Golzy et al.

BMC Nephrology 2013, 14:154

http://www.biomedcentral.com/1471-2369/14/154

RESEARCH ARTICLE

Open Access

Renal function, calcium regulation, and time to

hospitalization of patients with chronic kidney
disease
Mojgan Golzy1* , Russell W Bessette2 and Randy L Carter1

Abstract
Background: Chronic kidney disease is associated with disruption of the endocrine system that distorts the balance
between calcitriol, calcium, phosphate and parathyroid hormone in the calcium regulation system. This can lead to
calcification of the arterial tree and increased risk of cardiovascular disease and death. In this study we develop a
health metric, based on biomarkers involved in the calcium regulation system, for use in identifying patients at high
risk for future high-cost complications.
Methods: This study is a retrospective observational study involving a secondary analysis of data from the kidney
disease registry of a regional managed care organization. Chronic kidney disease patients in the registry from
November 2007 through November 2011 with a complete set of observations of estimated glomerular filtration rate,
calcitriol, albumin, free calcium, phosphate, and parathyroid hormone were included in the study (n = 284). Weibull
regression model was used to identify the most significant lab tests in predicting waiting time to hospitalization. A
multivariate linear path model was then constructed to investigate direct and indirect effects of the biomarkers on
this outcome.
Results: The results showed negative significant direct effects of phosphate and parathyroid hormone on waiting
time to hospitalization. Base on this result, the risk of hospitalization increases 16.8% for each 0.55 mg/dl increase in
phosphate level and 13.5% for each 0.467 increase in the natural logarithm of parathyroid hormone. Positive indirect
effects of calcitriol surrogate (calcidiol), free calcium, albumin and estimated glomerular filtration rate were observed
but were relatively small in magnitude.
Conclusion: Variables involved in the calcium regulation system should be included in future efforts to develop a
quality of care index for Chronic Kidney disease patients.
Keywords: Quality of care metric, Risk assessment, Prediction, Censored Weibull regression, Path modeling, Direct
and indirect effects

Background
Kidney disease is the ninth leading cause of death in the
United States [1]. Chronic kidney disease (CKD) is associated with disruption of the endocrine system that distorts
the balance between calcitriol, calcium, phosphate (PO4)
and parathyroid hormone (PTH) in the calcium regulation system [1-4]. This can lead to calcification of the
arterial tree and increased risk of cardiovascular disease
*Correspondence: [email protected]
1 Department of Biostatistics and Population Health Observatory, State
University of New York at Buffalo, Buffalo, NY, 14214-3000, USA
Full list of author information is available at the end of the article

(CVD) and death [5-8]. There are different opinions on

which serum enzymes or minerals reliably predict advancing illness and high cost healthcare in CKD patients [9].
Bessette and Carter [9] employed multivariable logistic
regression to investigate which serum chemistry values
are significantly associated with in-patient hospital costs
exceeding $3,000 in any single month. Their results suggested the calcium regulation system may play an important role in the health and cost of treatment of patients
with CKD. In that paper, due to the small sample size
and short follow up period, the average costs and average lab results over a 13 months period were analyzed.

2013 Golzy et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Golzy et al. BMC Nephrology 2013, 14:154

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Averaging would be a limitation in the current study

given our desired to describe causal relationships. Given a
longer follow up period of 4 years and a larger sample size,
we now can more precisely assess the impact of kidney
function and calcium homeostasis imbalances on the risk
of hospitalization using longitudinal instead of averaged
data.
The main purpose of this study is to develop a health
metric, based on variables involved in the calcium regulation system (calcium, PO4, PTH), a kidney function
indicator (eGFR), and a set of kidney function associates
(calcitriol and albumin), that is related to the risk of future
high-cost complications. We test the significance of estimated direct and indirect effects of these kidney function
measures and serum chemistry values on waiting time
to hospitalization in CKD patients with widely varying
severity of disease.
The National Kidney Foundation (NKF) defines CKD as
either kidney damage or a sustained kidney glomerular filtration rate (GFR) of less than 60 ml/min/1.73 m2 for 3 or
more months [10]. An estimate of GFR (eGFR) can be calculated from the patients routine blood tests. The highest
incidence rate of End-stage Renal Disease (ESRD) occurs
in patients older than 65 years [11]. Age, diabetes mellitus,
and hypertension are major predictors of chronic kidney
disease [11].
Phosphate (PO4), calcium, activated vitamin D 1,25dihydroxyvitamin D3 (calcitriol), parathyroid hormone
(PTH) and their influence on kidney function play an
important role in controlling the level of phosphate and
calcium in the bloodstream. Healthy kidneys are rich with
1-alpha hydroxylase enzyme, which plays a major role
in turning vitamin D into its active form, calcitriol. Calcitriol acts on vitamin D receptors, which control calcium
channels and therefore is an important component of the
calcium regulation system. Secondarily, it controls the
absorption of phosphate and in turn regulates PTH levels. When kidneys fail, their ability to activate vitamin D

