The New England Journal of Medicine


Original Article
Volume 346:77-84

January 10, 2002

Number 2
Comparison of Two Diets for the Prevention of Recurrent Stones in Idiopathic
Hypercalciuria
Loris Borghi, M.D., Tania Schianchi, M.D., Tiziana Meschi, M.D., Angela
Guerra, Ph.D., Franca Allegri, M.D., Umberto Maggiore, M.D., and Almerico
Novarini, M.D.

ABSTRACT
Background A low-calcium diet is recommended to prevent recurrent stones in
patients with idiopathic hypercalciuria, yet long-term data on the efficacy
of a low-calcium diet are lacking. Recently, the efficacy of a low-calcium
diet has been questioned, and greater emphasis has been placed on reducing
the intake of animal protein and salt, but again, long-term data are
unavailable.
Methods We conducted a five-year randomized trial comparing the effect of
two diets in 120 men with recurrent calcium oxalate stones and
hypercalciuria. Sixty men were assigned to a diet containing a normal amount
of calcium (30 mmol per day) but reduced amounts of animal protein (52 g per
day) and salt (50 mmol of sodium chloride per day); the other 60 men were
assigned to the traditional low-calcium diet, which contained 10 mmol of
calcium per day.
Results At five years, 12 of the 60 men on the normal-calcium,
low-animal-protein, low-salt diet and 23 of the 60 men on the low-calcium
diet had had relapses. The unadjusted relative risk of a recurrence for the
group on the first diet, as compared with the group on the second diet, was
0.49 (95 percent confidence interval, 0.24 to 0.98; P=0.04). During
follow-up, urinary calcium levels dropped significantly in both groups by
approximately 170 mg per day (4.2 mmol per day). However, urinary oxalate
excretion increased in the men on the low-calcium diet (by an average of 5.4
mg per day [60 µmol per day]) but decreased in those on the normal-calcium,
low-animal-protein, low-salt diet (by an average of 7.2 mg per day [80 µmol
per day]).
Conclusions In men with recurrent calcium oxalate stones and hypercalciuria,
restricted intake of animal protein and salt, combined with a normal calcium
intake, provides greater protection than the traditional low-calcium diet.
  _____

