- Email: [email protected]
Relationship between renal volume growth and renal function in autosomal dominant polycystic kidney disease: A longitudinal study
The Official Journal of the
National Kidney Foundation
AJKD
VOL 39, NO 6, JUNE 2002
American Journal of Kidney Diseases
ORIGINAL INVESTIGATIONS Pathogenesis and Treatment of Kidney Disease and Hypertension
Relationship Between Renal Volume Growth and Renal Function in Autosomal Dominant Polycystic Kidney Disease: A Longitudinal Study Godela M. Fick-Brosnahan, MD, Mark M. Belz, MD, Kim K. McFann, PhD, Ann M. Johnson, MS, and Robert W. Schrier, MD ● In autosomal dominant polycystic kidney disease (ADPKD), renal function remains normal for many years into adult life while cysts form and expand progressively, starting in childhood. The longitudinal relationships between renal volume growth, hypertension, and renal function loss have not been examined in detail. At the University of Colorado (Denver, CO), 229 adult subjects with ADPKD participated in a longitudinal study from 1985 to 2001. Sequential ultrasound examinations were performed at a mean interval of 7.8 ⴞ 3.1 years (range, 2.6 to 15.1 years). Renal volume was calculated using a standard formula for a modified ellipsoid. The Modified Diet in Renal Disease equation was used to calculate glomerular filtration rate (GFR). The mean annual increase in renal volume was 46 ⴞ 55 cm3, and mean annual decline in GFR was 2.4 ⴞ 2.8 mL/min/1.73 m2. Men had faster renal growth, more severe hypertension, and a faster decline in GFR than women of similar ages. Multiple linear regression showed a significant relationship between rate of change in GFR and renal volume growth rate, initial renal volume, proteinuria, and age at entry. Correlational analysis showed a significant correlation between GFR and renal volume over time (R ⴝ ⴚ0.53) and between follow-up renal volume and follow-up GFR (R ⴝ ⴚ0.50) for both men and women. We conclude that renal volume and rate of renal volume growth may be useful markers for disease progression in early stages of ADPKD when GFR is preserved. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Autosomal dominant polycystic kidney disease (ADPKD); ultrasound; computed tomography (CT); glomerular filtration rate (GFR); renal volume; proteinuria; gender; hypertension.
A
UTOSOMAL DOMINANT polycystic kidney disease (ADPKD) is the most common life-threatening hereditary renal disorder. ADPKD accounts for approximately 5% of endstage renal disease (ESRD) in the United States, and to date, there is no proven treatment to slow the progression of renal disease in ADPKD.1 In ADPKD, glomerular filtration rate (GFR) remains normal for a long period before it starts to decline inexorably.2 Interventions started at the stage of GFR decline have not proven effective, and the decline in GFR may be faster than that in most other renal disease.3 However, during the period of normal GFR, cyst expansion and renal enlargement continue to progress. The exact
From the Department of Medicine, University of Colorado Health Sciences Center, Denver, CO. Received October 9, 2001; accepted in revised form December 21, 2001. Supported in part by grant no. 5 P01 DK34039, Human Polycystic Kidney Disease, from the Department of Health and Human Services, Public Health Service, National Institute of Diabetes and Digestive and Kidney Diseases; grant no. MORR00051 from the General Clinical Research Centers Research Program of the Division of Research Resources, The National Institutes of Health; and the Zell Family Foundation. Address reprint requests to Robert Schrier, MD, Chairman, Department of Medicine, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/3906-0001$35.00/0 doi:10.1053/ajkd.2002.33379
American Journal of Kidney Diseases, Vol 39, No 6 (June), 2002: pp 1127-1134
1127
1128
FICK-BROSNAHAN ET AL