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is diminished. Without the activated vitamin D to facilitate calcium and phosphate absorption, PTH will increase,
which results in calcium and phosphate resorption from
the bone [12,13] (see Figure 1). An illustration of the interaction between calcium, phosphate, PTH, and calcitriol is
presented in Figure 1 . Silver et al. [3], and Palmer et al. [8]
provide additional information.

Method
Data

The data set analyzed contains blood test results: eGFR,

calcidiol, albumin, Ca++ , PO4, and PTH from 284
de-identified patients. The data did not include the measurement of the serum calcitriol and so we use 25hydroxyvitamin D (calcidiol) as a surrogate for serum
calcitriol. There is a significant biphasic relationship
between serum calcitriol and serum calcidiol. This relation is positive at normal calcidiol levels, because of the
effect of substrate deficiency on calcitriol production, but
negative at low calcidiol levels, because secondary hyperparathyroidism simulates the synthesis of calcitriol [14].
About 90% of the serum calcidiol measurements, in our
data set, were in normal range. So, it is reasonable to
used the strongly correlated calcitriol as a surrogate in our
study. Therefore, calcidiol effects found in our analyses
can be interpreted as calcitriol effects.
The data set were drawn from the kidney disease registry of a managed care organization (MCO) during the
4 year period from Nov. 2007 through Nov. 2011. The
data set also included age, gender, service date and a complete financial profile for all medical claims that were
paid for these patients over that same time period. Service date is a date that medical services were provided.
A service constitutes lab tests, procedures, hospital services, physician services, office visits, or other services
for which claims were submitted. Charges for services
were matched with corresponding date of service. This
data was obtained after review of the study protocol by

Figure 1 Interaction between calcium, phosphate, PTH, and calcitriol [12].

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the university at Buffalos Health Sciences Institutional

Review Board (HSIRB) and permission from the regional
MCO.
The registry contained records of 14,264 patients who
were treated for kidney disease during this time period.
5,799 of those had confirmed CKD (as defined by eGFR
calculated using the MDRD equation of less than 60
ml/min/1.73 m2 for 3 or more months.) 284 of those had
complete observation (see subsequent paragraphs). We
compared the 284 selected patients (study group) to the
remaining 5,515 CKD patients to check the representativeness of the sample analyzed. For each individual, we
calculated the average lab tests over the entire time period
and then used PROC TTEST in SAS software. Table 1
gives the summary of the results as the number of observations, mean, and standard deviation for each group and
the pooled p-value for mean differences for each variable. Considering the significant level = 0.05/7 =
0.007, using the Bonferroni correction, the means are not
significantly different. Thus, we have no significant evidence that the sample of 284 patients analyzed in this
study are not representative of all CKD patients in the
registry.
In this data set, a hospitalization is said to have
occurred when a month of charges exceeded $3,000 and
those charges were confirmed to be for hospital services.
We defined the date of hospitalization to be the service
date with maximum cost in a month with monthly cost
greater than $3,000. For each individual, we determined
the dates of all hospitalizations, if any.

