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CKD: Hyperphosphatemia (2010)


Martinez I, Saracho R, Montenegro J, Llach F.  The importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure.  Am J Kidney Dis 1997;29(4):496-502.

Worksheet created prior to Spring 2004 using earlier ADA research analysis template.
PubMed ID: 9100037
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

The purposes of this study were to 1) determine when abnormalities in calcium, phosphorus, and calcitriol occur and when hyperparathyroidism (HPT) develops in the course of CKD (cross-sectional design); and 2) how dietary calcium and phosphorus intake affect these early abnormalities once they occur (randomized control design).

Inclusion Criteria:

1. CKD

2. Kidney disease stable

3. Ad libitum diet

4. No interrecurrent illnesses

Exclusion Criteria:

1. Medication use: diuretics, phosphate binders, calcium supplements, vitamin D analogs

2. History of kidney stone

3. Serum albumin <3.5 g/dL

Description of Study Protocol:


Subjects were chosen that had a significant decrease in calcitriol (P<0.05) and CrCl >65 ml/min.

Design:  Cross-Sectional Study and RCT

Blinding Used (if applicable):  not applicable

Intervention (if applicable):

Study diet:

1. 3 different diet phases: baseline: subjects consumed usual diet during data collection for cross-sectional study; first 10 days low-protein/low phosphorus diet; second 10 days low-protein/low phosphorus + phosphorus load (+ 1 g phosphorus).

2. subjects were randomly assigned to study diet A or B.

3. both study diets provided 40 g protein, 600 mg phosphorus, 500 mg calcium and 1800 –2000 kcal.

4. study diet B (+ Ca) included an additional 0.5 g calcium.

5. adherence to study diet evaluated using protein and phosphorus clearance rate.

Statistical Analysis

ANOVA was used to compare the various groups of patients.  To evaluate significant differences between groups, the Duncan test was used.  One-way ANOVA for repeated measures was also used.  The paired t test was used to test significant differences between paired measurements of the same patients.  Linear regression analysis was used to test quantitative associations between the two variables.

Data Collection Summary:

Timing of Measurements

Biochemical determinations: same as for cross-sectional study; 24-hr urines on days 0,10,20; fasting blood on days 1, 11, 21.

Dependent Variables

  • Fasting blood sample taken for determinations of total and ionized calcium, phosphorus, creatinine, calcitriol, and PTH
  • 24-hr urine sample for analysis of calcium, creatinine, phosphorus

Independent Variables

Study diet:

1. 3 different diet phases: baseline: subjects consumed usual diet during data collection for cross-sectional study; first 10 days low-protein/low phosphorus diet; second 10 days low-protein/low phosphorus + phosphorus load (+ 1 g phosphorus).

2. subjects were randomly assigned to study diet A or B.

3. both study diets provided 40 g protein, 600 mg phosphorus, 500 mg calcium and 1800 –2000 kcal.

4. study diet B (+ Ca) included an additional 0.5 g calcium.

5. adherence to study diet evaluated using protein and phosphorus clearance rate.

Control Variables

Description of Actual Data Sample:

Initial N:  Cross-sectional study:  157 subjects (59 female, 98 male) in various stages of CKD.  RCT:  5 subjects in group A and 2 subjects in group B were excluded because of poor dietary compliance (PCR).

Attrition (final N):  157 in the Cross-Sectional study, In RCT:  Group A:  8 women, 12 men; Group B: 14 women, 17 men

Age:  Cross-Sectional Study:  mean age 55 years.  RCT Group A mean age 47 years, Group B 44 years

Ethnicity:  not mentioned

Other relevant demographics:


Location:  Hospital in Spain

Summary of Results:

Mean Biochemical Parameters


CrCl PTH Calcitriol I-Ca Phosphorus
  Ml/min ng/ml pg/ml mg/dL
9 10-19 164* 17 5.13 4.23
9 20-29 119* 18 4.54 3.83
11 30-39 115* 21 4.67 3.65
12 40-49 69 20 4.67 3.22
14 50-59 52 22 4.68 2.89
30 60-69 57 23 4.69 2.91
17 70-79 48 22 4.79 3.07
13 80-89 34 27 4.75 3.00
14 90-99 38 32** 4.72 3.11
28 >100 42 31** 4.54 3.05

* P<0.05 compared to CrCl >50 ml/min

**P<0.05 compared to CrCl <79 ml/min

HPT developed early in CKD when plasma calcium and phosphorus were normal. As CrCl decreased <80 ml/min, there was a significant decrease in calcitriol, a slow and progressive significant increase in PTH.

Causes of CKD in Study Subjects

Glomerular disease and/or %

Diabetic nephropathy 40

Interstitial disease and

Polycystic kidney disease 28

Vascular etiology and/or

Hypertension 16

Randomized control study:

Biochemical Parameters

Study Diet
Group A Basal Decrease pro/po4 + 1 g po4
i-Ca, mg/dl 4.75 4.72 4.69
Po4, mg/dl 2.91 2.66 2.78

Calcitriol (pg/ml)

23.0 22.8 22.0
PTH, pg/ml 42.8 43.1 50.8
Urine Po4 889 650 1,164

(mg/24 hr) CrCl, ml/min

90 77 84
PCR, g/24 hr 88 46 48
Group B Basal ? pro/po4 + 1 g po4
i-Ca, mg/dl 4.90 4.83 4.81
Po4, mg/dl 3.07 3.08 3.23

Calcitriol (pg/ml)

21.3 20.6


PTH, pg/ml 43.4 35.8 47.4
Urine Po4 845 475 988

(mg/24 hr) CrCl, ml/min

78 68 69
PCR, g/24 hr 79 42 42

Dietary protein and phosphorus restriction resulted in normalization of PTH only in subjects receiving 0.5 g calcium supplementation (total ~1 g calcium/d) (P<0.05). Phosphate loading (+ 1 g phosphorus, total 1.6 g) resulted in worsening of HPT in both study groups.

Author Conclusion:

HPT develops in early CKD when calcitriol levels may be within normal limits due to the incipient HPT. Once CrCl decreases <80 ml/min, it becomes apparent that a decrease in calcitriol synthesis is an important factor in HPT. The increased levels of PTH maintain appropriate levels of calcitriol as long as there is enough renal mass.

As CrCl decreases <40 ml/min, the levels of calcitriol decrease further, leading to a worsening of HPT.

In the RCT, an appropriate calcium intake together with phosphorus restriction resulted in better control of the HPT, suggesting that a calcium-containing phosphate binder, such as calcium carbonate, administered between meals and as a phosphate binder after meals, may be an important early therapeutic approach to the prevention of HPT by avoiding hyperphosophatemia and providing adequate calcium intake.

Funding Source:
University/Hospital: Hospital de Galdakao (Spain), Newark Beth Israel Medical Center University of Medicine and Dentistry of New Jersey
Reviewer Comments:

This study did not report the use of a dietitian in planning the diets or instructing the subjects on the study diet. It appears that the subjects were hospitalized during the study.

The cross-sectional study shows an association between increased PTH, decreased calcitriol and CrCl <50 ml/min.

The RCT showed an initial decrease in CrCl on the low protein/low phosphorus diet. Similar results have been reported in other studies after beginning a low protein diet. There was a 14% drop out rate because 7 subjects were unable to follow the protein-restricted diet.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes