Serum calcium, phosphate, parathyroid hormone, albumin, aluminium and cholesterol achievement on replacement therapy (Chapter 9)
1Department of Clinical Biochemistry, East Kent Hospitals NHS Trust, Kent and Canterbury Hospital, Canterbury, Kent CT1 3NG, UK, 2UK Renal Registry, Bristol and 3Leicester General Hospital, Leicester
Correspondence and offprint requests to: Edmund J Lamb, UK Renal Registry, Southmead Hospital, Southmead Rd, Bristol, BS10 5NB, UK. Email: Edmund.lamb{at}ekht.nhs.uk
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Abstract |
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 Top Abstract IntroductionMethodsSerum phosphateSerum calciumSerum parathyroid hormoneAlbuminAluminiumCholesterolAppendix for definition of...References |
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In the UK, there is a continuing year-on-year trend towards improvement in serum phosphate control in dialysis patients although overall it still remains poor. The Renal Association (RA) target (<1.8 mmol/l) was achieved in 65% of patients overall, (71% of peritoneal dialysis (PD) patients, 63% of haemo dialysis (HD) patients).
Seventy-six percent of UK dialysis patients achieve a corrected calcium concentration within the RA target range. As with serum phosphate, there is a trend of continuing year-on-year improvement.
Nearly two-thirds (69%) of patients achieve a calcium x phosphate product within the KDOQI guidelines (<4.4 mmol2/l2): again, achievement seems to have improved year-on-year. Control was better in PD patients compared with HD patients (73% vs 67% achieving the standard).
There remains large between-centre variation in the ability of renal centres to achieve the UK RA target for plasma parathyroid hormone (PTH). As seen in previous years, overall achievement was poor (median 63%, range 47–92% compliance with the standard).
Most transplant patients achieve good phosphate and calcium control (99%, range 95–100%) and the percentage of patients achieving serum calcium concentrations within the target range was 84% (range 43–97%). Nearly all (99%) of transplant patients achieved calcium x phosphate product concentrations within the KDOQI target range.
There would appear to be wide variation in clinical practice with respect to aluminium monitoring with a suggestion that few centres are following current UK, RA guidelines.
Overall in the UK, 83% of HD, 70% of PD and 62% of transplant patients achieve a total cholesterol concentration <5 mmol/l. The percentage of patients with cholesterol <5 mmol/l has increased significantly year-on-year in all three modalities
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Introduction |
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Disorders of mineral metabolism are a common complication of chronic kidney disease (CKD). Bone disease is a significant cause of morbidity and there is increasingly convincing evidence that vascular calcification and the high rates of cardiovascular morbidity and mortality seen in patients with CKD may also be linked to abnormal mineral metabolism. In light of this, KDIGO have issued a consensus statement to provide a unifying classification of these abnormalities which is now termed CKD–MBD (CKD–Mineral and Bone disorder) [1].
There have now been several recent large observational cohort studies which have shown an association between hyperphosphataemia and increased mortality in dialysis patients [2–4]. However, there are no prospective trials showing that improving phosphate control prolongs survival. These observational studies have also shown some association with calcium concentrations and survival, but this relationship is much less clearly defined.
The achievement of audit standards in this area is recognized to be poor worldwide. It remains poor overall in the UK although the UK is the first country to demonstrate a year-on-year improvement in serum phosphate [5].
Growing interest has stemmed from the introduction of new treatments which may aid in modifying markers of mineral metabolism and potentially prolong patient survival. The nature of any definite survival benefit from non-calcium containing phosphate binders, new vitamin D sterols [6] and calcimimetics remains to be defined with the results of the DCOR study of sevalamer versus calcium based phosphate binders proving negative. However, it seems likely that some or all of these newer therapeutic agents will lead to improved control of calcium phosphate balance and hopefully patient survival.
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Methods |
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This chapter analyses the prevalent RRT cohort for 2005. The definition of the cohort is found in the appendix at the end of the chapter. The number preceding the centre name in each figure indicates the percentage of missing data for that centre. Data from Northern Ireland are included for the first time this year.
The Registry extracts quarterly data electronically from UK renal units. Quarterly values are extracted for the last two quarters for calcium and phosphate, the last three quarters for iPTH and the entire year for cholesterol and aluminium. Patients who do not have these data are excluded from the analyses. Patients are analysed both as a complete cohort and also divided by renal replacement therapy (RRT) modality into groups. Some analyses are also performed on a combined dialysis group. The completeness of data are analysed at unit and country level. All patients are included in analyses but units with <50% completeness are excluded from the caterpillar plots showing unit performance. Data are also excluded from plots when there are <20 patients with data both at unit and country level.
These data are analysed to calculate summary statistics (maximum, minimum, mean and median values in addition to standard deviation and quartile ranges). These data are represented as caterpillar plots showing median values and quartile ranges. Where applicable, the percentage achieving the Renal Association or other surrogate standard is also calculated and represented as caterpillar plots with 95% confidence intervals. For the percentage achieving standards, chi-squared testing is used to identify significant variability between centres. Longitudinal analysis has also been performed for some data to calculate overall changes in achievement of standards annually from 1998 to 2005.
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Serum phosphate |
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The RA Standard states:
Serum phosphate (measured before a dialysis session in HD patients) should be below 1.8 mmol/l.
The RA sets no standard for the lower limit of serum phosphate in contrast to the KDOQI guidelines [7] which set a lower limit of 1.13 mmol/l: the KDOQI upper limit is 1.78 mmol/l, consistent with the Renal Association standard. The draft 4th edition of the RA standards propose a lower limit of serum phosphate of 1.1 mmol/l.
Data completeness
The completeness of data by modality is shown in Table 9.1.
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Achievement of serum phosphate
Serum phosphate control amongst dialysis patients remains poor with 65% of patients overall achieving the RA Standard. In general, the phosphate control is better on peritoneal dialysis (71% achieve the standard), compared with haemodialysis (63% achieve the standard) (Figures 9.1 and 9.2). Encouragingly the year-on-year improvement in phosphate control noted in previous Registry reports seems to have continued (Figure 9.3). The variation between units is wide (Figures 9.1 and 9.2). For both HD (
2 = 397, P < 0.001) and PD (2 = 102, P < 0.001) modalities, the percentage of patients with a serum phosphate <1.8 mmol/l differed significantly between centres. Amongst patients who had received a transplant, phosphate control was good (median 1.01 mmol/l, mean inter-quartile range 0.87–1.18 mmol/l, Figure 9.4) with all units achieving the target in at least 97% of patients. There was no evidence of significant variation between units (2 = 61, P = 0.1395).
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Identification of outliers in achievement of serum phosphate
The Registry is currently exploring different methods of analysing and presenting performance data for achievement of RA Standards. Use of a funnel plot helps to demonstrate centre performance against unit size (defined by number of patients) and prediction of outlier limits by plotting the threshold of 2 (95% limit) and 3 (99.8% limit) SDs from the UK mean. These limits correspond to P-values of 0.05 and 0.002, respectively. This helps to identify renal units that are performing statistically ‘better’ or ‘worse’ than average. With 50 centres, one unit may each fall above and below the 2 SD line by chance, but none should fall outside the 3 SD line by chance.
This year for the first time, achievement of the phosphate standard in haemodialysis patients is presented using a funnel plot. This is an exploratory analysis into the usefulness of these data for renal units. Figure 9.5 shows that eight units have ‘better’ than expected performance although there are also four units that have ‘worse’ than expected performance against the line of 3 SD.
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In last years report the UKRR demonstrated that older patients have a better achievement of the phosphate standard (Report 2005 Chapter 13), so a part of the demonstrated variation in Figure 9.5, may be accounted for by the difference in the median age of patients as these data are unadjusted for age. Table 9.2 can be used to assist individual units identify themselves by cross referencing unit size (X-axis) with the percentage of patients with phosphate <1.8 mmol/l (Y-axis) in Figure 9.5.
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These data should help exploration and promote discussion of the reasons for differences in these outlying units. Although these differences are statistically significant, it should be stressed that it cannot be automatically assumed that this means they are clinically important.
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Serum calcium |
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The RA Standard states:
Serum calcium, adjusted for albumin concentration, should be between 2.2 and 2.6 mmol/l, in HD (pre-dialysis sample) and in PD patients.