Definition of variables

It is generally agreed that the ionized (or free) calcium is

the form that is biologically active. Because of this, free
calcium (Ca++ ) is a more useful index than total calcium
and provides a better indication of calcium status [15-17].
Ionized calcium can be measured directly with the use
of calcium-specific electrodes. If ionized calcium cannot
be measured, however, certain approximations can be utilized to distinguish the protein bound calcium from the
ionized fraction calcium. We adopt the following formula
from [15] to calculate free calcium.
% protein-bound calcium 0.8 albumin(g/l)
+ 0.2 globulin (g/l) + 3
Free calcium (ionzed calcium Ca++ ) total calcium
protein bound to calcium
For patients with at least one hospitalization, we
searched the hospitalization intervals, from the first to
the last, for a complete set of observation of lab tests of
interest. Hospitalization intervals are; 3 weeks after the
first service date until 3 weeks before the first hospitalization, 3 weeks after one hospitalization until 3 weeks
before the next hospitalization, and 3 weeks after the
last hospitalization until the last service date. We did not
include lab tests taken within 3 weeks before a hospitalization due to the fact that these tests could be taken in
preparation for that hospitalization, which would make
for an artificially short waiting time to hospitalization. We

Table 1 Comparison of the study group and the remaining other CKD patients
Variable

Group

Mean

Unit

Standard

Age

Study group

284

67.9

Years

12.9

Other CKD pat.

5367

69.4

Study group

284

32.77

mL/min/1.73m

11.9

Other CKD pat.

5515

30.6

p-value

deviation

eGFR

Albumin

Calcidiol

PTH

PO4
Ca++

Study group

284

4.13

Other CKD pat.

4946

4.08

Study group

284

26.6

Other CKD pat.

1492

27.01

Study group

284

96.3

Other CKD pat.

819

93.27

Study group

284

3.61

Other CKD pat.

1296

3.66

Study group

284

5.25

Other CKD pat.

4535

5.22

0.09

14.4
0.04

17.48
gm/dl

0.29

0.02

0.4
ng/ml

13.7

0.6

13.54
pg/ml

106.6

0.6

113.7
mg/dl

0.60

0.3

0.68
mg/dl

0.45

0.3

0.41

The number of observations, mean and standard deviation for each group and the pooled p-value for mean differences for each variable. ( ) Study group is the
confirmed CKD patients in the registry with use-able complete observations. ( ) The remaining confirmed CKD patients in the registry (as defined by at least one
eGFR calculated and max{eGFR} 60 ml/min/1.73 m2 ).

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also excluded test taken within 3 weeks after the previous hospitalization due to the fact that these tests may
reflect a causal association of last hospitalization event on
test scores which is not direction of causation we want
to study.
To search for a complete set of lab tests in an interval, we selected the first set of observed lab test scores in
that interval. Since PO4 comes last in our causal ordering we selected an observation of PO4 which a complete
set of other lab tests was observed before or simultaneously with the selected observation. If the first interval did
not contain a complete set of lab scores then we moved
to the next interval and continued in this fashion until an
interval with a complete set of lab scores was observed.
If a complete set was not observed in at least one interval then the patient was not included in the analysis data
set. After completing this process for each patient, 284
patients remained in the data set to be analyzed.
To define the outcome variable, waiting time to hospitalization (WTH), we considered the hospitalization interval
in which a complete set of lab tests was observed and then
defined the waiting time to hospitalization by the time
from the left of that interval until the next hospitalization. For individuals with no hospitalization, we selected
the first lab tests in the time interval from 3 weeks after
first service date until the last service date. For these
individuals with no hospitalization, waiting time to hospitalization is censored at C, where C is the time from
3 weeks after the first service date until the last service
date. Also for individuals with at least one hospitalization and with a complete set of lab observations only after
the last hospitalization, waiting time to hospitalization is
also censored at C, where C is the time from 3 weeks
after the last hospitalization until the last service date.
(see Figure 2)

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Normal probability plots were used to assess the normality of each variable (in a statistical sense). If a variable was non-normal a normalizing transformation
was applied. We used the natural log transformation of the non-normal variable PTH to normalize it.
No transformation was required for other lab variables because they appeared to be normally distributed,
based on normal probability plot. The normal limits for lab test scores studied are given in Table 2.
Normal limits for ln(PTH) were calculated by similarly transforming the upper and lower normal limits of
PTH.
Using the normal limits in Table 2, we standardized each
ln(PTH) and each variable that did not require transformation. The average of the corresponding normal limits
was taken as the mean, and the range of the normal limits
divided by 4 as the standard deviation in the standardization calculations. Let z-eGFR, z-albumin, z-calcidiol,
z-PTH, z-PO4 and z-Ca++ denote the z-scores of the
corresponding variables (transformed variable in the
case of PTH).
Statistical methods