mechanism leading to the onset of GFR decline is unknown. Hypertension is common in patients with ADPKD with normal GFR, occurring in approximately 70% of patients by the age of 30 years.4 Hypertension is a significant risk factor for progression to ESRD5,6; however, whether hypertension in ADPKD contributes to faster progression, is primarily a marker of more severe disease leading to ESRD, or both is unknown. Hypertensive patients with ADPKD with normal renal function have larger kidneys than normotensive subjects of similar ages,7 and patients with larger kidneys may be at greater risk for progression to ESRD.8 Men with ADPKD progress faster than women, which has been attributed to a greater prevalence and severity of hypertension.8 A recent study found that patients with ADPKD with proteinuria have a greater annual increase in renal volume and greater annual decline in GFR than those without proteinuria.9 Relationships between renal enlargement, hypertension, sex, proteinuria, and renal dysfunction are complex and have not been examined in a large longitudinal study. Therefore, we examined these parameters longitudinally in 229 adults with ADPKD who were seen at the University of Colorado (Denver, CO) and who underwent renal ultrasound examinations at least 2.5 years apart. METHODS From 1985 to 2001, a total of 668 adult subjects with ADPKD participated in a longitudinal study of the natural history of ADPKD at the University of Colorado Health Sciences Center. All subjects provided written informed consent. Two hundred twenty-nine of 668 subjects met inclusion criteria for analysis: (1) at least two sequential ultrasound examinations performed at least 2.5 years apart, (2) older than 18 years, and (3) not in ESRD. Additionally, subjects from known polycystic kidney disease type 2 (PKD-2) families were excluded. Fifty-three of the 229 subjects also were involved in an interventional study to determine the optimal level of blood pressure control. The remaining 176 subjects were treated by their primary care physicians. At each study visit in the General Clinical Research Center (GCRC), participants had a history and physical examination, and renal ultrasound was performed. Initial and follow-up blood pressure measurements were performed by trained nurses and physicians of the GCRC using a Dinamap apparatus (Critikon Inc, Tampa, FL). Hypertension was defined as blood pressure of 140/90 mm Hg or greater or on antihypertensive medication therapy. Sequential renal ultrasound examinations were performed on each study subject. All were performed in the Radiology
Department of the University of Colorado Health Sciences Center using the same standards to measure renal volume. Renal volume was defined as the mean of both kidneys and calculated using a standard formula for a modified ellipsoid for each kidney as follows: Renal volume
冉
冊
anteroposterior diameter width 4 ⫹ ⫽ ⫻ 3 4 4
2
⫻
length 2
Renal volume growth rate was defined as the increase in renal volume per year. At each study visit, subjects had blood drawn to determine routine serum chemistry values. The Modified Diet in Renal Disease equation was used to calculate GFR10: GFR ⫽ 170 ⫻ 关P cr 兴 ⫺0.999 ⫻ 关age兴 ⫺0.176 ⫻ 关0.822 if patient is female兴 ⫻ 关1.180 if patient is black兴 ⫻ 关SUN兴 ⫺0.170 ⫻ 关alb兴 ⫹0.318 Where alb is serum albumin concentration (in grams per deciliter), Pcr is serum creatinine concentration (in milligrams per deciliter), and SUN is serum urea nitrogen concentration (in milligrams per deciliter). Blood also was drawn for linkage analysis for subjects who had several family members for study. Linkage analysis for PKD-1 and PKD-2 was performed in the laboratory of Dr Kimberling (Boystown National Institute, Omaha, NE) using established markers for the PKD-1 and PKD-2 genes.11 Proteinuria was determined by means of two 24-hour urine collections obtained during patients’ stays in the GCRC. Urinary protein concentrations were determined by the Coumassie blue dye-binding method. The mean of the two collections was used to assess each individual’s level of proteinuria (in milligrams per 24 hours). All data are expressed as mean ⫾ SD and range. Independent samples t-tests were used to test the mean difference between characteristics of men and women at baseline and follow-up. Independent samples t-tests also were used to test mean characteristic differences at baseline and follow-up between patients with a decline in GFR declined compared with those with no decline in GFR. Relationships among change in GFR, initial GFR, follow-up GFR, renal volume growth rate, initial renal volume, follow-up renal volume, initial age, initial mean arterial pressure (MAP), follow-up MAP, and proteinuria were examined using Pearson’s correlation coefficients and multiple linear regression. Results are considered significant at ␣ of 0.05.
RESULTS
Two hundred twenty-nine adult subjects (84 men, 145 women) from 156 ADPKD families were studied. Ninety-four subjects were from PKD-1 families, and genotype could not be determined for 135 subjects. Initial age of subjects was 37 ⫾ 11 years (range, 19 to 81 years). Average time between visits was 7.8 ⫾ 3.1 years
RENAL VOLUME GROWTH AND POLYCYSTIC KIDNEY DISEASE
(range, 2.6 to 15.1 years). One hundred eleven patients were on antihypertensive medication therapy at their first visit; 165 patients, at their second visit; and 109 patients, at both visits. Only 51 patients were normotensive without medication at both visits. Mean initial systolic blood pressure was 127 ⫾ 12 mm Hg (range, 105 to 161 mm Hg), and mean initial diastolic blood pressure was 85 ⫾ 9 mm Hg (range, 65 to 110 mm Hg), for an MAP of 98 ⫾ 8 mm Hg (range, 80 to 125 mm Hg). Follow-up systolic blood pressure was 127 ⫾ 13 mm Hg (range, 99 to 165 mm Hg) and follow-up diastolic blood pressure was 82 ⫾ 8 mm Hg (range, 61 to 109 mm Hg), for a follow-up MAP of 97 ⫾ 9 mm Hg (range, 76 to 124 mm Hg). Follow-up diastolic blood pressure and MAP were significantly lower than initial values (P ⬍ 0.0001 and P ⬍ 0.001, respectively). Mean proteinuria at the initial visit was protein of 143 ⫾ 90 mg/24 h (range, 18 to 685 mg/24 h), and at the follow-up visit, 248 ⫾ 410 mg/24 h (range, 0 to 4,470 mg/24 h). Diabetes mellitus was diagnosed in one patient with nephrotic-range proteinuria. Initial mean renal volume was 561 ⫾ 354 cm3, with a wide range from normal-sized to very enlarged kidneys (range, 120 to 2,072 cm3). Follow-up mean renal volume was 942 ⫾ 597 cm3 (range, 136 to 3,038 cm3). Mean annual increase in renal volume for all subjects was 46 ⫾ 55 cm3. Initial mean GFR was 71 ⫾ 22 mL/min/1.73 m2 (0.68 ⫾ 0.21 mL/s/m2; range, 20 to 152 mL/min/1.73 m2), and follow-up mean GFR was 52 ⫾ 26 mL/min/1.73 m2 (0.50 ⫾ 0.25 mL/s/m2; range, 7 to 119 mL/min/ 1.73 m2). Effect of Sex Initial ages of men (37 ⫾ 8.7 years) and women (38 ⫾ 11.6 years) at entry onto the study were similar (P ⫽ not significant [NS]). However, there were several differences between male and female ADPKD populations. Initial renal volumes were much greater in men than in women (684 ⫾ 407 versus 490 ⫾ 299 cm3; P ⬍ 0.001). Renal growth rates were significantly greater for men than for women (65 ⫾ 63 versus 35 ⫾ 47 cm3/y; P ⬍ 0.005). Men had significantly greater systolic, diastolic, and MAPs at both baseline and follow-up than women (initial systolic blood pressure,
1129
131 ⫾ 10 versus 125 ⫾ 12 mm Hg; P ⬍ 0.0001; follow-up systolic blood pressure, 130 ⫾ 12 versus 126 ⫾ 13 mm Hg; P ⬍ 0.05; initial diastolic blood pressure, 90 ⫾ 9 versus 83 ⫾ 8 mm Hg; P ⬍ 0.0001; follow-up diastolic blood pressure, 84 ⫾ 9 versus 80 ⫾ 8 mm Hg; P ⬍ 0.005; initial MAP, 104 ⫾ 9 versus 97 ⫾ 9 mm Hg; P ⬍ 0.0001; and follow-up MAP, 99 ⫾ 9 versus 95 ⫾ 9 mm Hg; P ⬍ 0.005). A greater percentage of men than women were administered antihypertensive medications (P ⬍ 0.01). Although initial GFR values were similar in men (73 ⫾ 21 mL/min/1.73 m2; 0.70 ⫾ 0.20 mL/s/m2) and women (71 ⫾ 23 mL/min/1.73 m2; 0.68 ⫾ 0.22 mL/s/m2; P ⫽ NS), there was a significantly greater rate of decline in GFR in men (⫺2.99 mL/min/1.73 m2/y; ⫺0.029 mL/s/ m2/y) compared with women (⫺1.98 mL/min/ 1.73 m2/y; ⫺0.019 mL/s/m2/y; P ⬍ 0.01). Degrees of proteinuria at baseline (protein, 167 ⫾ 114 versus 128 ⫾ 72 mg/24 h; P ⬍ 0.01) and follow-up (364 ⫾ 589 versus 180 ⫾ 229 mg/24 h; P ⬍ 0.005) also were greater in men than in women. Comparison of Characteristics of Patients With Versus Without GFR Decline Overall, the rate of decline in GFR was ⫺2.4 ⫾ 2.8 mL/min/1.73 m2/y (⫺0.023 mL/s/m2/y). A subgroup of 36 subjects (7 men, 29 women) did not experience a decline in renal function during a mean follow-up of 6.5 ⫾ 2.2 years, whereas 193 subjects (77 men, 116 women) had a decline in GFR during a mean follow-up of 8.1 ⫾ 3.2 years (Table 1). Subjects with stable GFRs over time had significantly smaller initial renal volumes and renal growth rates over time than patients in whom GFR declined over time. Although their initial systolic, diastolic, and MAPs were significantly lower at baseline, there was no difference in blood pressure at follow-up between the two groups. Proteinuria values were similar at baseline, but were significantly different at follow-up; subjects with a decline in GFR had significantly greater follow-up proteinuria. Of 56 subjects who were normotensive at both visits without medication, 18 subjects did not have a decline in GFR. This ratio (18 of 56 patients) is significantly greater than that for the rest of the population with hypertension (18 of 173 patients; P ⬍ 0.0001). After controlling for
1130
FICK-BROSNAHAN ET AL Table 1.