Idiopathic hypercalciuria is an important 1
<http://content.nejm.org/cgi/content/full/346/2/#R1>  and common 2
<http://content.nejm.org/cgi/content/full/346/2/#R2>  risk factor for the
formation of stones, and uncontrolled hypercalciuria is a cause of
recurrences. 3 <http://content.nejm.org/cgi/content/full/346/2/#R3>
Thiazides can reduce urinary calcium excretion, 4
<http://content.nejm.org/cgi/content/full/346/2/#R4>  but since calcium
excretion depends in part on diet, 5
<http://content.nejm.org/cgi/content/full/346/2/#R5>  initial attempts to
decrease hypercalciuria should involve dietary modification. Since most
patients with hypercalciuria have intestinal hyperabsorption of calcium, 6
<http://content.nejm.org/cgi/content/full/346/2/#R6>  it is common clinical
practice to recommend a low-calcium diet. However, there are no long-term
data on the efficacy of this approach.
Short-term studies have shown that a low calcium intake significantly
reduces urinary calcium excretion but can cause a deficiency of calcium and
an increase in urinary oxalate. 7
<http://content.nejm.org/cgi/content/full/346/2/#R7> , 8
<http://content.nejm.org/cgi/content/full/346/2/#R8>  Curhan et al. 9
<http://content.nejm.org/cgi/content/full/346/2/#R9>  reported that among
men without a history of nephrolithiasis, those with a high intake of
calcium (>26.2 mmol per day) had a 34 percent lower risk of stone formation
than did those with a low calcium intake (<15.1 mmol per day), a finding
that makes the protective efficacy of a low-calcium diet doubtful. 10
<http://content.nejm.org/cgi/content/full/346/2/#R10>  This observation was
later confirmed in women. 11
<http://content.nejm.org/cgi/content/full/346/2/#R11>  Moreover, studies
have shown that animal protein 12
<http://content.nejm.org/cgi/content/full/346/2/#R12> , 13
<http://content.nejm.org/cgi/content/full/346/2/#R13> , 14
<http://content.nejm.org/cgi/content/full/346/2/#R14> , 15
<http://content.nejm.org/cgi/content/full/346/2/#R15> , 16
<http://content.nejm.org/cgi/content/full/346/2/#R16>  and salt 17
<http://content.nejm.org/cgi/content/full/346/2/#R17> , 18
<http://content.nejm.org/cgi/content/full/346/2/#R18> , 19
<http://content.nejm.org/cgi/content/full/346/2/#R19> , 20
<http://content.nejm.org/cgi/content/full/346/2/#R20> , 21
<http://content.nejm.org/cgi/content/full/346/2/#R21> , 22
<http://content.nejm.org/cgi/content/full/346/2/#R22>  also have a
considerable influence on calcium excretion.
We compared the efficacy of the traditional low-calcium diet with that of a
diet containing a normal amount of calcium but reduced amounts of animal
protein and salt. Increased consumption of water was recommended with both
regimens.
Methods
Study Population
Men referred to our outpatient department were eligible for the study if
they met all the following criteria: idiopathic hypercalciuria (urinary
calcium excretion, >300 mg per day [7.5 mmol per day]) on an unrestricted
diet, recurrent formation of calcium oxalate stones (at least two documented
events — that is, colic episodes with expulsion of stones or radiographic
evidence of retained stones), no known condition that is commonly associated
with calcium nephrolithiasis (e.g., primary hyperparathyroidism, primary
hyperoxaluria, enteric hyperoxaluria, bowel resection, inflammatory bowel
disease, renal tubular acidosis, sarcoidosis, or sponge kidney), no previous
visit to a stone disease center, no current treatment for the prevention of
recurrent stones except for the advice to increase water intake, and
residence in the area of Parma, Italy.
Eligibility was determined after a run-in period of two to three months, 23
<http://content.nejm.org/cgi/content/full/346/2/#R23> , 24
<http://content.nejm.org/cgi/content/full/346/2/#R24>  during which the
cause of stone formation was determined. Each patient was seen at least
three times during the run-in period. Ultrasound and radiologic studies and
serum measurements were performed, as well as urinalysis, culture, and
chemical measurements in two 24-hour urine specimens, while the men remained
on an unrestricted diet. All patients were clinically evaluated by one of
us.
Eligible men were asked whether they were willing to comply with the
assigned dietary regimen for at least five years. They received detailed
information about the risk factors for urinary stones, with a focus on the
role of calcium, animal protein, and salt in the diet. They were informed
that the purpose of the trial was to determine which of the two diets under
study was more effective.
Randomization
After the run-in period, the men who had given written informed consent were
randomly assigned to one diet or the other. The treating physicians assigned
the men to the dietary regimens on the basis of a random-number sequence (an
odd number for the low-calcium diet and an even number for the diet
containing a normal amount of calcium and reduced amounts of animal protein
and salt). The sequence was generated by one of us, who enclosed the numbers
indicating the assignments in sealed, numbered envelopes.
Dietary Regimens
The men assigned to the low-calcium diet were instructed to avoid milk,
yogurt, and cheese so that calcium intake would be reduced to approximately
10 mmol per day. As part of our routine clinical practice, we also advised
the men to avoid consuming large amounts of oxalate-rich foods (e.g.,
walnuts, spinach, rhubarb, parsley, and chocolate).
The other dietary regimen was more complex and specific ( Table 1
<http://content.nejm.org/cgi/content/full/346/2/#T1> ). The men assigned to
this regimen were given written explanations and detailed information
designed to help them comply with the regimen. As compared with the typical
diet in our region, 25 <http://content.nejm.org/cgi/content/full/346/2/#R25>
this diet was low in protein, particularly that of animal origin, and low in
salt, with a normal-to-high intake of calcium. We also advised the men on
this diet to avoid consuming large amounts of foods that are rich in
oxalate. Patients who found the diet to be too low in calories were
instructed to increase their consumption of bread, pasta, vegetables, and
fruit rather than their consumption of meat or fish. Both diets included 2
liters of water per day in cold weather and 3 liters per day in warm
weather. Moderate consumption of wine, beer, carbonated beverages, and
coffee was allowed. Further information on the dietary instructions is
available as Supplementary Appendix 1
<http://content.nejm.org/cgi/content/full/346/2/#T4>  with the full text of
this article at http://www.nejm.org.