We first used a censored regression model [18,19] to estimate the effect of each kidney function and each calcium
homeostasis covariate while controlling for other covariates on the mean of the natural log of waiting time to hospitalization. The other variables in causal ordering given
in the next section are modeled as function of the previous variables in that ordering, using multiple regression
analysis.
In the censored regression model ln(Y ) = +  Z + .
with Weibull distribution for Y, is the scale parameter
and  is the error term. Z is vector of covariates and
is the vector of regression coefficients, which represent

Figure 2 Calculation of waiting time to hospitalization in four situations. I. Patients with no hospitalization with a complete set of
observations after t1 , where t1 is 21 days after the first service date. II. Patients with hospitalization with a complete set of observations in the first
hospitalization interval [t1 , t2 ], where t1 is 21 days after the first service date and t2 is 21 days before the first hospitalization. III. Patients with
hospitalization who had their first complete set of observation in the kth hospitalization interval [t1k , t2k ], where t1k is 21 days after the kth
hospitalization and t2k is 21 days before the (k + 1)th hospitalization. IV. Patients with hospitalization who had their first complete set of observation
in the last hospitalization interval [t1l , t2l ], where t1l is 21 days after the last hospitalization and t2l is the last service date.

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Table 2 The normal limits for the lab test scores and
transformed lab test scores
Variable

Normal limits

Unit

The hazard ratio corresponding to the k th variable for a

Weibull model is given by exp(k / ) where k is the
corresponding regression coefficient for the k th variable
and is the scale parameter.

eGFR

Male (100, 140), Female (85, 115)

mL/min/1.73m2

Albumin

(3.6, 5)

gm/dl

Multivariate path analysis

Calcidiol

(9.7, 41.7)

ng/ml
pg/ml

Path analysis is a statistical technique used to examine

direct and indirect relationships among a set of causally
ordered variables. Such relationships, if linear, can be
described in a system of linear equations with random
variables of interest and unknown parameters. Path analysis was first developed by Sewall Wright in the 1930s for
use in phylogenetic studies [20,21]. Classical path analysis assumes a complete casual ordering of variables with
unidirectional relationships (i.e., no feedback loops.) Path
analysis allows us decompose total effects of upstream
variables on subsequent variables in the causal ordering
into direct effects and indirect effects. While classical
methods require a complete causal ordering of variables,
Multivariate Linear Path Model (MLPM) allows a relaxation of this assumption, requiring only a causal ordering
of sets of variables. For details we refer to Pak [22,23].
In linear path analysis direct effects, which are the corresponding regression coefficients, and indirect effects; i.e.,
those acting through an intermediate variable W, in the
pathway X W Z, can be examined. Indirect effects
can be calculated by multiplying the corresponding direct
effects. For example, indirect effect of X on Z in the pathway X W Z is product of direct effect of X on W
and direct effect of W on Z. The p-value for testing the
indirect effects can be found using the Intersection Union
Test (IUT) [24]. Total effects are defined as the sum of
direct and all possible indirect effects.
In this study not all of the variables of interest can be
causally ordered in a unidirectional fashion. Sets of variables, however, can be ordered. Thus, we use multivariate
linear path modeling, which requires only partial ordering; i.e., an ordering of sets of variables. The models then
involve multivariate regression models in place of the univariate regression models associated with the classical
path analysis. In the multivariate setting causal ordering is
not necessary within each set of variables and the errors
in the model for those variables are not required to be
independent. In this application we assume the following
causal ordering.

PTH

(10, 65)

ln(PTH)

(2.3, 4.17)

