Short-Term Effects of Protein Intake, Blood Pressure, and Antihypertensive Therapy on Glomerular...

Journal of the American Society of Nephrology 2097

Short-Term Effects of Protein Intake, Blood Pressure, andAntihypertensive Therapy on Glomerular Filtration Rate inthe Modification of Diet in Renal Disease Study1’2Modification of Diet in Renal Disease Study Group3’4

From the National Institute of Diabetes. Digestive andKidney Diseases. National Institutes of Health, Be-thesda, MD

Prepared by: Andrew S. Levey. M.D.. Gerald J. Beck.Ph.D. Juan P. Bosch. M.D., Arlene W. Caggiula, Ph.D.,Tom Greene. Ph.D.. Lawrence G. Hunsicker, M.D., andSaulo Klahr, M.D.

(J. Am. Soc. Nephrol. 1996; 7:2097-2109)

ABSTRACTGlomerular filtration rate is often used to assess thelevel of renal function and the progression of renaldisease. However, the short-term effects of dietaryprotein restriction, blood pressure reduction, and spe-cific classes of antihypertensive agents on GFR maybe opposite in direction from their observed long-term beneficial effects on the progression of renaldisease. The purpose of these analyses was to char-acterize these short-term effects and determinewhether they can obscure the relationship betweenrenal structure and function in patients with slowlyprogressive renal disease. The Modification of Diet inRenal Disease Study was a randomized trial of theeffect of dietary protein restriction and strict bloodpressure control on the decline in GFR in 840 patients

with mean (range) baseline GFR of 36. 1 (1 3 to 55)mL/min per 1 .73 m2. In this study, comparisons of therandomized groups and correlational analyses wereused to determine the short-term (4-month) effects onGFR of changes in protein intake, mean arterial pres-sure (MAP), and class of antihypertensive agents(computed as the reduction in GFR associated withstarting versus stopping medications) during the first 4months of follow-up and in subsequent 4-month inter-vals during the first 2 yr offollow-up. Combining resultsover the first 2 yr of follow-up, and controlling forchanges in antihypertensive medications, the inde-pendent effect on GFR of changes in protein intake

1 Received January 31 . 1996. Accepted April 30. 1996.

2 This study was presented In part at the 28th Annual Meeting of the American

Society of Nephrology, San Die9o, November 5-8. 1995.

3 correspondence to Dr. AS. Levey, Division of Nephrology, New EnglandMedical Center. 750 WashIngton Street. Boston. MA 021 1 1.

4 The institutions and Investigators who participated in the MDPD Study are listedin Reference 12.

10.46-6673/0710-2097$03.00/0Journal of the American society of NephrologyCopyright C 1996 by the American Society of Nephrology

and MAP was 1 . 1 mL/min per 0.4 g/kg per day and0.9 mL/min per 10 mm Hg, respectively (P < 0.001).

These effects were observed in patients with increas-ing or decreasing protein intake or MAP, and inpatients with stable or changing antihypertensive reg-imens. Starting treatment with diuretics, p-blockers, orangiotensin-converting enzyme inhibitors was associ-ated with a 4.4-, 3.2-, or 2.2-mL/min greater GFR de-

dine, respectively, than was stopping this treatment(P < 0.001). The effect of changes in protein intake,MAP, and diuretics was greater in patients with higherinitial GFR. After controlling for initial GFR, there wereno significant differences between the short-term ef-

fects observed during the first 4 months of follow-upand the short-term effects during subsequent follow-up. Changes in protein intake, blood pressure, andantihypertensive agents have small but statisticallysignificant short-term effects on GFR. These effects canlead to clinically significant changes in renal functionin patients undergoing multiple interventions and arelarge enough to confound the results of clinical trialsin patients with slowly progressive renal disease. Fu-

ture studies using GFR to assess the progression ofrenal disease should take into account these short-term effects when the length of follow-up is beingplanned.

Key Words: GFR, dietary’ protein. blood pressure, antihyper-

tensive therapy

G bomerular filtration rate is generally considered

the best index of renal function in health and

disease ( 1 ). For this reason, serial estimates of GFR

are frequently used to assess the progression of renal

disease (2). Implicit in this practice is the assumption

that the level of renal function, measured as the GFR,

reflects the severity ofrenab structural injury, and that

the rate of decline in GFR reflects the progression of

injury.

In principle, the GFR is the product of the number of

functioning nephrons and the single-nephron GFR.

Although the number of functioning nephrons may

reflect the severity of renal injury, the single-nephron

GFR may be affected both by the severity of the renal

injury and by hemodynamic changes. Indeed, it is well

known that dietary protein restriction, blood pressure

reduction, and specific classes of antihypertensive

agents can have short-term effects on GFR because of

their direct effects on the hemodynamic determinants

of single-nephron GFR (3,4). Moreover, the short-term

effects of these interventions are opposite in direction

Effects of Diet and Blood Pressure Control on GFR

2098 Volume 7 . Number 10 . 1996

to their observed long-term beneficial effect on the

progression of renal disease (5-8). Therefore, these

short-term fluctuations in GFR could potentially ob-

scure the relationship between renal function and

structure, thereby confounding the interpretation of

clinical trials and limiting the usefulness of these

therapies in clinical practice.

The short-term effects of changes in protein intake,

blood pressure, and antihypertensive agents on the

GFR in patients with renal disease are not well de-

fined. We analyzed data from the Modification of Diet

in Renal Disease (MDRD) Study, a multicenter con-

trobled clinical trial to determine the effect of dietary

protein restriction and strict blood pressure control on

the rate of decline in GFR in patients with chronic

renal disease (9-12), to characterize these short-term

effects. In particular. we determined the short-term

effects on GFR of changes in protein intake, blood

pressure, and the use of antihypertensive agents,

whether these effects were reversible, independent of

each other, and influenced by the initial level of GFR.

In addition, we explored whether the short-term

changes in GFR that occurred during the first 4

months after randomization, when patients were

striving to reach new diet and blood pressure goals,

differed from the short-term changes observed during

the subsequent follow-up period, when patients’ goals

were not changing. The results have implications for

clinical practice and for the design of clinical trials.