Comparison of Subjects With and Without GFR Decline During the Course of the Study
Initial age (y) Initial renal volume (cm3) Follow-up renal volume (cm3) Change in renal volume (cm3/y) Initial SBP (mm Hg) Follow-up SBP (mm Hg) Initial DBP (mm Hg) Follow-up DBP (mm Hg) Initial MAP (mm Hg) Follow-up MAP (mm Hg) Initial GFR (mL/min/1.73 m2)* Follow-up GFR (mL/min/1.73 m2)* Change in GFR (mL/min/1.73 m2)* Initial proteinuria (mg/24 h) Follow-up proteinuria (mg/24 h)
Subjects With Decline (n ⫽ 193)
Subjects Without Decline (n ⫽ 36)
P
38 ⫾ 11 598 ⫾ 368 1,017 ⫾ 605 49 ⫾ 57 128 ⫾ 12 127 ⫾ 13 86 ⫾ 9 82 ⫾ 9 100 ⫾ 9.4 97 ⫾ 9.4 71 ⫾ 23 46 ⫾ 22 ⫺3.18 ⫾ 1.97 144 ⫾ 93 274 ⫾ 442
34 ⫾ 11 366 ⫾ 168 537 ⫾ 342 30 ⫾ 41 123 ⫾ 10 128 ⫾ 12 83 ⫾ 9 82 ⫾ 7 96 ⫾ 8.6 96 ⫾ 8.6 73 ⫾ 16 85 ⫾ 19 ⫺2.09 ⫾ 2.41 133 ⫾ 81 113 ⫾ 78
0.0185 ⬍0.0001 ⬍0.0001 0.0167 0.0283 0.7698 0.0478 0.9747 0.0295 0.8770 0.5801 ⬍0.0001 ⬍0.0001 0.4754 ⬍0.0001
NOTE. Values expressed as mean ⫾ SD. Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; GFR, calculated by MDRD (Modification of Diet in Renal Disease) formula. *To convert GFR values to milliliters per second per square meter, divide by 34.7.
age and sex, subjects with a diagnosis of hypertension at any point in the study had larger kidneys at baseline (P ⫽ 0.0002) and follow-up (P ⬍ 0.0001), faster renal volume growth rate (P ⫽ 0.001), similar GFR at baseline (P ⫽ NS), but worse GFR at follow-up (P ⬍ 0.0001), and a faster rate of decline in GFR (P ⫽ 0.0024) than subjects without a diagnosis of hypertension (data not shown).
Correlation and Multiple Linear Regression Analyses Correlational analyses using all data points showed that GFR correlated significantly with renal volume (R ⫽ ⫺0.53; P ⬍ 0.0001), initial age (R ⫽ ⫺0.44; P ⬍ 0.0001), and proteinuria (R ⫽ ⫺0.30; P ⬍ 0.0001), but not blood pressure (R ⫽ ⫺0.02; P ⫽ NS). Figure 1 shows the
Fig 1. Relationship between GFR and renal volume in 229 subjects with ADPKD over the course of the study using all data points for each subject. *GFR calculated by MDRD formula.
RENAL VOLUME GROWTH AND POLYCYSTIC KIDNEY DISEASE
1131
Fig 2. Relationship between rate of change in GFR and renal volume growth rate in 229 subjects with ADPKD.
relationship between GFR and renal volume during the course of the study. Rate of decline in GFR correlated with renal volume growth rate (Fig 2), initial age, initial renal volume, follow-up renal volume, initial proteinuria, follow-up proteinuria, and initial MAP, but not follow-up MAP (Table 2). Follow-up GFR also correlated with age at study entry, initial renal volume, MAP and proteinuria, as well as follow-up renal volume and proteinuria, and renal volume growth rate (Table 2). Analyses by sex showed that for men, GFR Table 2. Correlations of Follow-Up GFR and Change in GFR With Characteristics of 229 Patients With ADPKD Follow-Up GFR
Initial age Renal volume growth rate Initial renal volume Follow-up renal volume Initial MAP Follow-up MAP Initial proteinuria Follow-up proteinuria
Change in GFR
r
P
r
P
⫺0.48
⬍0.0001
⫺0.16
⬍0.05
⫺0.24
⬍0.0005
⫺0.20
⬍0.005
⫺0.45
⬍0.0001
⫺0.25
⬍0.0001
⫺0.50 ⫺0.18 0.12 ⫺0.29
⬍0.0001 ⬍0.01 NS ⬍0.0001
⫺0.29 ⫺0.17 ⫺0.01 ⫺0.18
⬍0.0001 ⬍0.05 NS ⬍0.01
⫺0.32
⬍0.0001
⫺0.25
⬍0.005
correlated significantly with renal volume (R ⫽ ⫺0.61; P ⬍ 0.0001), age at entry (R ⫽ ⫺0.40; P ⬍ 0.0001), and proteinuria (R ⫽ ⫺0.35; P ⬍ 0.0001), but not blood pressure (R ⫽ ⫺0.09; P ⫽ NS). For men, decline in GFR correlated with change in renal volume (R ⫽ ⫺0.25; P ⬍ 0.05), level of initial proteinuria (R ⫽ ⫺0.22; P ⬍ 0.05), and follow-up proteinuria (R ⫽ ⫺0.30; P ⬍ 0.01). For women, GFR correlated significantly with renal volume (R ⫽ ⫺0.49; P ⬍ 0.0001), age (R ⫽ ⫺0.47; P ⬍ 0.0001), and proteinuria (R ⫽ ⫺0.30; P ⬍ 0.0001), but not blood pressure (R ⫽ ⫺0.06; P ⫽ NS). Additionally, in women, change in GFR correlated with initial renal volume (R ⫽ ⫺0.26; P ⬍ 0.01), initial age (R ⫽ ⫺0.20; P ⬍ 0.05), initial MAP (R ⫽ ⫺0.16; P ⬍ 0.05), and follow-up proteinuria (R ⫽ ⫺0.17; P ⬍ 0.05), but not rate of change in renal volume or initial proteinuria. The number of pregnancies in women did not correlate with GFR or rate of decline in GFR. Multiple linear regression analyses with 229 subjects showed that renal volume growth rate (P ⬍ 0.01), initial renal volume (P ⫽ 0.001), initial age (P ⬍ 0.0001), baseline GFR (P ⬍ 0.0001), and proteinuria (P ⫽ 0.0004) were significantly related to change in GFR, whereas sex (P ⫽ NS) and blood pressure (P ⫽ NS) were not. Multiple linear regression by sex showed
1132