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Table 1. Composition of the Normal-Calcium, Low-Protein, Low-Salt Diet.



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Supplementary Appendix 1. Dietary Information Given to the Study
Participants.

Data Collection and Follow-up
Twenty-four-hour urine specimens were obtained at base line (with values
documented as the average of the two sets of measurements performed before
randomization), one week after randomization, and at yearly intervals during
the five years of the study. Urinary volume was measured as a marker of
liquid consumption, sodium (measured by atomic-absorption spectrophotometry)
as a marker of salt intake, urea (measured by the urease method) as a marker
of total protein intake, and sulfate (measured by ion chromatography) as a
marker of animal-protein intake. Calcium excretion was measured by
atomic-absorption spectrophotometry, oxalate excretion by ion
chromatography, and creatinine excretion by the Jaffe reaction. The urine
specimen obtained one week after randomization was analyzed to check
compliance with the dietary regimen. The ratio of creatinine excretion to
body weight was used to verify that the urine had been collected correctly.
The relative calcium oxalate saturation was measured with the use of the
Equil computer program at base line and after the first week of the diet.
Subsequently, the relative calcium oxalate saturation was estimated
according to a formula obtained by regression analysis with the use of data
from previous studies. 23
<http://content.nejm.org/cgi/content/full/346/2/#R23> , 24
<http://content.nejm.org/cgi/content/full/346/2/#R24>
Outcome Measures
The primary outcome measure was the time to the first recurrence of a
symptomatic renal stone or the presence of a radiographically identified
stone (see below). In the event of a recurrence, the treatment was
considered to have failed, and the patient was withdrawn from the trial. If
there were no recurrences, patients were followed until the fifth annual
visit (month 60). Patients who required treatment with thiazides or
allopurinol for conditions such as hypertension or gout were withdrawn from
the trial.
Recurrences were considered to be either silent or symptomatic. Silent
recurrences were diagnosed on the basis of renal ultrasound and abdominal
flat-plate examinations performed at yearly intervals. If renal stones were
detected, stratigraphy (thin-plane radiography) was also performed. The
imaging studies were performed by a central radiologic service, and the
radiologist had no knowledge of the trial or the group assignments. A
recurrence was classified as silent if a previously unreported stone was
detected in the absence of symptoms. A symptomatic recurrence was defined as
typical renal colic, an episode of hematuria, or the expulsion or removal of
a previously undiscovered stone. If a symptomatic recurrence was documented
on the basis of renal colic or hematuria, the recurrence had to be confirmed
radiographically.
Secondary outcome measures included changes in calcium and oxalate
excretion, the calcium oxalate product, and the relative calcium oxalate
saturation.
Statistical Analysis
The analysis was based on the intention-to-treat principle. We used
Kaplan–Meier analyses to determine the cumulative incidence of recurrent
stones, and we used Cox proportional-hazards regression to determine the
crude and adjusted relative risks of recurrence. Analyses were performed
with Stata software (version 7, Stata, College Station, Tex.). Before the
study, we estimated that an overall sample of 120 men was required for 80
percent power at a significance level of 0.05 to detect a difference of 25
to 50 percent in the risk of a recurrence between the two study groups,
using a two-sided log-rank test.
Although we had not previously planned to do so, we adjusted the relative
risk of a recurrence for clinical characteristics known to be strong
predictors of the likelihood of a recurrence 26
<http://content.nejm.org/cgi/content/full/346/2/#R26>  — namely, the total
number of stones formed previously and the number of episodes of renal colic
in the previous year. In addition, we tried to determine whether the effects
of dietary treatments varied according to the severity of the disease. To
this end, we established a subgroup of men at highest risk — those in the
highest decile for either of the two predictors of a recurrence. The men at
highest risk (23 of 120, or 19.2 percent) were those with a history of five
or more episodes of colic in the year before randomization, 10 or more
stones formed (as documented on the basis of expulsion or radiography)
before randomization, or both. The highest-risk men tended to have higher
base-line urinary indexes, such as higher levels of oxalate, calcium,
sulfate, sodium, and urea, than the other men, though they also had higher
urinary volume. We then performed an analysis with a Cox model that included
an interaction term for dietary group and the highest-risk category.
For the analysis of the urinary indexes, we compared the two groups with
respect to the absolute change from the base-line value at each time point.
These comparisons were carried out with use of the Mann–Whitney test.
Base-line continuous variables were compared with use of the Mann–Whitney
test and Student's t-test whenever appropriate; categorical variables were
compared with use of Fisher's exact test.
All data are expressed as means ±SD. A P value of less than 0.05 was
considered to indicate statistical significance. All reported P values are
two-sided.
Results
A total of 120 men were enrolled in the study between June 1993 and December
1994, and 60 men were assigned to each diet. Seventeen men did not complete
the study ( Figure 1 <http://content.nejm.org/cgi/content/full/346/2/#F1> ).
Of these 17, 3 assigned to the normal-calcium, low-protein, low-salt diet
withdrew because they did not want to continue with the diet; 7 assigned to
the low-calcium diet withdrew because of hypertension, a possible adverse
effect of low calcium intake. 27
<http://content.nejm.org/cgi/content/full/346/2/#R27>  The base-line
demographic and clinical characteristics of the two groups were similar (
Table 2 <http://content.nejm.org/cgi/content/full/346/2/#T2> ).