METHODS

Study Design

The MDRIJ Study consisted of two randomized, multi-center, two-by-two factorial trials of 840 patients with var)-ous chronic renal diseases (10,12). In 585 patients withbaseline GFR of 25 to 55 mL/min per 1 .73 m2 (Study A), wecompared a usual versus low-protein diet (1.3 versus 0.58g/kg per day) and a usual versus low blood pressure goal(mean arterial pressure � 107 versus �c92 mm Fig). In 255patients with baseline GFR between 13 and 24 mL/min per1 .73 m2 (Study B), we compared a low- versus very-low (0.28g/kg per day)-protein diet, supplemented by a keto acid-amino acid mixture (0.28 g/kg per day), and a usual versuslow blood pressure goal. The keto acid-amino acid supple-ment in Study B contained approximately 0. 18 g/kg per dayamino acids and 0. 10 g/kg per day keto acids. Therefore, theprescribed intake of amino acids from food and supplementin Study B was approximately 0.58 and 0.46 g/kg per day inthe low- and very-low-protein diets, respectively. In bothStudies A and B. the blood pressure goals were 6 mm Hghigher for patients older than 61 yr of age. Glomerularfiltration rate was measured during baseline (before random-ization), after 2 months, after 4 months, and every 4 monthsthereafter. The mean duration of follow-up was 2.2 yr.

Dietitians at each clinical center were trained to implementand monitor the intervention. Patients were informed of thedietary assignment at the first follow-up visit after random-ization (within 1 month). Thereafter, patients were counseledmonthly or more frequently as necessary to attain the pre-scribed levels of intake.

Blood pressure was controlled by a combination of phar-macologic and nonpharmacologic interventions. Nonphar-

macologic therapy consisted primarily of recommendationsfor regular exercise and reductions in weight and in alcoholand sodium intake. Pharmacologic therapy was based on thestepped-care approach defined in the 1988 Report of theJoint National Committee ( 13). All antihypertensive drugswere allowed, but angiotensmn-converting enzyme (ACE) in-hibitors, with or without a diuretic, were encouraged as theagents of first choice. Calcium channel blockers, with orwithout a diuretic, were encouraged as agents of secondchoice. Blood pressure regimens were implemented at thefirst follow-up visit after randomization and were modifiedmonthly or more often as necessary to achieve goal bloodpressure levels.

Measuring Protein Intake, Blood Pressure,Antihypertensive Medications, and GFR

Protein intake (g/day) was calculated as 6.25 X IUUN(g/day) + SBW (kg) x 0.03 1 (g/kg SBW per day)l, where UUNis the urea nitrogen excretion rate and SBW is the standardbody weight ( 1 4, 1 5). For patients in Study B assigned to thevery-low-protein diet, this equation estimates the intake of

protein from food as well as amino acids in the keto acid-amino acid supplement. As reported elsewhere (16), aftercontrolling for intake of protein from food as well as aminoacids in the supplement, there was no difference betweendiet groups in the long-term response of GFR to the dietinterventions in Study B. Hence, for the analyses reportedhere, we calculated changes in protein intake as changes inintake of protein from food and amino acids in the supple-ment. For simplicity, this quantity is referred to as “totalprotein intake.”

Blood pressure was measured using a Hawksley random-zero sphygmomanometer (Copiague, NY) according to estab-lished methodology ( 13). Patients were placed in a quiet roomfor 5 mm before measurement. The sitting blood pressurewas taken three times by the same nurse or technician. Theaverage of the last two measurements was used as the bloodpressure for the visit ( 1 7). Mean arterial pressure (MAP) wascalculated as DBP + #{189}(SBP -DBP). where DBP and SBP arediastolic and systolic blood pressure, respectively.

Glomerular filtration rate was measured as the renal clear-ance of 35 gzCi of ‘2�liothalamate after bolus subcutaneousadministration without concomitant epinephrine (18,19).Measurements were performed in the sitting position, in themorning, after an 8-h fast.

Statistical Methods

Comparison of randomized groups. As reported elsewhere(1 2), the effects of the diet interventions on the rate of GFRdecline in both Studies A and B were similar in the usual andlow blood pressure groups. Likewise, the effects of the bloodpressure intervention on the rate of GFR decline were similarin the usual and low-protein diet groups in Study A and inthe low- and very-low-protein diet groups in Study B. Con-sequently, comparisons of the diet groups are presented forall patients. regardless of blood pressure assignment, andthe blood pressure groups are compared for all patients,regardless of diet assignment.

Effects on GFR were reported previously ( 1 2) and areshown in Figure 1 to illustrate (1) the differences betweenrandomized groups in the initial GFR decline. during the first4 months after randomization, when diet and MAP goals werechanging, and during subsequent follow-up, when goalswere stable; and (2) the greater differences between the initialand subsequent GFR declines in patients with higher base-

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Figure 1 . Estimated mean (SE) GFR decline from baseline to selected follow-up times In Studies A and B. B3 denotes the finalbaseline visit. F denotes monthly follow-up visits. The paffern of GFR deviates significantly from linearity in Study A, but notin StudyB. In Study A, In the first 4 months after baseline, the GFR decline was significantly faster in the low-protein diet group (A) and thelow blood pressure group (B), compared with the usual protein diet group and usual blood pressure group, respectively. After4 months, the GFR decline was 28% slower (P = 0.009) in the low-protein diet group and 29% slower (P = 0.006) In the low bloodpressure group. From baseline to 3 yr offollow-up, the projected decline was 1.2 mI/mm less in the low-protein diet group (P =

0.3) and 1.6 mI/mm less in the low blood pressure group (P = 0.18). In Study B, the GFR decline was 19% less in thevery-low-protein diet group, compared with the low-protein diet group (P = 0.07) and 12% less in the low blood pressure group,compared with the usual blood pressure group (P = 0.28). Figures 1A and lB reproduced with permission from the New EnglandJournal of Medicine 330; 877-884, 1994.

line GFR (Study A compared with Study B). For the analysespresented here, the diet groups and blood pressure groupsare compared from baseline to 4 months of follow-up, with-

out regard to the changes in GFR between the fourth monthof follow-up and the end of the study. This method ofcomputing the GFR decline differs from the previous report( 1 2), but the differences in GFR decline between diet groupsand between blood pressure groups are similar to the previ-ous report.

Correlational analyses. Standard least-squares multipleregression (20) was used to relate the change in GFR in thefirst 4-month interval to changes in achieved protein intake,blood pressure, and in classes of antthypertensive medica-tions. To determine how the short-term responses of GFR tochanges in these factors varied with baseline level ofGFR andwith the duration of follow-up, the successive 4-monthchanges in GFR over the first 2 yr of follow-up were alsorebated to contemporaneous 4-month changes in proteinintake, blood pressure, and in the use of the respectivemedication classes in a combined longitudinal analysis (21).The model included interaction terms of each of these pre-dictor variables with baseline GFR and with the duration of

follow-up. To account for correlations between the successive4-month changes in GFR, a Toeplitz error structure (22) withtwo bands was assumed.