PO4

(2.1, 4.3)

mg/dl

Ca++

(4.5, 5.6)

mg/dl

the associations of each covariate with ln(Y). The values of a Weibull random variable range over the interval
(0, ) and WTH > 21 is garanteed given its definition in
section Definition of variables, WTH is 21 days greater
than the length of the hospitalization interval. Therefore,
we used the transformation Y = WTH-21, which ranges
from zero up, to better fit the Weibull model. Plot of the
log of the negative log of the estimated survival function
against log time (LLS plot) provided a visual check of the
appropriateness of the Weibull model for Y.
We chose the Weibull model for the following reasons:
empirical evidence that it is reasonable; (We
graphically assessed whether or not the data set
follows Weibull distribution by checking the Weibull
probability plot,using proc lifereg in sas.)
the ability to calculate MSE and R-square type
statistics that are analogous to those calculated for
multivariate linear regression models;
the greater efficiency one can expect to achieve when
using a fully parametric model versus the
nonparametric Cox model;
and, because if fits when the parametric model
assumptions are satisfied a linear mean function and,
thus is a convenient choice for multivariate linear
path modeling. (Multivariate linear path models
involve linear mean function specifications.)
The Weibull model also has a proportional hazards
interpretation. We used residuals to investigate the proportional hazards assumption, using martingale and
deviance residuals for the Cox proportional hazards
regression analysis. There is no indication of a lack of fit
of the model to individual observations. We also created
plots of the cumulative martingale residuals against the
values of the each covariate and computed the p-value of
a Kolmogorov-type supremum tests based on a sample
of 1,000 simulated residual patterns. There was no evidence to reject the proportional hazard assumption. With
the Cox proportional hazards model, the regression coefficients correspond directly to the log of hazard ratios.

The causal ordering in the multivarite path model for

calcium regulation

z-eGFR

 


(calcitriol
++

age
z-calcidiol surogate) z-Ca
z-albumina


[z-PTH] [z-PO4] ln(Y)

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Considering age as the exogenous variable and ln(Y)

as the endpoint endogenous variable, we assume the following casual ordering of the variables, illustrated above.
Note that we do not assume any causal ordering between
z-eGFR, z-albumin and z-calcidiol, thus making our problem one that is conducive to MLPM.
The assumption of casual ordering of variables, illustrated above, is based on the review of the literature
presented above. Low eGFR, low calcitriol and low albumin can be manifestations of underlying kidney damage.
Calcitriol has effects on calcium levels in the bloodstream.
Low calcitriol inhibits absorption of calcium more than
phosphate from the intestines, while resorption from the
bone is equal, thus contributing to high serum phosphate
levels. Low calcium induces high PTH, which causes calcium and phosphate resorption from bone. This bone
resoption raises calcium to its proper level while raising
phosphate above its desired level.
Estimation of the multivariate path model parameters
is achieved by the ordinary least square method [24,25]
applied separately to each model (univariate or multivariate, as appropriate) for all variables except ln(Y) = ln
( WTH-21). For ln(Y) and associated censored regression
model, ordinary least square estimation of the parameters
would produce biased estimators. So, we used PROC LIFEREG, in SAS software [19], which estimates the parameters using maximum likelihood estimation for regression
of the lab tests on ln(Y), assuming a Weibull distribution
for Y.
For the measures of goodness of fit, in the simple linear regression models, we used the squared coefficient of
multiple determination, R2 , to measure the predictivity of
the model outcome variable in terms of explained variability of the dependent variable [25]. We note that for
the censored regression model, R2 can not be calculated
due to censoring. So for the measure of explained variation by this model, we used the Kent and OQuigley [26]
product-moment correlation coefficient R2PM to measure
the strength of relationship of ln(Y) with the covariates, in
total. For the Censored regression model given by ln(Y ) =
+  Z + ., we have
R2PM =

Var(  Z)
Var(  Z) + 2 2

where is the scale parameter and 2 = 2 /6 1.645

is the variance of error term in the Weibull model. This
quantity was estimated by
R 2PM =

Sample variance(  Z)
,
Sample variance(  Z) + 2 2

where and are the MLEs of and from the Weibull

regression analysis.

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Results
Statistic calculations were performed using the SAS software. For the sample of 284 patients, the mean age was
66.3 years with standard deviation 12.8 (range = (21, 90)
years). There were 34 patients in stage 5 (kidney failure
with eGFR 15), 85 patients in stage 4 (kidney damage
with severely low eGFR 16-29), and 165 patients in stage 3
(kidney damage with moderately low eGFR 30-60).
There were 70 individual with no hospitalization out of
the 284 patients in our study and, hence, had censored
observation. From the 214 individuals with hospitalization only 137 patients had a complete set of observed lab
tests prior to the next hospitalization and 77 patients had
a complete set of observed lab tests only after the last hospitalization. We had 147 (70 + 77) right censored values
out of the 284 observations.
Results of path modeling