Comparative audit in this area remains difficult, due to differences in analytical methods between units (and even between satellite units managed by one clinical team), different mathematical methods being applied to correct serum calcium for serum albumin concentration and different methods in analysing serum albumin (see the Registry reports 1999–2003). However, as discussed in previous Registry reports, since nephrologists in each unit will be making clinical decisions based on their local corrected calcium results, these data are in some sense the most valid and this data has been chosen for illustration. Some units provide data already corrected for albumin concentration and these are analysed directly; uncorrected calcium data provided by some units is corrected using a formula in widespread use [8]:
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Data completeness
The completeness of data by modality is shown in Table 9.3.
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Achievement of serum calcium
The median corrected calcium is 2.37 mmol/l (mean inter-quartile range 2.26–2.49 mmol/l) for HD patients and 2.40 mmol/l for PD patients (mean inter-quartile range 2.30–2.51 mmol/l) with 76% of dialysis patients (75% HD and 79% PD) achieving a concentration within the RA target range (Figure 9.6). There has been a general trend towards improved performance over the period 1998–2005 with a quite marked improvement in the PD population in particular in the last year (Figure 9.7). The variation between units is wide: for both HD (
2 = 299, P < 0.0001) and PD (2 = 96, P = 0.0002) modalities, the percentage of patients with serum corrected calcium within the RA target range differed significantly between centres.
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Achievement of the calcium target amongst patients who had received a transplant was better than that amongst dialysis patients, with 85% of transplant patients achieving corrected calcium concentrations within the target range (Figures 9.8 and 9.9). The percentage of transplant patients with a serum corrected calcium within the RA target range differed significantly between centres (
2 = 191, P < 0.0001).
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Serum calcium x phosphate product
The RA has no standard for the serum calcium x phosphate product
The RA currently has no standard for the serum calcium x phosphate product, but the draft 4th edition of the RA guidelines recommends that the product should be < 4.8 mmol2/l2. The KDOQI guidelines recommend the product should be < 4.4 mmol2/l2 (=55 mg2/dl2). Two-thirds (69%) of patients achieve this but the range of 49–84% between units remains wide (Figure 9.10). Control is better on PD, with 73% (range 47–89%) of patients achieving the standard when compared with 67% of patients on HD (range 45–83%) and this is shown in Figures 9.11 and 9.12. The variation between units was significant for both HD (
2 = 417, P < 0.001) and PD (2 = 120, P < 0.001) modalities. There is evidence of a year-on-year improvement in attainment of this standard (Figure 9.13).
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Serum parathyroid hormone |
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The RA Standard states:
Parathyroid hormone (PTH) concentration should be less than four times the upper limit of normal of the assay used in patients being managed for chronic renal failure or after transplantation and in patients who have been on HD or PD for longer than three months.
Comparison of serum PTH values from different units is difficult due to the variety of methods and reference ranges in use. To enable some form of comparative audit, the Registry has expressed all results in pmol/l, and chosen an upper limit of four times the median upper lab value: this equates to 32 pmol/l. This is also similar to the upper limit of the KDOQI guidelines (31 pmol/l). In the UK, no lower limit for PTH is specified although KDOQI recommends a limit of 15 pmol/l.
Data completeness
The completeness of data by modality is shown in Table 9.4.
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Achievement of serum iPTH
The median PTH for all dialysis patients was 22 pmol/l although the range of medians was wide (13 to 38 pmol/l), with four centres achieving a median concentration above the upper limit set for all patients which indicates that < 50% of patients were within target (Figure 9.14). Median PTH appeared to be slightly higher overall amongst PD (25, inter-quartile range 12–47, range of medians 15–48 pmol/l) patients compared with HD (22, inter-quartile range 10–47, range of medians 13 to 38 pmol/l) patients. Overall, 63% of dialysis patients (61% PD; 63% HD) achieved the RA standard, but the spread of data was remarkable, ranging from 47% to 92% compliance with the standard (Figure 9.15). This analysis is almost certainly compromised by the wide variations in analytical recovery of PTH in commercial assays and also the lack of security around the reference limits that laboratories have selected as being appropriate for their assays [9]. Laboratory standardization of these measurements remains under discussion.
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Albumin |
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The RA has no standard for the serum albumin
The RA Standards document recognizes the importance of serum albumin as a marker of outcome, but does not recommend setting an audit standard for serum albumin, predominantly due to lack of standardization of albumin assays between laboratories. Serum albumin concentration is influenced significantly by the dye used in the assay method; either bromocresol green (BCG) or bromocresol purple (BCP) and has been discussed at length in previous reports.
For the Registry report in previous years, centres have been separated by methodology of albumin measurements. This year data were analysed on quarterly median albumin by each HD satellite unit or main unit (n = 181 centres), over a 7-year period. Except where albumin methodologies were changed, median albumin results remained unchanged over time to within 1 g/l. As there would have been a large shift in patients over this time period, this probably indicates that differences between centres in median albumin are accounted for by laboratory methodologies.
In the 2005 Report Chapter 10, it was commented on that continued presentation of albumin achievement data in the Registry annual report was of limited value. Unless there were strong calls from the renal community with an opposing viewpoint, these data would not be published in the following years report. For this reason the data on median albumin by centre are not shown.
The Registry continues to collect individual patient data on albumin which will be incorporated in analyses of patient outcome, as ‘within-patient’ fall in serum albumin remains an important surrogate marker of patient survival.
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Aluminium |
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The RA Standard states:
Serum aluminium concentration should be measured every three months in all patients on HD and in all PD patients receiving oral aluminium hydroxide.During 2005, the Registry received aluminium data from 13 168 HD samples and 3690 PD samples. Overall, 36% of HD patients and 9% of PD patients (compared with 39% of HD patients and 15% of PD patients in 2004) had a serum aluminium concentration checked once during the year. However, there was enormous variation in reported compliance with this standard with 15 centres reporting no aluminium data for HD patients and a further 13 centres reporting data in <10% of their patients. Amongst PD patients, 30 centres reported no aluminium data and a further 12 centres data in <10% of their patients.
It is possible that the Registry is not capturing all of the aluminium monitoring that is taking place, not least because aluminium measurement is not generally available in local laboratories and there may, therefore, be practical limitations in respect of data transmission back to the renal unit database. However, it also seems probable that many renal centres have abandoned routine monitoring of aluminium in dialysis patients or have at least deviated from the RA standard recommendations in terms of frequency of testing. Generally it is acknowledged that aluminium-related bone disease is a diminishing problem and water treatment facilities in HD units are tested on a monthly basis for aluminium. The KDOQI guidelines are slightly less stringent than the RA guidelines, with the recommendation that serum aluminium should be measured at least yearly and every 3 months in patients receiving aluminium-containing medications [7]. The draft 4th Edition of the RA guidelines advises limiting serum aluminium concentration monitoring to patients receiving oral aluminium hydroxide.
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Cholesterol |
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The RA Standard states:
Primary prevention:Statins should be considered in dialysis patients with a 10-year risk of coronary disease > 30% to achieve a total cholesterol concentration < 5 mmol/l or a 30% reduction from baseline.
Secondary prevention:
In patients in whom lipid-lowering drug treatment is used, total cholesterol should be reduced by 30% or to below 5 mmol/l, whichever reduction is the greater.
Data completeness
The completeness of data by modality is shown in Table 9.5 for each modality
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Achievement of serum cholesterol
The Registry collects serum total cholesterol data, audited against a target concentration of 5 mmol/l. New data items added to the quarterly Registry extraction downloads from renal systems include HDL cholesterol and use of ‘statins’. These new data items will greatly enhance the interpretation of the cholesterol data.
Amongst HD patients the median serum cholesterol was 3.9 mmol/l (inter-quartile range 3.3–4.6 mmol/l) and 83% of patients achieved the target of <5 mmol/l, although this ranged between units from 71% to 92% (Figure 9.16). Amongst PD patients the median serum cholesterol was 4.4 mmol/l (inter-quartile range 3.7–5.1 mmol/l) and 70% of patients achieved the target of <5 mmol/l, although this ranged between units from 54% to 89% (Figure 9.17). Amongst transplant recipients the median serum cholesterol was 4.7 mmol/l (inter-quartile range 4.1–5.3 mmol/l) and 62% of patients achieved the target of <5 mmol/l, although this ranged between units from 38% to 80% (Figure 9.18).
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Chi-square testing indicates that the difference between centres for all three treatment modalities is significant (P < 0.0001). As in previous years, cholesterol concentrations are lower in HD patients than PD patients and higher in transplant patients than in dialysis patients (Figure 9.19).