Assessing measurement error. The changes in proteinintake and blood pressure used in the correlational analyseswere derived from measurements at single time points. Thesemeasurements are subject to error (for example, errors in24-h urine collections and laboratory measurements of theurine urea nitrogen levels used to compute protein intake).and do not account for hourly or daily fluctuations. Inprinciple, the effect of measurement error in ascertainingprotein intake and blood pressure would be to weaken theobserved association between changes in these variables and

changes in GFR (23). The size of the biases in these estimatesdepends on the magnitude of the measurement errors, withlarger errors leading to larger biases.

Error in laboratory measurement of urine urea nitrogenwas estimated from 65 masked, split samples of urine ob-tamed as part of the quality control of the study (data notshown). Error in measurement of blood pressure was as-sessed by the variation between the second and third sittingblood pressure measurements (22). The multiple regression


2100 Volume 7 . Number 10 . 1996

analyses were repeated to control for attenuation (24) asso-

ciated with these estimates of measurement error. We did notattempt to assess the additional biases that might resultfrom patient errors in urine collections or daily fluctuationsin levels of protein intake and blood pressure.

RESULTS

Effects of Protein Intake and Blood Pressure

We examined relationships ofshort-term changes in

protein intake and blood pressure on GFR during two

periods: the first 4 months after randomization, to

assess short-term effects, and from 4 months onward,

at successive 4-month intervals, to assess continua-

tion of short-term effects.

Changes in protein intake and blood pressure from

baseline to 4 months of follow-up. In Study A, mean

(SD) protein intake remained stable at 1 . 1 2 (0. 1 8) and

1 . 1 1 (0.20) g/kg per day from baseline to 4 months in

the usual protein diet group, but declined from 1.12

(0.20) to 0.78 (0. 16) g/kg per day in the low-protein

diet group. In Study B, mean total protein intake (from

food and supplements) declined from 0.86 (0. 18) to

0.73 (0. 14) g/kg per day in the low-protein diet group

and declined from 0.87 (0. 19) to 0.65 (0. 13) g/kg per

day In the very-low-protein diet group. Thus the dif-

ference between randomized groups in mean protein

intake was greater in Study A than in Study B. In

Study A, MAP remained stable at 97.5 ( 10.6) and 97.3

( 10.5) mm Hg from baseline to 4 months in the usual

blood pressure group, but declined from 98. 1 ( 10.7) to

94.8 (10.6) mm Hg in the bow blood pressure group.

Similarly, in Study B, MAP remained stable at 98.0

( 1 1 . 1 ) and 98.6 ( 1 1 . 1 ) mm Hg in the usual blood

pressure group, but declined from 98.4 (10.7) to 95.9

( 10.7) mm Hg in the low blood pressure group.

Changes in GFR during the first 4 months of fol-

bow-up (short-term changes). We compared the GFR

declines between patients assigned to different diets

and blood pressure goals in Studies A and B, irrespec-

tive of achieved levels of protein intake or blood pres-

sure. In addition, we correlated changes in protein

intake and blood pressure and changes in GFR in both

studies, irrespective of assigned diet or blood pres-

sure.

Comparisons of diet groups and blood pressure

groups. Table 1 shows the effect of the bow-protein diet

and low blood pressure goal on changes in GFR during

the first 4 months after randomization in Studies A

and B and in subgroups of patients in Study A defined

by baseline GFR. In Study A, the GFR decline in the

bow-protein diet group was 1 .84 mL/min greater than

in the usual protein diet group (P = 0.00 1 ). There was

a trend (P = 0.07) toward a greater difference between

diet groups among patients with higher baseline GFR.

The mean GFR decline in the bow blood pressure group

was 1 .90 mL/min greater than in the usual blood

pressure group (P = 0.00 1 ), and the difference was

significantly greater among patients with higher base-

line GFR (P = 0.005). In Study B, the mean GFR

decline was similar between the two diet groups and

between the two blood pressure groups.

Correlations of changes in GER with changes in

protein intake and blood pressure. Figure 2 shows

correlations between changes in protein intake or

blood pressure with changes in GFR, irrespective of

diet or blood pressure group. Significant, but weak,

direct correlations were observed for changes in pro-

tein intake in Study A (r = 0. 13, P = 0.007, Figure 2A)

and changes in blood pressure in both Studies A (r =

0.19, P< 0.001, Figure 2B)and B(r = 0.28, P< 0.001,

Figure 2D). The correlation was not significant for

changes in total protein intake in Study B (r = 0.09,

P = 0.21, Figure 2C).

Table 2 shows the relationship (the slope of the

regression line) between changes in protein intake or

blood pressure with changes in GFR Studies A and B

and compares the slopes for various subgroups of

patients within each study. Overall in Study A, there

was a 3. 1 1 -mL/min decline in GFR per 1 .0-g/kg per

day reduction in protein intake (P = 0.007) and a

0.12-mL/min decline in GFR per 1.0-mm Hg reduc-

tion in MAP (P = <0.00 1 ), with stronger relationships

(steeper slopes of the regression lines) in patients with

higher baseline GFR. Consistent with this finding

TABLE 1 . Comparison of change (�) in GFR between diet groups and between blood pressure groups duringthe first 4 months of follow-up, as a function of baseline GFR

Baseline GFR Range(mL/min)

NDiet Interventiona Blood Press ure lnterventlonb

Mean � GFR SE PMean � GFR SE P

Overall Study A 528 + 1,84c 0.58 0.002 + 1 ,90d 0.58 0.00 1Study A GFR > 48.5 172 +2.68 1.13 0.02 +4.43 1.14 <0.001Study A GFR 36.5 to 48.5 181 +2.25 0.96 0.02 +1.13 0.96 0.24Study A GFR <36.5 175 +0.65 0.85 0.45 +0.01 0.84 0.99Overall Study B 231 -0.08 0.48 0.87 +0.02 0.48 0.97

a Study A: Low-protein diet group-usual protein diet group. Study B: Very-low-protein diet group-low-protein diet group.b Studies A and B: Low blood pressure group- usual blood pressure group.C Among patients in Study A. mean change in GFR was 1.84 mL/min greater for the low-protein diet group than for the usual protein diet group.

There is a trend toward a greater difference between the diet groups in patients with higher baseline GFP (P = 0.07).d Among patients in Study A. mean change in GFR was 1 .90 mL/min greater for the low blood pressure group than for the usual blood pressure

group. The greater difference between the blood pressure groups in patients with higher baseline GFR was statistically significant (P = 0.005).