FICK-BROSNAHAN ET AL
that for men, change in GFR was significantly related to renal volume growth rate (P ⬍ 0.01), baseline GFR (P ⬍ 0.05), and proteinuria (P ⬍ 0.005), but not to initial age (P ⫽ NS), blood pressure (P ⫽ NS), or initial renal volume (P ⫽ NS). For women, change in GFR was significantly related to initial age, initial renal volume, initial GFR, and proteinuria (P ⬍ 0.05), but not to renal volume growth rate (P ⫽ NS), blood pressure (P ⫽ NS), or number of pregnancies (P ⫽ NS). DISCUSSION
This longitudinal study shows that GFR and rate of decline in GFR in patients with ADPKD correlate with renal volume and rate of increase in renal volume, and men have greater increases in renal volume and declines in GFR than women of similar ages. Two other studies have examined the relationship between renal volume growth and decline in GFR by means of computed tomography with contrast media.9,12 However, both studies were small, including only 10 and 9 patients, whereas we present longitudinal data for 229 subjects followed up for a mean of 7.8 years (range, 2.6 to 15.1 years). Similar to the computed tomographic studies, the majority of our patients had preserved renal function at baseline. Initial and follow-up renal volumes varied widely among patients on all three studies. However, overall renal volume growth rates were similar (46 ⫾ 55 cm3/y/kidney in the current study, 24 ⫾ 22 cm3/y/kidney in the study by King et al,9 and 54 ⫾ 10 cm3/y/kidney in the study by Sise et al12). Whereas Sise et al12 did not report annual change in GFR, the mean rate of decline in GFR in the study by King et al9 (2.8 ⫾ 2.8 mL/min/1.73 m2/y; 0.027 mL/s/m2/y) was similar to that on our study (2.4 ⫾ 2.8 mL/min/1.73 m2/y; 0.023 mL/s/m2/y). Importantly, King et al9 found a significant correlation between increase in renal cyst volume and decline in GFR. This is similar to our finding of a significant correlation between increase in total renal volume and decline in GFR because the increase in total renal volume is caused by the increase in cyst volume. Because our study included 229 patients with ADPKD, we also were able to determine the impact of sex and blood pressure on renal volume growth rate and identify characteristics of
patients with no decline in GFR during follow-up compared with those with a decline in GFR. In previous studies, men were found to enter ESRD an average of 5 to 6 years earlier than women.8,13-15 In the present study, men had more severe disease than women of similar age. Specifically, they had larger kidneys at baseline, faster renal enlargement, faster declines in GFR, and higher blood pressures despite antihypertensive medication. However, the rate of change in GFR in men was linearly related to only change in renal volume, level of initial proteinuria, and follow-up proteinuria, not initial or follow-up MAP. The strongest correlation (R ⫽ ⫺0.61) was between renal volume and GFR, suggesting that effects of renal volume growth, ie, renal cyst expansion, are the most important measurable determinants of GFR decline in men with ADPKD. For women, the rate of change in GFR was linearly related to initial renal volume, initial age, initial MAP, and follow-up proteinuria. As in men, the strongest correlation (R ⫽ ⫺0.49) was between renal volume and GFR, suggesting a relationship between renal volume increase and decline in GFR in women, as well. Why men with ADPKD have more severe disease than women with ADPKD cannot be answered by this study. Subjects with ADPKD who did not experience a decline in GFR over the short term (follow-up, 6.5 years) were young; had relatively small kidneys, slow renal growth rates, and normal blood pressures; and most were not administered medication. This is important prognostic information for the natural history of ADPKD and for planning intervention studies. A previous cross-sectional study showed that overt proteinuria (protein ⬎ 300 mg/d) was associated with larger renal volumes, higher blood pressures, and lower creatinine clearances in patients with ADPKD.16 The computed tomographic study of King et al involving nine patients with ADPKD showed that subjects with greater initial proteinuria had a significantly larger increase in renal volume and decline in GFR than those with less proteinuria.9 The present study confirms these results. Overall, the present study shows that renal growth, hypertension, proteinuria, and decline in GFR are interrelated. However, the degree of
RENAL VOLUME GROWTH AND POLYCYSTIC KIDNEY DISEASE