  <http://content.nejm.org/cgi/content/full/346/2/77/F1>
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Figure 1. Enrollment, Randomization, and Follow-up.
Both deaths were accidental. The two men who were lost to follow-up moved to
another area.



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Table 2. Base-Line Characteristics in the Two Study Groups.

Twenty-three of the 60 men on the low-calcium diet and 12 of the 60 on the
normal-calcium, low-protein, low-salt diet had recurrences. The cumulative
incidence of recurrent stones in the two groups is shown in Figure 2
<http://content.nejm.org/cgi/content/full/346/2/#F2> . The relative risk of
a recurrence among the men in the normal-calcium, low-protein, low-salt
group, as compared with the men in the low-calcium group, was 0.49 (95
percent confidence interval, 0.24 to 0.98; P=0.04). After adjustment for the
total number of stones formed before randomization and the number of colic
episodes in the year before randomization, the relative risk of a recurrence
was 0.37 (95 percent confidence interval, 0.18 to 0.78; P=0.006). Further
adjustment for the remaining base-line characteristics did not change the
estimate of the relative risk (data not shown). The incidence of recurrent
stones differed significantly between the two groups only late in the
follow-up period ( Figure 2
<http://content.nejm.org/cgi/content/full/346/2/#F2> ). As the stratified
analysis in Figure 3 <http://content.nejm.org/cgi/content/full/346/2/#F3>
shows, this delayed effect was due to early recurrences in the highest-risk
patients, regardless of the diet to which they were assigned.


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Figure 2. Kaplan–Meier Estimates of the Cumulative Incidence of Recurrent
Stones, According to the Assigned Diet.
The relative risk of a recurrence in the group assigned to the
normal-calcium, low-protein, low-salt diet, as compared with the group
assigned to the low-calcium diet, was 0.49 (95 percent confidence interval,
0.24 to 0.98; P=0.04).



  <http://content.nejm.org/cgi/content/full/346/2/77/F3>
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Figure 3. Kaplan–Meier Estimates of the Cumulative Incidence of Recurrent
Stones, According to the Risk of Recurrence at Base Line.
The men at highest risk were those with five or more colic episodes in the
year before randomization, 10 or more stones before randomization, or both.
Among the men who were at highest risk for recurrent stones, the relative
risk of a recurrence was 0.81 (95 percent confidence interval, 0.28 to 2.35)
for the men on the normal-calcium, low-protein, low-salt diet, as compared
with those on the low-calcium diet. Among all the other men, the relative
risk of a recurrence was 0.23 (95 percent confidence interval, 0.08 to 0.67)
for the men on the normal-calcium, low-protein, low-salt diet. The relative
risk of a recurrence did not differ significantly between the two subgroups
of men (P=0.09).