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Figure 2. Relationships of changes in protein intake and blood pressure to changes In GFR In Studies A and B. Scatter plots ofindividual patient values for changes In GFR versus changes in protein intake or mean arterial pressure from baseline to thefourth month offollow-up. Extreme values are not Included on the plot (16 extreme values In A and 20 extreme values In B), butare included In the calculation of the regressions and correlations. The figures shows the regression lines (solid) and 95%confidence intervals forthe regression lines (dashed lines). The doffed horizontal line indicates the mean GFR decline during the4-month Interval for each study (-2.79 mL/mln In Study A and -2.13 mI/mm in Study B). Total protein intake in Study B refers tointake of protein from food and amino acids In the keto acid-amino acid supplement.


A


B

were the weaker relationships (less steep slopes) in

Study B; a l.73-mL/min decline in GFR per l.0-g/kg

per day reduction in total protein intake (P = not

significant) and a 0.094-mL/min decline in GFR per

1 .0-mm Hg reduction in MAP (P < 0.00 1 ). These

relationships were observed whether protein intake or

blood pressure was increasing or decreasing, which

strongly suggests that the reduction in GFR after

decreased protein intake or decreased blood pressure

is the result of physiologic changes in the GFR rather

than the progression of renal disease. Moreover, these

relationships were observed whether the class of pre-

scribed antihypertensive agents was constant or

changing, indicating that the changes in GFR were the

result of changes in protein intake or blood pressure,

per Se, and not the result of hemodynamic effects of

antthypertensive agents.

Changes in GFR during subsequent 4-month inter-

vals (continuation of short-term changes). Although

the mean levels of protein intake and blood pressure

were generally stable after the first 4 months of follow-

up, protein intake, blood pressure, and use of antihy-

pertensive agents fluctuated in individual patients. To

assess whether these short-term changes continued

to affect GFR during follow-up, we repeated the corre-

lation analyses described above in successive

4-month intervals during the first 2 yr of follow-up.

In Study A, the relationship between changes in

protein intake and changes in GFR was significant in

five of the six 4-month intervals throughout the first 2

yr. In both Studies A and B, the relationship between

changes in blood pressure and changes in GFR was

significant during all six 4-month intervals. In Study

B, there was a significant relationship between

changes in total protein intake and changes in GFR

during two of the six 4-month intervals. In separate

analyses, we found no significant effect of the fol-

low-up interval on these relationships in either study

(data not shown); hence, we combined all 4-month

intervals to compute an average slope for the relation-

ship of changes in protein intake or blood pressure to

changes in GFR. Table 3 shows these relationships

(the slopes of the regression lines relating changes in

protein intake and blood pressure with changes in

GFR) in the first four months and over all 4-month

intervals. Because of the barge number of measure-

ments, the estimates of the slopes of the regression

lines over all 4-month intervals are more precise than


2102 Volume 7 - Number 10 ‘ 1996

TABLE 2. Relationships (slopes of regression lines) of changes (�) in protein intake and mean arterial pressure(MAP) with changes in GFR during the first 4 months of follow-up

Study A (GFR 25 to 55 mL/min per 1.73 m2) Study B (GFR 13 to 24 mI/mm per 1.73 m2)

‘� GFR versus � ProteinIntake

�GFR versus � MAPGFR versus � Total

.

Protein Intakeaz� GFR versus z� MAP

N Slopec SEN Slope’� SE N Slopec SE N Slopeb SE

All Patients 441 3.1 1d ] .14 519 012d 0.026 21 1 1.73 1.38 224 009d 0.022

Baseline GFR(mL/min)

>48.5 147 6.lOd 2.13 171 016d 0.04736.5 to 48.5 146 3.20 2.17 177 0.07 0.048

<36.5 148 0.40 1.60 171 0.09e 0.038Protein Intake

>0 139 104d 3.86 139 014d 0.047 31 -0.36 8.38 31 o.lle 0.051<0 302 47#{176} 2.05 300 010d 0.036 180 2.65 1.79 177 0.1l’� 0.026

MAP>0 197 3.38e 1.52 224 0.11#{176} 0.053 88 1.26 2.01 97 0.05 0.054<0 242 2.68 1.68 295 019d 0.058 120 1.34 1.83 127 017d 0.049

Change in MedsNo 316 3.10#{176} 1.30 376 009d 0.032 145 3.04 1.55 155 008d 0.029Yes 111 3.08 2.50 127 015d 0.046 58 -2.32 2.96 60 0.lOe 0.038

a Total protein intake from food and supplements.b Study A: mean change in GFR (mL/min) per 1.0 g/kg per day change in protein intake. Study B: mean change in GFR (mL/min) per 1.0 g/kg per

day change in total protein intake from food and supplements.C Studies A and B: mean change In GFR (mL/min) per 1.0 mm Hg change in MAP.dp< 0.01.eooi < P< o.os.

the estimates in each 4-month interval, as shown by

the smaller standard errors.

Thus, fluctuations in protein intake and blood pres-

sure were associated with short-term effects on GFR

throughout follow-up. However, because the mean

protein intake and blood pressure were relatively sta-

ble in each the diet and blood pressure groups, the

effect of these fluctuations on GFR would be expected

to cancel. Hence, the GFR mean decline was relatively

constant after 4 months.

Effects of Antihypertensive Medications

The MDRD Study was not designed to assess the

effect of different classes of antihypertensive agents on

the decline GFR. Nonetheless, a variety of antihyper-

tensive agents was used and a large number of pa-

tients changed antihypertensive medications during

follow-up. In Study A, the percent of patients either

starting or stopping the various classes of antihyper-

tensive medications in each 4-month interval ranged

from 2.2 to 1 2.3% in Study A and from 0.7 to 14.7% in

Study B.

For these analyses, we assessed the association of

changes in antihypertensive therapy to short-term

changes in GFR. Thus, we compared GFR changes

between subgroups of patients starting a class of

medications to those stopping the class of medications

during each 4-month interval during the first 2 yr of

follow-up. Specifically, we compared patients who

were not taking a class of medications at the begin-

ning of the interval but who were taking the medica-

tion at the end of the interval to patients who were

taking a class of medications at the beginning of the

interval but not at the end of the interval. In principle,

the difference in GFR change between patients start-

ing and stopping a medication class might be twice as

barge as the difference in GFR change between pa-

tients starting and those remaining off the medication

or between patients stopping and those remaining on

the medication.