correlations suggests that other unidentified factors also are likely determinants of renal function decline in ADPKD. Activation of the reninangiotensin-aldosterone system has been implicated in ADPKD,17 presumably secondary to renal cyst expansion and local ischemia. Because angiotensin II is a known stimulator of growth factor and fibrosis5,18-20 and aldosterone is known to stimulate fibrosis,21 a role of the reninangiotensin-aldosterone system in cyst formation, interstitial fibrosis, and hypertension has been proposed.5,22,23 Animal experiments and histological studies suggest that inflammatory cytokines and apoptosis of normal tubules24 may contribute to progressive tubular atrophy, glomerulosclerosis, and interstitial fibrosis.23 These processes likely are linked to the expanding cysts, which contain numerous growth factors and inflammatory cytokines.23 At present, the progressive renal parenchymal remodeling in ADPKD cannot be quantified using an imaging method. Therefore, total renal volume or renal cyst volume must be used to assess the progression of ADPKD at a stage when GFR is preserved. In this stage, slowing renal cyst growth and preventing a future decline in renal function may be most effective. In conclusion, the present results indicate that renal volume measurements can be used to follow-up progression of ADPKD. Because the optimal goal in ADPKD treatment is ESRD prevention, rather than just slowing the time to ESRD, early intervention to prevent progressive cyst enlargement may be necessary. Whether controlling blood pressure and reducing proteinuria in patients with ADPKD can slow renal volume growth is unclear. However, blood pressure control is important because cardiovascular complications are now the major cause of death in these individuals.25,26 Our recent 7-year randomized study of patients with ADPKD showed that rigorous antihypertensive therapy with a blood pressure goal of less than 120/80 mm Hg can reverse left ventricular hypertrophy, an important cardiovascular risk factor, significantly better than standard therapy with a blood pressure goal of 135 to 140/85 to 90 mm Hg.27 In regard to kidneys, it appears that therapies aimed at inhibiting cyst expansion may have the best potential to preserve renal function. Such therapies are now being developed.28
1133
REFERENCES 1. US Renal Data System: USRDS 2000 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Baltimore, MD, 2000 2. Franz KA, Reubi FC: Rate of functional deterioration in polycystic kidney disease. Kidney Int 23:526-529, 1983 3. Klahr S, Breyer JA, Beck GJ, et al: Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group [published erratum in J Am Soc Nephrol 6:1318, 1995]. J Am Soc Nephrol 5:2037-2047, 1995 4. Fick-Brosnahan GM, Ecder T, Schrier R: Polycystic kidney disease, in Schrier R (ed): Diseases of the Kidney and Urinary Tract. Philadelphia, PA, Lippincott, Williams and Wilkins, 2001, pp 547-588 5. Ecder T, Schrier RW: Hypertension in autosomaldominant polycystic kidney disease: Early occurrence and unique aspects. J Am Soc Nephrol 12:194-200, 2001 6. Chapman AB, Schrier RW: Pathogenesis of hypertension in autosomal dominant polycystic kidney disease. Semin Nephrol 11:653-660, 1991 7. Gabow PA, Chapman AB, Johnson AM, et al: Renal structure and hypertension in autosomal dominant polycystic kidney disease. Kidney Int 38:1177-1180, 1990 8. Gabow PA, Johnson AM, Kaehny WD, et al: Factors affecting the progression of renal disease in autosomaldominant polycystic kidney disease. Kidney Int 41:13111319, 1992 9. King BF, Reed JE, Bergstralh EJ, Sheedy PF II, Torres VE: Quantification and longitudinal trends of kidney, renal cyst, and renal parenchyma volumes in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 11:1505-1511, 2000 10. Levey AS, Bosch JP, Breyer-Lewis J, Greene T, Rogers N, Roth D, for the Modification of Diet in Renal Disease Study Group: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130:461-470, 1999 11. Hadimeri H, Johansson AC, Haraldsson B, Nyberg G: CAPD in patients with autosomal dominant polycystic kidney disease. Perit Dial Int 18:429-432, 1998 12. Sise C, Kusaka M, Wetzel LH, et al: Volumetric determination of progression in autosomal dominant polycystic kidney disease by computed tomography. Kidney Int 58:2492-2501, 2000 13. Gretz N, Zeier M, Geberth S, Strauch M, Ritz E: Is gender a determinant for evolution of renal failure? A study in autosomal dominant polycystic kidney disease. Am J Kidney Dis 14:178-183, 1989 14. Stewart JH: End-stage renal failure appears earlier in men than in women with polycystic kidney disease. Am J Kidney Dis 24:181-183, 1994 15. Choukroun G, Itakura Y, Albouze G, et al: Factors influencing progression of renal failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 6:16341642, 1995 16. Chapman AB, Johnson AM, Gabow PA, Schrier RW: Overt proteinuria and microalbuminuria in autosomal domi-