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In all three treatment modalities there have been marked year-on-year improvements in the percentage of patients achieving the target concentration (Figure 9.20). As discussed above, the Registry does not currently collect prescribing data to enable this to be linked to a lipid-lowering treatment effect and these data are confounded by the known associations between chronic disease, inflammation, malnutrition and hypocholesterolaemia. Likewise, higher cholesterol concentrations in transplant recipients may reflect improved appetite or the hypercholesterolaemic influence of steroids, calcineurin inhibitors and sirolimus.
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Appendix for definition of prevalent cohort for biochemistry chapter |
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TopAbstractIntroductionMethodsSerum phosphateSerum calciumSerum parathyroid hormoneAlbuminAluminiumCholesterolAppendix for definition of...References |
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Definition of prevalent cohort
- Prevalent patients are defined as all patients (including the incident cohort for that year) alive on 31st December for that year
- Data set called Qtreat
Qtreat
- Usual UKRR checking programs run on data set
- Exclusion criteria applied to create data set Qtemp
Exclusion criteria are:
- Patients who had died before the first day of the quarter
- Patients on dialysis with a treatment centre of elsewhere (not identified)
- Patients receiving treatment at a non-Registry site
- Patients with no date of starting ERF treatment
- Patients who had been receiving treatment for a negative number of days i.e. incorrect starting dates or incorrect patient number on data sent in
- Patients who had recovered before the start of the quarter
- Where data on a patient are submitted from more than one centre, only data from the primary centre are used
Qtemp
- Further exclusion criteria applied to Qtemp to create data set called Quarter
Exclusion criteria are:
- Patients who have transferred out of the centre (qhcent) by the end of the quarter
- Patients who had not yet transferred in to the centre (qhcent) by the end of the quarter
- Patients who had recovered by the end of the quarter
- Patients who had stopped treatment by the end of the quarter
- Patients who had died by the end of the quarter
- Patients who were lost to follow up by the end of the quarter
Quarter
- Further exclusion criteria applied to quarter to create data set called Bichem
Exclusion criteria are:
- Patients who had been on ERF treatment for
90 days at the end of the quarter
- Patients who changed treatment modality in the quarter
- Patients who transferred into the centre (qhcent) at some time in the quarter
Conflict of interest statement. None declared
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References |
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TopAbstractIntroductionMethodsSerum phosphateSerum calciumSerum parathyroid hormoneAlbuminAluminiumCholesterolAppendix for definition of...References |
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- Moe S, Dreuke T, Cunningham J, et al. Kidney disease: improving global outcomes. Definition, evaluation and classification of renal osteodystrophy. In: Kidney Int (2006) 69:1945–1953. A position statement from Kidney Disease; Improving Global Outcomeswww.kdigo.org.[CrossRef][ISI][Medline]
- Block GA, Klassen PS, Lazurus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality and morbidity in maintenance haemodialysis. J Am Soc Nephrol (2004) 15:2208–2218.
[Abstract/Free Full Text] - Kalantar-Zadeh K, Kuwae N, Regidor GL, et al. Survival predictability of time-varying indicators of bone disease in maintenance haemodialysis patients. Kidney Int (2006) 70:771–780.[CrossRef][ISI][Medline]
- Stevens LA, Djurdjev O, Cardew S, Cameron EC, Levin A. Calcium, Phosphate and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes. J Am Soc Nephrol (2004) 15:770–779.
[Abstract/Free Full Text] - Ansell D, Feest T, Williams A, Winearls C, eds. UK Renal Registry Report 2005. Bristol, UK: UK Renal Registry.
- Teng M, Wolf M, Lowrie E, Ofsthun N. Survival of patients undergoing haemodialysis with paracalcitol or calcitriol therapy. N Engl J Med (2003) 349:446.
[Abstract/Free Full Text] - Eknoyan G, Levin A, Levin NW. K/DOQI Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis (2003) 42(Suppl 3):s1–s201.[Medline]
- Ansell D, Feest TG. The Third Annual Report of the UK Renal Registry 2000, Bristol, UK. (2000).
- Lamb EJ, Vickery S, Ellis AR. Parathyroid hormone, kidney disease, evidence and guidelines. Ann Clin Biochem (2007) 44:1–4.[ISI][Medline]
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