These analyses were performed using multiple re-

gression so that the effects of changing the respective

medication classes were assessed after controlling for

the effects of starting or stopping other classes of

medications. We first compared the changes in GFR

between subgroups of patients who started and those

who stopped various classes of antihypertensive

agents in each 4-month interval in Studies A and B

(data not shown). The follow-up interval had no sig-

nificant effect on the association between the change

in any of the medication classes and the change in

GFR in either Study A or B; hence, we combined all

4-month intervals to determine an average associa-

tion over all 4-month intervals (Table 4).

The strongest association in both Studies A and B

was with diuretics (a 5.41- and 2. 18-mL/min greater

GFR decline in patients starting medications versus

patients stopping medications [P < 0.001 and P =

0.0041 in Studies A and B, respectively). Significant

associations were also observed with ACE inhibitors



TABLE 3. Relationships (slopes of regression lines) of changes (z�) in protein intake and mean arterial pressure(MAP) with changes in GFR over successive 4-month intervals during follow-up

Study A (GFR 25 to 5 5 mI/mm per 1.73 m2) Study B (GFR 13 to 24 mL/min per 1 .73 m2)

Month ofFollow-Up

L� GFR versus � ProteinIntake

GFR versus z� MAPz� GFR versus � Total

Protein IntakeGFR versus z� MAP

N Slope0 SE N Slopeb SE N Slope0 SE N Slopeb SE

Oto4 441 +3.lc 1.1 519 +0.12c .03 211 +1.7 1.4 224 +0.09c 0.020 to 24d +3.0w 0.6 +0.12c .01 +2.7c 0.7 +0.07c 0.01

a Study A: mean change in GFR (mL/min) per 1.0 g/kg per change in protein intake. Study B: mean change in GFR (mL/min) per 1.0 g/kg per daychange in total protein intake from food and supplements.b Studies A and B: mean change in GER (mL/mln) per 1 .0 mm Hg change in MAP.C p< 0.01.d No significant interaction with follow-up interval.

in Studies A and B (a 3.54- and 1.50-mL/min greater

GFR decline [P = <0.001 and P = 0.0351, respectively)

and with 3-bbockers in Studies A and B (a 3. 15- and

2.330-mL/min greater GFR decline [P = 0.016 and

P = 0.0101, respectively). No significant association

was observed for starting or stopping calcium channel

blockers or other classes of antihypertensive medica-

tions.

Independent Effects of Protein Intake, BloodPressure, and Antihypertensive Agents

Multivariable regression analyses. To assess the

independent effects of changes in protein intake,

blood pressure, and medication classes on GFR, we

performed comprehensive multiple regression analy-

ses for all 4-month intervals. In addition, the observed

associations were related to different levels of initial

GFR and to different 4-month intervals during follow-

up. To assess the effects of error in measurement of

TABLE 4. Association of changes (�) in classes of

antihypertensive medications with changes in GFRover all 4-month intervals0

L� Medication z� GFRbc SE P Value

Study A (GFR 25 to 55 mI/mmper 1.73 m2)

ACE Inhibitors -3.54 0.79 <0.001f3Blockers -3.15 1.31 0.016Calcium Channel Blockers -0.67 1.05 0.52Diuretics -5.41 0.85 <0.001Others -2.14 1.22 0.79

Study B (GFR 13 to 24 mL/minper 1.73 m2)

ACE Inhibitors -1.50 0.71 0.035j3 Blockers -2.33 0.90 0.01Calcium Channel Blockers -0.18 0.83 0.83Diuretics -2.18 0.76 0.004Others -0.81 0.90 0.37

a ACE, angiotensin-converting enzyme.b GFR decline in patients starting versus those stopping the class of

antihypertensive agent.C No significant interaction with follow-up Interval.

protein intake and blood pressure, the analyses were

repeated with and without controlling for measure-

ment error in the first 4-month interval.

After controlling for the changes in class of antihy-

pertensive medications, short-term changes in both

protein intake and blood pressure remained indepen-

dently associated with short-term changes in GFR (left

half ofTable 5). A change in protein intake of 1 .0 g/kg

per day was associated with a 2.77-mL/min change in

GFR (P < 0.001). Hence, a reduction in protein intake

of 0.4 g/kg per day would bead to a decline in GFR of

about 1 . 1 mL/min. Likewise, a change in MAP of 1.0

mm Hg was associated with a 0.092-mL/min change

in GFR (P < 0.00 1 ). Thus, a reduction in MAP by 10

mm Hg, without a change in class of antihypertensive

medication, would lead to a decline in GFR of about

0.9 mL/min.

The above relationships were determined in patients

with a range of baseline GFR from 13 to 55 mL/min

per 1.73 m2 (mean GFR = 36.1 mL/min per 1.73 m2).

However, the magnitude ofthe effects ofprotein intake

and MAP on GFR was highly dependent on baseline

GFR, with a larger effect in patients with higher GFR.

For changes in protein intake, the effect is 0.94 mL/

mm per 1 .0 g/kg per day greater for each 10-mL/min

increase in baseline GFR (P = 0.002) (right half of

Table 5). For example, reducing protein intake by 0.4

g/kg per day would bead to a 1 .6-mL/min GFR decline

in a patient with an initial GFR of 50 mL/ mm per 1.73

m2 and a 0.3-mL/min GFR decline in a patient with an

initial GFR of 15 mL/min per 1 .73 m2. For changes in

blood pressure, the decline in GFR is 0.014 mL/min

per 1 .0 mm Hg greater for each 10 mL/min increase in

baseline GFR (P = 0.015). For example, a 10-mm Hg

decline in MAP would be associated with a 1 . 1 -mL/

mm GFR decline in a patient with an initial GFR of 50

mL/min per 1 .73 m2, compared with a 0.6-mL/min

GFR decline in a patient with an initial GFR of 15

mL/min per 1 .73 m2.