Table 3 gives a summary of the results of direct effects (top

value in each cell) and the p-values (bottom value) for the
variables in each equation in the multivariate path model.
It also gives the estimates of the mean square errors (MSE)
and r-squares of the regression equations.
In Table 3, each column gives the estimated equation for
the variable named at the top of the table. The top value
in each cell is the direct effect (regression coefficient) and
the bottom value is the corresponding p-value. For example, the fourth column gives the estimated equation for
z-Ca++ , which is
zCa ++ = 2.34 0.003 Age + 0.089 zeGFR
0.357 zAlbumin + 0.108 zCalcidiol
We note that the error term in the censored regression model for ln(Y), Y = WTH-21, is  where is
the scale parameter of the Weibull distribution, with estimated value = 0.88 from the result, and  is an error
with variance 2 = 2 /6 1.645. Thus, the estimate
of the conditional variance of the ln(Y) given covariates
in the model, which is 2 2 1.27, is given in Table 3
instead of MSE. For this censored regression model the
Kent and OQuigley product-moment correlation coefficient measure R 2PM = 0.09 is given, while the usual R2 is
presented for each other equation.
The primary purpose of path modeling is to propose
a plausible interpretation of the observed data and to
describe effects in terms of significant direct and indirect
effects. To find the best fitted model we used backward
selection with significance level = 0.05 for each linear model to obtain the most parsimonious model that
includes only significant effects.
Table 4 gives the estimates of direct effects and the pvalues for the variables that remained in the parsimonious

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Table 3 Estimates of direct effects in the multivariate path model

Response

z-eGFR

z-albumin

z-calcidiol

z-Ca++

z-PTH

z-PO4

ln(Y)

0.003

-0.002

0.018

-0.003

0.002

-0.0007

-0.0064

0.7

0.6

0.026

0.46

0.77

0.9

0.3

0.089

-0.199

-0.206

-0.039

0.015

0.001

< 0.0001

0.46

Explanatory
Age

z-eGFR

z-albumin

z-calcidiol

-0.357

-0.557

-0.208

0.131

< 0.0001

< 0.0001

0.017

0.15

0.108

-0.191

-0.046

-0.0219

0.001

0.0008

0.3

0.61

-0.369

-0.045

-0.054

0.0002

0.57

0.54

0.0047

-0.102

z-Ca++

z-PTH

0.91
z-PO4

0.039
-0.141
0.022

Intercept

MSE
R2

-8.87

-0.35

-0.96

2.34

0.57

-1.03

7.7

< 0.0001

0.23

0.08

< 0.0001

0.45

0.08

< 0.0001

2.6

0.93

3.15

0.96

2.56

1.54

0.0005

0.0006

0.017

0.137

0.23

0.12

1.27

0.09

Estimates of direct effects (top value in each cell), and the p-values (bottom value) for the variables in each model, estimates of MSE and r-squares are given. The
significant values are shown in bold. ( ) The value of 2 2 is given instead of MSE. ( ) The value of R 2PM is given for the explained variation measure instead of r-square.

model. It also gives the estimates of mean square errors

and r-squares for the models for upstream variables in the
causal ordering.
Direct, indirect and total effects

Figure 3 illustrates the significant associations of variables in the parsimonious multivariate path model with
ln(Y). The arrows indicate single direct effects and the
estimates of these direct effects are given on each arrow.
The sign on each estimate of each direct effect indicates the direction of the association. Theses path coefficients measure the effect of a one standard deviation
change in each original predictor variable on the response
variable.
Indirect effects can be calculated by multiplying the corresponding direct effects along the indirect path from a
variable to ln(Y). For example, indirect effect of X on Z in
the pathway X W Z is product of direct effect of
X on W and direct effect of W on Z. The p-value for testing the indirect effects can be found using the Intersection
Union Test (IUT) [20,21,24]. For example, significant positive indirect effect of z-Ca++ through z-PTH is 0.0414 =
(0.37)(0.113) with p-value = max{0.0002, 0.011} =
0.011. Total effects are defined as the sum of direct and all
possible indirect effects.

