could centration with the re-introduction of 1.75 mmol/L be achieved through (i) the use of longer, more frequent dialysate Ca to avoid problems with secondary HPT. The dialysis such as NHD, (ii) stricter dietary phosphate re- use of noncalcemic vitamin D analogues and calcimimetics strictions, or (iii) the addition of more phosphate binders, also allows for higher dialysate Ca baths.
The decision to use a certain dialysate Ca should be Lanthanum would also be effective as a noncalcium- made with results of Ca loading or depleting during di- based phosphate binder, although regulatory restrictions alysis in association with information regarding the oral and cost issues in some countries may limit its use if Ca intake allowing an even total-body Ca balance. The sevelamer is unattainable as well. If there are concerns type and degree of renal bone disease and the associated about aluminum toxicity with aluminum-based binders, cardiovascular co-morbidities should also influence the an increase in Ca-containing phosphate binders (increas- individualized dialysate Ca level. Biochemical markers of ing the currently prescribed calcium carbonate to 3 tab- renal bone disease should be a consideration as a lower lets, 3 times daily) could be an option; however, there is a dialysate Ca concentration may be an advantage to those further risk of exacerbating hypercalcemia. The dialysate HD patients with adynamic bone disease to increase bone calcium concentration in this situation should be lowered formation and resorption. Cardiovascular status should and a dialysate calcium level of 1.25 to 1.5 mmol/L is be appreciated when choosing dialysate Ca baths, both probably most appropriate. With the use of a 1.25 mmol/ with the attempt at reduction of accelerated arterioscle- L Ca bath, there may be an overall negative Ca balance rosis as well as providing hemodynamic stability if there potentially worsening hyperparathyroidism (HPT).
Reducing serum phosphate should also help manage Recommendations are that patients taking Ca-based secondary HPT. Noncalcemic vitamin D analogues would phosphate binders should be dialyzed against Ca of 1.25 probably not provide any additional advantage to the cur- to 1.5 mmol/L. Lower dialysate concentrations (1.25 mmol/ rently prescribed calcitriol, although paricalcitol may prove L) should be used if adynamic bone disease exists with low in further studies to reduce hypercalcemia, vascular calci- PTH levels. Dialysate concentrations of 1.75 mmol/L may fication, and subsequent mortality and therefore may be be used to improve hemodynamics, especially for patients more beneficial. The addition of a calcimimetic agent, like Hemodialysis International 2006; 10:326–337 cinacalcet, would be another possible management option 11 Malberti F, Surian M, Poggio F, Minoia C, Salvadeo A.
to lower PTH without the risk of increasing serum calcium.
Efficacy and safety of long-term treatment with calcium The optimal dialysate calcium concentrations with the use carbonate as a phosphate binder. Am J Kidney Dis. 1988; of cinacalcet and paricalcitol have not been determined although higher levels would most likely be necessary.
12 Argiles A, Kerr P, Canaud B, Flavier J, Mion C. Calcium kinetics and the long term effects of lowering dialysate If the dialysis modality was changed to NHD with an calcium concentration. Kidney Int. 1993; 43:630–640.
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Manuscript received February 2006; revised April 2006.
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Hemodialysis International 2006; 10:326–337


Microsoft word - explanatory notes- 19 of 2009_2_.doc

SEC 2009 / 11 DCGS/ SCC/ CC/ DCC/AA.I.C/ SAA/AA Inland Revenue (Amendment) Act No. 19 of 2009 Explanatory Notes and Instructions The Inland Revenue Act No. 10 of 2006 (referred to in this note as the " principal enactment”) has been amended by the Inland Revenue (Amendment) Act No.19 of 2009 certified on 31st March 2009 (referred to in this note as the “Amendment Act”)

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