Controlling for changes in protein intake and blood

pressure, we found significant effects from changes in

a number of classes of antihypertensive agents (left

half of Table 5). Once again, the largest effect was


2104 Volume 7 . Number 10 . 1996

TABLE 5. Longitudinal model predicting changes (z�) in GFR from changes in protein intake,a mean arterialpressure (MAP),b and class of antihypertensive medicationsc over the first 2 years of follow�upd

Variable

Overall Interaction

GFR SE P Value GFR x 10 SEP

Value

Protein Intakee +2.77 0.51 <0.001 +0.94 0.30 0.002MAPS +0.09 0.01 <0.001 +0.01 0.01 0.02ACE Inhibitorse -2.18 0.65 <0.001 -0.59 0.42 0.16

.� f3 Blockerse -3.21 1.10 <0.003 -0.90 0.69 0.19

.� Ca Channel Blockerse +0.23 0.85 0.79 +0.80 0.60 0.18Diureticse -4.45 0.67 <0.001 - 1.05 0.45 0.02Otherse -1.71 0.95 0.07 -0.43 0.60 0.48

a Change in GFR (mL/min) per change in protein intake of 1 .0 g/kg per day (from food only in Study A and from food and supplements in Study

B).b Change in GFR (mL/min) per change in MAP of 1 .0 mm Hg.C Difference in GFR associated with starting versus stopping various classes of medications.a Overall coefficients (left half) refer to the change in GFR in a patient with an initial GFR of 36.1 mL/min per 1 .73 m2. Interaction coefficients (right

half) indicate the amount by which the overall coefficients change for every 10-mL/min per 1 .73 m2 difference in initial GFR from the mean of 36.1mL/min per 1 .73 m2. ACE, angiotensin-converting enzyme.e No significant interaction with follow-up interval.

associated with diuretics (a patient starting diuretics

experienced a 4.45-mL/min greater GFR decline than

a patient stopping diuretics [P < 0.001 1). Significant

effects were also associated with changes in n-block-

ers (a 3.21-mL/min greater GFR decline [P = 0.0041)

and ACE inhibitors (a 2. 18-mL/min greater GFR de-

dine [P < 0.00 1 1). There was no apparent association

with changes in calcium channel blockers, but the

association with changes in other classes of antihy-

pertensive medications was nearly significant (a 1.71-

mL/min faster GFR decline [P = 0.0551).

The association of changes in diuretics with

changes in GFR was greater in patients with higher

initial GFR. Compared with an average GFR of 36.1

mL/min, the decline in GFR was 1 .0 mL/min greater

for each 10 mL/min increase in baseline GFR (P =

0.02 1 ) (right half of Table 5). For example, the differ-

ence in GFR decline between patients starting and

stopping diuretics would be 5.9 mL/min if baseline

GFR is 50 mL/min per 1.73 m2, and 2.2 mL/min if

baseline GFR is 15 mL/min per 1.73 m2. The effects of

other antihypertensive agents (other than calcium

channel blockers) was also greater at higher initial

GFR, although they were not statistically significant

(P > 0.15 for each class).

After controlling for the initial level of GFR, we found

no effect for the duration of follow-up on the relation-

ship of changes in protein intake, blood pressure, or

medication class to changes in GFR (data not shown).

Thus the short-term changes in protein intake, blood

pressure, and class of antihypertensive agents af-

fected GFR not only in the first 4 months but also

throughout follow-up.

To determine the effect of measurement error (van-

ability In urine urea nitrogen and blood pressure

measurement) on these analyses, the multiple regres-

slon analyses for the first 4-month interval were per-

formed with and without controlling for measuremeiit

error. In general, the differences in the observed reba-

tionships were small. The effect of controlling for

measurement error was to increase slightly the asso-

ciation of changes in protein intake and blood pres-

sure and to decrease slightly the association of

changes in classes of antihypertensive agents (data

not shown).

Relationship of changes in protein intake, blood

pressure, and class of antihypertensive agents to the

differences in GFR between the diet and blood pres-

sure groups. To assess whether the observed relation-

ships account for the observed differences in GFR

between the diet groups and between the blood pres-

sure groups during the first 4 months in Studies A and

B, we compared the observed differences with those

predicted from the observed changes in protein in-

take, blood pressure and classes of antihypertensive

medications. As discussed earlier, because of mea-

surement error, the predicted differences are generally

expected to be less than the observed differences.

In Study A, the predicted mean difference in GFR

decline between diet groups was 1.34 mL/min, com-

pared with the observed difference of 1 .84 mL/min.

The predicted mean difference between blood pres-

sure groups was 0.59 mL/min, compared with the

observed difference of 1 .90 mL/min. The substantial

underestimation of the difference between the blood

pressure groups may be the result of hourly or daily

fluctuations in blood pressure that are not reflected by

measurement at a single visit every 4 months. It may

also be the result of other factors that were not

accounted for in these analyses, such as changes in

antihypentensive agents in the same class and to

changes in dosage without changes in the agent.

In Study B, both the predicted and observed differ-

ences in the Initial changes in GFR were small. The

predicted mean difference between diet groups was

0.48 mL/min, and the observed difference was -0.08



mL/min. The predicted mean difference between

blood pressure groups was 0.3 1 mL/min, and the

observed difference was 0.02 mL/min.

DISCUSSION

These analyses show, for the first time, the indepen-

dent effects of changes in protein intake, blood pres-

sure, and different classes of antihypertensive agents

on GFR in a large number of patients with chronic

renal disease. GFR was influenced by increases or

decreases in protein intake and blood pressure,

whether antihypertensive regimens were stable or

changing. Starting diuretics, n-blockers, or ACE in-

hibitors was associated with a greater GFR decline

than was stopping them. The effect of changes in

protein intake, MAP, and diuretics was greater in

patients with higher initial GFR. These short-term

effects on GFR were not confined to the initial fol-

low-up period. Fluctuations in these factors contin-

ued to have short-term effects on GFR throughout

follow-up. Most importantly, these findings are con-

sistent with the hypothesis that these short-term

changes in GFR were caused by alterations in thehemodynamic determinants of GFR, rather than by

permanent changes in nephron structure. Although

the magnitude of these short-term effects is small, as

discussed below, they are potentially important in

clinical practice and in clinical trials.

The MDRD Study is the largest study of the effect of

dietary protein and blood pressure on the decline in

GFR in patients with chronic renal disease. A total of

840 patients with a variety of chronic renal diseases

were included. Baseline GFR ranged from 13 to 55

mL/min per 1.73 m2, with a mean of36. 1 mL/min per

1 .73 m2. During follow-up, GFR was measured seri-

ally using a standard method, the renal clearance of

‘251-iothalamate after subcutaneous injection (18,19).

Thus, we were abbe to assess accurately the relation-

ship of changes in protein intake and blood pressure

to changes in GFR. Moreover, because of the random

assignment to different diets and blood pressure

goals, we can infer cause and effect in the relationship

between these changes.

The MDRD Study was not designed, however, to

assess the effect of different classes of antihyperten-

sive agents on the decline in GFR. Nonetheless, a

variety of antihypertensive medications was used and

a large number of patients changed antihypertensive

medications during follow-up, which permits us to

assess the association between changes in GFR and

changes in classes of antihypertensive medications.

Assignment of cause and effect in these analyses is

more speculative; however, as discussed below, the

effects we observed are generally consistent with the

reported effects of antihypertensive agents.