From the result of the parsimonious path model, the

direct and indirect effects of variables on ln(Y), Y = WTH21, are as follows:
z-PTH and z-PO4 had significant direct effects of
-0.112 (p-value = 0.011) and -0.137 (p-value = 0.016),
respectively.
z-Ca++ had significant positive indirect effect
through z-PTH of 0.0414 (p-value = 0.011.)
z-calcidiol (calcitriol surrogate) had a significant
positive indirect effect through z-PTH of 0.0212
(p-value = 0.011) and a positive indirect effect
through z-Ca++ of 0.0043. The total effect of
z-Calcidiol is 0.0255.
z-albumin had a significant positive indirect effect
through z-PO4 of 0.0293, a significant indirect
positive effect through z-PTH of 0.0626 and a
significant indirect negative effect through z-Ca++
of 0.0145. Thus, its total effect on ln(Y) was
0.0774.
z-eGFR had a positive significant indirect effect
through z-PO4 of 0.02918, a significant positive
indirect effect through z-PTH of 0.02217 and a
significant positive indirect effect through z-Ca++ of
0.00364. Thus, its total effect onln(Y) was 0.0549.

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Table 4 Estimates of direct effects in Parsimonious model

Response var.

z-eGFR

z-albumin

z-calcidiol

z-Ca++

z-PTH

z-PO4

ln(Y)

Explanatory var.

Total effects
on ln(Y)

Age

0.017

0.00043

0.026
z-eGFR

z-albuminl

z-calcidiol

0.088

-0.198

-0.213

0.016

0.0012

< 0.0001

-0.355

-0.559

-0.214

< 0.0001

< 0.0001

0.0059

0.105

-0.189

0.0015

0.0008

z-Ca++

0.0549

0.0774

0.0255

-0.37

0.0414

0.0002

0.011

z-PTH

-0.112
0.011

0.011

z-PO4

-0.137

-0.137

0.016

0.016

Intercept

MSE
R2

-8.6

-0.49

-0.96

2.12

0.715

-1.2

7.49

< 0.001

< 0.0001

0.08

< 0.0001

0.2

0.0032

< 0.0001

2.6

0.96

3.15

0.95

2.5

1.54

0.017

0.14

0.23

0.11

1.27

-0.112

0.078

Estimates of direct effects (top value in each cell) and the p-values (bottom value) for the variables in the parsimonious model, estimates of MSE and r-squares. The
calculated total effects are given in the last column. ( ) The value of 2 2 is given instead of MSE. ( ) The value of R 2PM is given for the explained variation measure
instead of r-square.

Age had a significant second order indirect effects,

one through z-calcidiol and then through z-PTH
(0.0003598, p-value< 0.05) and a third order indirect
effect through z-calcidiol, z-Ca++ and z-PTH
(0.0000739, P-value< 0.05) for the total effect of
0.00043. This effect is clinically insignificant.

Discussion
From the result of the censored regression model, we
identified that PTH and PO4 are the most significant
predictors of high-cost hospitalization and, along with
albumin, they have the largest effects (see Table 3). The
prediction equation from the parsimonious model is
Predicted ln(WTH21) = 7.490.112 z PTH0.137 zPO4

Figure 3 The parsimonious multivariate path model.

The right hand side of this equation defines a calcium

regulation-base health metric for CKD.
The negative significant effect of PTH on waiting time
to hospitalization indicates patients with higher PTH are
at higher risk of hospitalization. With Weibull model for
ln(Y), the regression coefficients correspond directly to
the log of hazard ratios so that a negative coefficient
for a particular covariate corresponds to a higher risk of
hospitalization occurring. The estimated hazard ratio corresponding to the effect of PTH is exp(0.112/0.88) =
1.135. The hazard ratio of 1.135 indicates that the risk
of hospitalization will increase 13.5% for each 1 standard
deviation increase in z-PTH. A one standard deviation
increase in z-PTH corresponds to an approximate 0.467
increase in the natural logarithm of PTH level (recall