1134
nant polycystic kidney disease. J Am Soc Nephrol 5:13491354, 1994 17. Chapman AB, Johnson A, Gabow PA, Schrier RW: The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N Engl J Med 323:10911096, 1990 18. Peters H, Noble NA: Angiotensin II and I-arginine in tissue fibrosis: More than blood pressure. Kidney Int 52:14971510A, 1997 (abstr) 19. Pimentel JL, Sundell CL, Wang S, Kopp JB, Montero A, Martinez-Maldonado M: Role of angiotensin II in the expression and regulation of transforming growth factor-beta in obstructive nephropathy. Kidney Int 48:1233-1246, 1995 20. Peters H, Border WA, Noble NA: Targeting TGF-beta overexpression in renal disease: Maximizing the antifibrotic action of angiotensin II blockade. Kidney Int 54:1570-1580, 1998 21. Hostetter T: Aldosterone in renal disease. Curr Opin Nephrol Hypertens 10:105-110, 2001 22. Ecder T, Edelstein CL, Fick G, Johnson CM, Gabow PA, Schrier RW: Diuretics versus angiotensin-converting enzyme inhibitors in autosomal dominant polycystic kidney disease. Am J Nephrol 21:98-103, 2001
FICK-BROSNAHAN ET AL
23. Grantham JJ: Mechanisms of progression in autosomal dominant polycystic kidney disease. Kidney Int 52:S93S97, 1997 (suppl 63) 24. Ecder T, Melnikov V, Korular D, Lucia MS, Schrier RW, Edelstein C: Caspases, Bcl-2 proteins and apoptosis in autosomal dominant polycystic kidney disease. Kidney Int 61:1220-1230, 2002 25. Iglesias CG, Torres VE, Offord KP, Holley KE, Beard CM, Kurland LT: Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980. Am J Kidney Dis 2:630-639, 1983 26. Fick GM, Johnson AM, Hammond WS, Gabow PA: Causes of death in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 5:2048-2056, 1995 27. Schrier R, McFann K, Johnson A, et al: Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal dominant polycystic kidney disease: Results of a seven-year prospective randomized study. J Am Soc Nephrol (in press) 28. Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED: Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int 57:33-40, 2000
National Kidney Foundation
AJKD
VOL 39, NO 6, JUNE 2002
American Journal of Kidney Diseases
ORIGINAL INVESTIGATIONS Pathogenesis and Treatment of Kidney Disease and Hypertension
Relationship Between Renal Volume Growth and Renal Function in Autosomal Dominant Polycystic Kidney Disease: A Longitudinal Study Godela M. Fick-Brosnahan, MD, Mark M. Belz, MD, Kim K. McFann, PhD, Ann M. Johnson, MS, and Robert W. Schrier, MD ● In autosomal dominant polycystic kidney disease (ADPKD), renal function remains normal for many years into adult life while cysts form and expand progressively, starting in childhood. The longitudinal relationships between renal volume growth, hypertension, and renal function loss have not been examined in detail. At the University of Colorado (Denver, CO), 229 adult subjects with ADPKD participated in a longitudinal study from 1985 to 2001. Sequential ultrasound examinations were performed at a mean interval of 7.8 ⴞ 3.1 years (range, 2.6 to 15.1 years). Renal volume was calculated using a standard formula for a modified ellipsoid. The Modified Diet in Renal Disease equation was used to calculate glomerular filtration rate (GFR). The mean annual increase in renal volume was 46 ⴞ 55 cm3, and mean annual decline in GFR was 2.4 ⴞ 2.8 mL/min/1.73 m2. Men had faster renal growth, more severe hypertension, and a faster decline in GFR than women of similar ages. Multiple linear regression showed a significant relationship between rate of change in GFR and renal volume growth rate, initial renal volume, proteinuria, and age at entry. Correlational analysis showed a significant correlation between GFR and renal volume over time (R ⴝ ⴚ0.53) and between follow-up renal volume and follow-up GFR (R ⴝ ⴚ0.50) for both men and women. We conclude that renal volume and rate of renal volume growth may be useful markers for disease progression in early stages of ADPKD when GFR is preserved. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Autosomal dominant polycystic kidney disease (ADPKD); ultrasound; computed tomography (CT); glomerular filtration rate (GFR); renal volume; proteinuria; gender; hypertension.