Table 3 <http://content.nejm.org/cgi/content/full/346/2/#T3>  shows the
values for the urinary variables throughout the follow-up period. The
24-hour urinary volume increased to a similar extent in the two groups. As
expected, urinary excretion of sodium, urea nitrogen, and sulfate did not
change with the low-calcium diet, whereas all three indexes decreased with
the normal-calcium, low-protein, low-salt diet. The decrease in these
indexes reflects dietary compliance, which was excellent in the first week
and still fairly good, although somewhat reduced, during follow-up.


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Table 3. Urinary Variables at Base Line and during Treatment.

As shown in Table 3 <http://content.nejm.org/cgi/content/full/346/2/#T3> ,
calcium excretion decreased with both diets (by approximately 170 mg per day
[4.2 mmol per day]). The calcium oxalate product and the relative calcium
oxalate saturation decreased with both diets, although the reduction was
greater with the normal-calcium, low-protein, low-salt diet. The main
difference between the two diets was oxalate excretion, which increased with
the low-calcium diet (by approximately 5.4 mg per day [60 µmol per day]) but
decreased with the normal-calcium, low-protein, low-salt diet (by
approximately 7.2 mg per day [80 µmol per day]). There were no differences
in dietary compliance between the men who had recurrent stones and those who
did not, irrespective of the diet.
Discussion
This study shows that a diet with a normal amount of calcium but with
reduced amounts of animal protein and salt is more effective than the
traditional low-calcium diet in reducing the risk of recurrent stones in men
with idiopathic hypercalciuria. The difference appears to be due to the
different effects of the two diets on oxalate excretion.
Studies extending short-term investigations 8
<http://content.nejm.org/cgi/content/full/346/2/#R8>  have shown that a
low-calcium diet has long-term efficacy in reducing calcium excretion.
However, this diet may cause an increase in urinary oxalate excretion
through increased intestinal absorption, resulting from the low level of
calcium available to form a complex with oxalate in the intestinal lumen. 28
<http://content.nejm.org/cgi/content/full/346/2/#R28> , 29
<http://content.nejm.org/cgi/content/full/346/2/#R29>  In terms of
saturation, the increase in oxalate tends to be offset by the reduction in
calcium, but the concurrent increase in urinary volume causes a substantial
reduction of the calcium oxalate molar product and, hence, of the relative
calcium oxalate saturation.
We found that a diet with a normal amount of calcium but reduced amounts of
animal protein and salt resulted in a reduction in calcium excretion that
was, on the whole, equivalent to that associated with a low-calcium diet.
Indeed, after the first week of treatment, the drop in urinary calcium
excretion was more marked with this diet than with the low-calcium diet.
Subsequently, this difference tended to disappear, probably because of a
partial reduction in compliance. The decrease in urinary calcium excretion,
despite normal calcium intake, is probably the consequence of the combined
tubular action of the decreased intake of salt and animal protein, a
phenomenon previously documented in short-term studies. 12
<http://content.nejm.org/cgi/content/full/346/2/#R12> , 13
<http://content.nejm.org/cgi/content/full/346/2/#R13> , 14
<http://content.nejm.org/cgi/content/full/346/2/#R14> , 15
<http://content.nejm.org/cgi/content/full/346/2/#R15> , 16
<http://content.nejm.org/cgi/content/full/346/2/#R16> , 17
<http://content.nejm.org/cgi/content/full/346/2/#R17> , 18
<http://content.nejm.org/cgi/content/full/346/2/#R18> , 19
<http://content.nejm.org/cgi/content/full/346/2/#R19> , 20
<http://content.nejm.org/cgi/content/full/346/2/#R20> , 21
<http://content.nejm.org/cgi/content/full/346/2/#R21> , 22
<http://content.nejm.org/cgi/content/full/346/2/#R22>
The other important result of the normal-calcium, low-protein, low-salt diet
was the consistent reduction in urinary oxalate excretion. The explanation
for the reduction in oxalate excretion with the normal-calcium diet is the
converse of the explanation for its increase with the low-calcium diet. With
the normal-calcium diet, more calcium is available in the intestinal lumen
to form a complex with oxalate, thus reducing its absorption — a phenomenon
reported in short-term studies. 30