The analyses correlating changes in GFR with

changes in protein intake and blood pressure can be

affected by errors in the measurement of each van-

able. We found little effect on the strength of the

observed relationships when controlling for measure-

ment error. However, our assessment of the effect of

measurement error did not include the effect of tran-

sient fluctuations (occurring in hours to days), errors

in collection of urine, errors in recording changes in

classes of antihypertensive medications, changes in

medications within the same class, or changes in

dosage of medications. Thus, it is likely that we have

not fully accounted for the effects of measurement

error. The true effects of changes in protein intake and

blood pressure are likely to be greater than our esti-

mates, and the true effects of changes in medication

classes are likely to be less than our estimates.

Our finding of small, but significant, effects on GFR

ofchanges in dietary protein (a 1. 1-mL/min reduction

in GFR after a 0.4-g/kg per day reduction in protein

intake), blood pressure (a 0.9-mL/min decline in GFR

after a 10-mm Hg reduction in MAP), and various

classes of antihypertensive agents (a 4.5-mL/min

greater GFR decline in patients starting versus those

stopping diuretics, a 3.2-mL/min greater GFR decline

in patients starting versus stopping �-bbockers, and a

2.2-mL/min greater GFR decline in patients starting

versus stopping ACE inhibitors) are consistent with

other studies over many years (3,4,25-36). Are these

small changes likely to be clinically important, and

how did they affect the outcome of the MDRD Study?

In clinical practice, changes in GFR of only 2 to 4

mL/min may have little or no consequences. However,

because the effects of changes in diet, blood pressure,

and antihypertensive agents are independent, they

are additive, and in some patients could be dramatic.

For example, in a group of patients with GFR of

36. 1 -mL/min per 1 .73 m2 (the mean GFR of the

MDRD Study population), a 0.4-g/kg per day reduc-

tion in dietary protein, and a 20-mm Hg reduction in

MAP after initiation of an ACE inhibitor, a �-bbocker,

and a diuretic, would bead to a mean decline in GFR by

7.8 mL/min within 4 months to a final value of 28.3

mL/min per 1.73 m2 (a 22% reduction). As stated

earlier, we may have underestimated the size of the

mean effect as a result of measurement error. More-

over, in some patients, the observed effect would be

even banger simply as a result of variability in the

population. The absolute (but not the percentage) GFR

decline would also be expected to be banger in patients

with higher baseline GFR. For example, if the relation-

ships that we observed can be extrapolated to patients

with normal GFR (125 mL/min pen 1.73 m2), a 0.4-

g/kg per day reduction in protein intake would lead to

a 4.4-mL/min GFR decline, a 20-mm Hg reduction in

MAP would bead to a 4.2-mL/min GFR decline, and

starting diuretics would lead to a 6.9-mL/min GFR

decline. However, the effects of starting an ACE inhib-

itor (a 1.1-mL/min GFR decline) and a �-bbocker (a

1.6-mL/min GFR decline) are not affected by baseline

GFR. Therefore, initiating all of these interventions in

a patient with a normal baseline GFR would lead to an

18.2-mL/min (14.6%) decline.

One practical implication of the short-term effects of


2106 Volume 7 . Number 10 - 1996

dietary protein restriction and antihypertensive then-

apy on GFR is that physicians should anticipate that

these interventions may be followed by a decrease in

renal function. In practice, physicians estimate GFR

from serum creatinine concentration. In principle, the

serum creatinine concentration would tend to rise

more after beginning antihypentensive therapy than

after dietary protein restriction than because of the

concomitant decrease in the urine creatinine excre-

tion rate with protein restriction (37). Furthermore,

the absolute rise in serum creatinine concentration

would be greater in patients with elevated baseline

serum creatinine concentration, because a decline in

GFR provokes a greater absolute increase in serum

creatinine concentration if baseline GFR is reduced.

Thus, a rise in serum creatinine concentration after

starting an antihypertensive agent is not necessarily

an adverse event and should not bead to “automatic”

withdrawal of the agent. Whether the agent should be

continued depends on the level of renal function, for

example, whether metabolic abnormalities on uremic

symptoms arise.

In the MDRD Study, the importance of these small

changes in GFR is best demonstrated by comparing

the hypothesized and observed effects of the interven-

tions. Based largely on studies of patients with dia-

betic nephropathy, the rate of GFR decline in the

MDRD Study was hypothesized to be 6 mL/min per yr

(10). In Study A (baseline GFR, 25 to 55 mL/min per

1 .73 m2), the hypothesized effect of the bow-protein

diet (compared with the usual protein diet) and the low

blood pressure goal (compared with the usual blood

pressure goal) was a 30% on greaten slowing in the rate

of GFR decline, equivalent to a difference between

groups of at least 1 .8 mL/min per yr. During a mean

follow-up interval of 3 yr. this would correspond to a

final difference between groups of at least 5.4 mL/

mm.

Instead, the observed mean rate of GFR decline in

Study A was 1 1 .5 mL/min pen 3 yr. equivalent to

3.8-mL/min peryn(12). At this rate, itwould take 12.6

yr for GFR to decline from 55 mL/min per 1 .73 m2 (the

upper limit of GFR in patients eligible for the MDRD

Study) to 7 mL/min pen 1 .73 m2 (the average GFR at

the onset of renal failure in the MDRD Study I 161).

Thus, the average rate of progression of renal disease

in the MDRD Study was slow. At these slower-than-

expected rates of progression, a 30% slowing in the

rate of GFR decline would correspond to a difference

between diet groups or between blood pressure groups

ofabout only 1 . 1 mL/min per yr or 3.3 mL/min over 3

yr.

In the first 4 months, the difference in GFR between

diet groups and blood pressure groups was 1 .84 and

1 .90 mL/min, respectively, but opposite in direction

to the hypothesized effects (Table 1 ). Correlational

analyses showed that the difference between diet

groups on between blood pressure groups attributable

to the short-term effects of changes in protein intake,

blood pressure, and class of antihypentensive agent

was at least 1.34 and 0.59 mL/min, respectively.

Although these effects were small, they were barge in

proportion to the hypothesized effects of the study

interventions.

The long-term effects (from the fourth month to the

end of follow-up) of the low-protein diet (a 28%-slower

GFR decline) and low blood pressure goal (a 29%-

slower GFR decline) were significant (P = 0.009 and

0.006, respectively) and almost as barge as the hypoth-

esized beneficial effects (Figures 1, A and B) (12).