Golzy et al. BMC Nephrology 2013, 14:154

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that the natural logarithm transform was used in defining

z-PTH) or, equivalently a 60% increase in PTH.
The negative significant effect of phosphate indicates
higher risk of hospitalization for patients with higher
phosphate levels. A hazard ratio of 1.168 associated with
this effect indicates that the risk of a hospitalization will
increase 16.8% for each 1 standard deviation increase in
z-PO4. A one standard deviation increase in z-PO4 is
approximately 0.55 mg/dl increase in PO4 level. Thus, the
risk of hospitalization is estimated to increase by 16.8% for
each 0.55 mg/dl increase in PO4.
Extreme elevations of PTH levels along with hyperphosphatemia could result from an abnormal form of plasma
PTH. The latter could result from an abnormal conversion
of the pro-hormone to its secreted form [27].
Although, we did not find significant direct effects of
eGFR, albumin, calcidiol (calcitriol surrogate) and Ca++
on ln(Y), and hence on WTH, they are the most significant
predictors of PTH and PO4. Therefore they had significant indirect effects on WTH through PTH and PO4.
These effects are small, however, relative to the direct
effects of PTH and PO4 on WTH.
Free calcium (Ca++ ) was not observed directly in
this study. Instead a derived version [16] was used as
an approximation. We repeated our analysis using total
serum calcium (Ca) instead of free calcium (Ca++ ) and
obtained essentially the same results. Since Ca++ is what
is regulated [15,16] by the calcium regulation system, we
chose to present the analysis of Ca++ in this paper.
Although, previous studies suggest that high serum
alkaline phosphatase (ALP) levels predict mortality independent of bone metabolism parameters and liver function tests in CKD and chronic hemodialysis patients [28],
we did not find any association between ALP and WTH
when adding ALP in the model. Thus, we removed ALP
from our model.
The current results provide a calcium regulation based
health metric for identifying patients who are at high risk
for future high-cost complications and that can be used
as an outcome variable in assessing quality of care. Since
the OQuigley R2 for the ln(Y) equation is low, however,
more work is needed to identify additional lab results
that are also predictive. The potential role of Fibroblast
growth factor FGF-23 should be considered as candidates
for addition. Fibroblast growth factor FGF-23 is a recently
discovered regulator of calcium-phosphate metabolism.
In CKD patients, FGF-23 levels rise in parallel with declining renal function long before a significant increase in
serum phosphate concentration can be detected [29].
Unfortunately, FGF-23 was not available in our data set.
Race is known to be associated with both CKD progression and outcomes and is believed to have effects on
PTH and calcium-phosphate metabolism. Our data, however, was provided without a race variable. It should be

Page 9 of 10

noted that the MCO calculated race specific eGFRs and

that those analyzed in this study are race adjusted. Further
study should include race as a factor in addition to using it
in the calculation of eGFR.
From 14,264 patients in the registry of the MCO only
5,799 had confirmed CKD. 546 of them had observed lab
test scores of interest during the 4 year period of study.
Out of 546 patients 284 had observed lab scores in at least
one hospitalization interval. Work to develop methods
of imputation in the context of longitudinal data analysis is ongoing. Once completed, the method developed
will allow more complete utization of data in the kidney
registry.
Additional work with data rich in lab scores is needed
to identify the additional risk factors for use in predictive
models to develop a health metric for assessing the quality of care of CKD patients, while adjusting for the illness
severity of their case mix. Such a metric, if highly predictive of hospitalization, ESRD or death outcome could
serve as the foundation of a reimbursement system that
fairly rewards physicians for quality of care. The results
of the current study are encouraging and justify a similar
prospectively designed investigation.

Conclusion
Variables involved in the calcium regulation system
should be included in future efforts to develop a quality of
care index for Chronic Kidney disease patients.
Competing interests
The authors have no competing interests to declare.
Authors contributions
RLC and RWB designed research; RLC and MG performed and analyzed the
data and wrote the paper; RLC and RWB edited the manuscript. All authors
read and approved the final manuscript.
Acknowledgements
We would like to express our very great appreciation to referees for their
valuable and constructive suggestions for improving the result of this study.
Author details
1 Department of Biostatistics and Population Health Observatory, State
University of New York at Buffalo, Buffalo, NY, 14214-3000, USA. 2 Abell
Administration Center, University of Louisville, 323 East Chestnut St., Louisville,
Kentucky, 40202, USA.
Received: 2 September 2012 Accepted: 15 July 2013
Published: 18 July 2013
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Cite this article as: Golzy et al.: Renal function, calcium regulation, and time
to hospitalization of patients with chronic kidney disease. BMC Nephrology
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