<http://content.nejm.org/cgi/content/full/346/2/#R30> , 31
<http://content.nejm.org/cgi/content/full/346/2/#R31>  In addition, the
reduced intake of protein may lower the endogenous synthesis of oxalate. 32
<http://content.nejm.org/cgi/content/full/346/2/#R32>
The normal-calcium, low-protein, low-salt diet decreases urinary excretion
of both calcium and oxalate, which in combination with an increase in
urinary volume causes a marked reduction in the calcium oxalate molar
product and in the relative calcium oxalate saturation. These effects may
explain the 50 percent reduction in the risk of a recurrence among the men
assigned to this diet, as compared with those assigned to the low-calcium
diet. However, this advantage was evident only after several years of
follow-up. We speculate that the early advantage of the normal-calcium,
low-protein, low-salt diet over the low-calcium diet might have been
obscured by the enrollment of men who were at high risk for an early
recurrence. This interpretation is consistent with that of Parks and Coe, 26
<http://content.nejm.org/cgi/content/full/346/2/#R26>  who speculated that
at the start of treatment, patients at high risk may have stones that are
too small to be seen on radiographs but that grow and are later identified
as new stones.
Because the patients enrolled in our trial came to us with an explicit
request to receive dietary treatment for the prevention of recurrences, it
would not have been possible or ethical to include a control group. However,
several other studies have included a placebo group or a
conservative-treatment group, 33
<http://content.nejm.org/cgi/content/full/346/2/#R33> , 34
<http://content.nejm.org/cgi/content/full/346/2/#R34> , 35
<http://content.nejm.org/cgi/content/full/346/2/#R35> , 36
<http://content.nejm.org/cgi/content/full/346/2/#R36> , 37
<http://content.nejm.org/cgi/content/full/346/2/#R37> , 38
<http://content.nejm.org/cgi/content/full/346/2/#R38> , 39
<http://content.nejm.org/cgi/content/full/346/2/#R39> , 40
<http://content.nejm.org/cgi/content/full/346/2/#R40> , 41
<http://content.nejm.org/cgi/content/full/346/2/#R41>  and in all these
studies, the risk of a recurrence among patients receiving placebo or
conservative treatment was higher than the risk with either diet in our
study. Moreover, in studies of the natural history of the disease, 42
<http://content.nejm.org/cgi/content/full/346/2/#R42> , 43
<http://content.nejm.org/cgi/content/full/346/2/#R43> , 44
<http://content.nejm.org/cgi/content/full/346/2/#R44>  the risk of a
recurrence at five years was approximately 50 percent, which is higher than
the risk with either diet in our trial.
While our study was in progress, the results of a trial that examined the
protective effect of a diet characterized by low levels of animal protein
and high levels of fiber were reported. 45
<http://content.nejm.org/cgi/content/full/346/2/#R45>  The authors concluded
that this regimen was not more beneficial than the simple advice to increase
the intake of liquids. However, this study differed from ours in several
ways. The subjects were patients with a first episode of nephrolithiasis,
only 17 percent of whom had hypercalciuria. The dietary prescription did not
include restricted salt intake, and there was little control of calcium
intake. Moreover, compliance with the diet was poor.
In conclusion, our study suggests that a diet characterized by normal
calcium, low animal protein, and low salt levels is more effective than the
traditional low-calcium diet for the prevention of recurrent stones in men
with idiopathic hypercalciuria. We speculate that this type of diet will be
of greatest value when it is started early in the course of the disease.
Supported in part by grants from the University of Parma and the Italian
Ministry for Universities and for Scientific and Technological Research.
We are indebted to Dr. Maurizio Rossi of the Department of Pedagogic
Sciences at the University of Parma for his valuable assistance with the
computerized data base.

Source Information
From the Departments of Clinical Sciences (L.B., T.S., T.M., A.G., F.A.,
A.N.) and Internal Medicine and Nephrology (U.M.), University of Parma,
Parma, Italy.
Address reprint requests to Dr. Borghi at the Department of Clinical
Sciences, University of Parma, Via Gramsci 14, 43100 Parma, Italy, or at
[log in to unmask] <mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.