However, the mean projected GFR decline from base-

line to 3 yr of follow-up was only 1 .2 mL/min less in

the bow-protein diet group (P = 0.3) and only 1.6

mL/min less in the low blood pressure group (P =

0. 18). Hence, considering the entire study population,

we could not detect a beneficial effect of either inter-

vention in Study A on the progression of renal disease.

In principle, given the slow rate of progression of renal

disease and the magnitude of the short-term and

long-term effects of the diet and blood pressure inter-

ventions that we observed, a longer follow-up would

have been required to detect a beneficial effect of the

interventions in Study A. On the other hand, in the

subgroup of patients with protemnuria, the rate of

progression was fasten, and a beneficial effect of the

low blood pressure goal was observed within the fob-

low-up period ( 12).

In Study B (baseline GFR between 13 and 24 mL/

mm pen 1 .73 m2), the correlational analyses also

suggested that the effect of changes in protein intake

and blood pressure on changes in GFR were opposite

in direction to the hypothesized effects, but smaller

than in Study A (Table 3). However, there was no

evidence of a significant deviation from linearity in

GFR decline in any of the diet or blood pressure

groups. Hence, the short-term effects had, at most, a

small effect on the outcome of Study B. Throughout

the entire follow-up period, the mean rate of GFR

decline was 19% less in the very-low-protein diet

group than in the low-protein diet group (P = 0.07)

and 1 2% bess in the low blood pressure group com-

pared with the usual blood pressure group (P = 0.28)

(Figures 1C and D).

Other studies of the progression of renal disease in

patients with baseline GFR at on above the range in

Study A also show short-term effects of the interven-

tions consistent with our observations. The effects are

most apparent in studies of ACE inhibitors on the

progression of diabetic nephropathy. In the study of

Bjorck et al. (38), 40 patients with Type 1 diabetes and

mean baseline GFR of 47 mL/min pen 1.73 m2 were

randomly assigned to treatment with ACE inhibitors

or f3-bbockers. During the first 6 months, patients

treated with ACE inhibitors had an approximately

2-mL/min faster GFR decline than patients treated

with �-bbockers, but a slower GFR decline thereafter.

By the end of the 2-yr mean follow-up interval, the

GFR decline was significantly less in patients treated

with ACE inhibitors. Other studies also report a faster

GFR decline soon after beginning ACE inhibitors,



compared with �-bbockers, calcium channel blockers,

and other antihypertensive agents in patients with

diabetic nephropathy (39-46).

Consistent with our conclusion that short-term

changes in GFR reflect hemodynamic rather than

structural changes, Hansen et al. (47) and Apperboo et

al. (48) have suggested in diabetics and nondiabetics,

respectively, that the early decline in GFR during

antihypertensive treatment with ACE inhibitors is

reversible after discontinuing therapy months later.

We also reported similar effects after further manipu-

bation of diet and blood pressure during the extended

follow-up of the MDRD Study A cohort (49). On the

basis of these observations, we suggest that the ca-

pacity of the gbomerulus to respond to changes in

protein intake, blood pressure, and antihypertensive

agents by alteration in the determinants of single-

nephron GFR can interfere with the use of GFR to

assess the progression ofnenal disease. Because these

alterations appear to be greater at higher GFR, we

suggest that measuring GFR to assess the effects of

interventions to slow the progression of renal disease

may be less useful in patients with higher baseline

GFR.

In particular, the finding of a greater short-term

effect of ACE inhibitors in patients with higher base-

line GFR may account for the unexpected finding of

Lewis et al. (5) of a greater beneficial effect of ACE

inhibition to slow the decline of renal function in

diabetic nephropathy in patients with higher baseline

serum creatinine concentrations (lower baseline

GFR). Indeed, in subgroup analyses, no beneficial

effect was observed In patients with baseline serum

creatinine concentrations below 1 .5 mg/dL. However,

Mogensen and colleagues (50) have found a beneficial

effect of ACE inhibition on slowing the progression of

microalbuminuria to albuminuria in patients with

normal GFR. Thus, it seems likely that ACE Inhibition

is truly effective in slowing the progression of diabetic

nephropathy In patients with higher GFR. We suggest

that the apparent lack of benefit in patients with

higher GFR in the study ofLewis et al. (5) was, in part,

the result of greater difficulty in detecting the benefi-

dab effect in patients with higher baseline GFR.

In summary, the MDRD Study shows that changes

in protein intake, blood pressure, and antthyperten-

sive therapy have independent short-term effects on

GFR in patients with chronic renal disease. A change

in protein intake of 0.4 g/kg per day was associated

with a change in GFR of 1. 1 mL/min. A change in MAP

of 10 mm Hg was associated with a change in GFR of

0.9 mL/min. Starting diuretics, /3-blockers, or ACE

inhibitors was associated with a 4.4-, 3.2-, and 2.2-

mL/mln greater GFR decline, respectively, than was

stopping them. The effect ofchanges in protein intake,

MAP, and diuretics was greater in patients with higher

initial GFR. These short-term effects are likely caused

by hemodynamic adjustments in GFR rather than

renal structural Injury. Thus, protein intake, blood

pressure, and antihypertensive agents independently

modulate the level of GFR in chronic renal disease.

Dietary protein restriction, blood pressure control,

and specific classes of antihypertensive drugs are

used to slow the progression of chronic renal diseases

in practice and in clinical trials. Although their short-

term effects on GFR are small, they are independent of

one another and are additive; hence, clinically signif-

icant changes in renal function can occur in patients

undergoing multiple interventions. In clinical trials,

these short-term effects are opposite in direction to

their hypothesized beneficial effects on the progres-

sion of renal disease, and large enough to confound

the results of the trial. In principle, confounding is

most likely to occur if the rate of progression of renal

disease is slow, if the duration of follow-up is short, or

if the baseline bevel of GFR is high. Future studies

should focus on specific renal diseases or subgroups

of patients with faster rates of progression, anticipate

the possible short-term effects of the interventions on

GFR, and appropriately extend the duration of follow-

up. For patients with slowly progressing renal dis-

eases, it may be not be practical to study the effects of

these interventions on the rate of decline in GFR.

Instead, it may be necessary to develop other mea-

sures to detect the progression of renal disease.

ACKNOWLEDGMENTS

This study was supported by the National Institute of Diabetes.

Digestive and Kidney Diseases and the Health Care Financing Admin-istration. We are indebted to the patients who participated in theModification of Diet in Renal Disease Study. Marion Merrell Dow,Kansas City, Missouri, donated diltiazem (Cardizem�), and MerckSharp and Dohme, West Point. Pennsylvania. donated enalapril

(Vasotec�) to study participants.

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