A
UTOSOMAL DOMINANT polycystic kidney disease (ADPKD) is the most common life-threatening hereditary renal disorder. ADPKD accounts for approximately 5% of endstage renal disease (ESRD) in the United States, and to date, there is no proven treatment to slow the progression of renal disease in ADPKD.1 In ADPKD, glomerular filtration rate (GFR) remains normal for a long period before it starts to decline inexorably.2 Interventions started at the stage of GFR decline have not proven effective, and the decline in GFR may be faster than that in most other renal disease.3 However, during the period of normal GFR, cyst expansion and renal enlargement continue to progress. The exact
From the Department of Medicine, University of Colorado Health Sciences Center, Denver, CO. Received October 9, 2001; accepted in revised form December 21, 2001. Supported in part by grant no. 5 P01 DK34039, Human Polycystic Kidney Disease, from the Department of Health and Human Services, Public Health Service, National Institute of Diabetes and Digestive and Kidney Diseases; grant no. MORR00051 from the General Clinical Research Centers Research Program of the Division of Research Resources, The National Institutes of Health; and the Zell Family Foundation. Address reprint requests to Robert Schrier, MD, Chairman, Department of Medicine, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/3906-0001$35.00/0 doi:10.1053/ajkd.2002.33379
American Journal of Kidney Diseases, Vol 39, No 6 (June), 2002: pp 1127-1134
1127
1128
FICK-BROSNAHAN ET AL
mechanism leading to the onset of GFR decline is unknown. Hypertension is common in patients with ADPKD with normal GFR, occurring in approximately 70% of patients by the age of 30 years.4 Hypertension is a significant risk factor for progression to ESRD5,6; however, whether hypertension in ADPKD contributes to faster progression, is primarily a marker of more severe disease leading to ESRD, or both is unknown. Hypertensive patients with ADPKD with normal renal function have larger kidneys than normotensive subjects of similar ages,7 and patients with larger kidneys may be at greater risk for progression to ESRD.8 Men with ADPKD progress faster than women, which has been attributed to a greater prevalence and severity of hypertension.8 A recent study found that patients with ADPKD with proteinuria have a greater annual increase in renal volume and greater annual decline in GFR than those without proteinuria.9 Relationships between renal enlargement, hypertension, sex, proteinuria, and renal dysfunction are complex and have not been examined in a large longitudinal study. Therefore, we examined these parameters longitudinally in 229 adults with ADPKD who were seen at the University of Colorado (Denver, CO) and who underwent renal ultrasound examinations at least 2.5 years apart. METHODS From 1985 to 2001, a total of 668 adult subjects with ADPKD participated in a longitudinal study of the natural history of ADPKD at the University of Colorado Health Sciences Center. All subjects provided written informed consent. Two hundred twenty-nine of 668 subjects met inclusion criteria for analysis: (1) at least two sequential ultrasound examinations performed at least 2.5 years apart, (2) older than 18 years, and (3) not in ESRD. Additionally, subjects from known polycystic kidney disease type 2 (PKD-2) families were excluded. Fifty-three of the 229 subjects also were involved in an interventional study to determine the optimal level of blood pressure control. The remaining 176 subjects were treated by their primary care physicians. At each study visit in the General Clinical Research Center (GCRC), participants had a history and physical examination, and renal ultrasound was performed. Initial and follow-up blood pressure measurements were performed by trained nurses and physicians of the GCRC using a Dinamap apparatus (Critikon Inc, Tampa, FL). Hypertension was defined as blood pressure of 140/90 mm Hg or greater or on antihypertensive medication therapy. Sequential renal ultrasound examinations were performed on each study subject. All were performed in the Radiology
Department of the University of Colorado Health Sciences Center using the same standards to measure renal volume. Renal volume was defined as the mean of both kidneys and calculated using a standard formula for a modified ellipsoid for each kidney as follows: Renal volume
冉
冊
anteroposterior diameter width 4 ⫹ ⫽ ⫻ 3 4 4
2
⫻
length 2
Renal volume growth rate was defined as the increase in renal volume per year. At each study visit, subjects had blood drawn to determine routine serum chemistry values. The Modified Diet in Renal Disease equation was used to calculate GFR10: GFR ⫽ 170 ⫻ 关P cr 兴 ⫺0.999 ⫻ 关age兴 ⫺0.176 ⫻ 关0.822 if patient is female兴 ⫻ 关1.180 if patient is black兴 ⫻ 关SUN兴 ⫺0.170 ⫻ 关alb兴 ⫹0.318 Where alb is serum albumin concentration (in grams per deciliter), Pcr is serum creatinine concentration (in milligrams per deciliter), and SUN is serum urea nitrogen concentration (in milligrams per deciliter). Blood also was drawn for linkage analysis for subjects who had several family members for study. Linkage analysis for PKD-1 and PKD-2 was performed in the laboratory of Dr Kimberling (Boystown National Institute, Omaha, NE) using established markers for the PKD-1 and PKD-2 genes.11 Proteinuria was determined by means of two 24-hour urine collections obtained during patients’ stays in the GCRC. Urinary protein concentrations were determined by the Coumassie blue dye-binding method. The mean of the two collections was used to assess each individual’s level of proteinuria (in milligrams per 24 hours). All data are expressed as mean ⫾ SD and range. Independent samples t-tests were used to test the mean difference between characteristics of men and women at baseline and follow-up. Independent samples t-tests also were used to test mean characteristic differences at baseline and follow-up between patients with a decline in GFR declined compared with those with no decline in GFR. Relationships among change in GFR, initial GFR, follow-up GFR, renal volume growth rate, initial renal volume, follow-up renal volume, initial age, initial mean arterial pressure (MAP), follow-up MAP, and proteinuria were examined using Pearson’s correlation coefficients and multiple linear regression. Results are considered significant at ␣ of 0.05.
RESULTS
Two hundred twenty-nine adult subjects (84 men, 145 women) from 156 ADPKD families were studied. Ninety-four subjects were from PKD-1 families, and genotype could not be determined for 135 subjects. Initial age of subjects was 37 ⫾ 11 years (range, 19 to 81 years). Average time between visits was 7.8 ⫾ 3.1 years
RENAL VOLUME GROWTH AND POLYCYSTIC KIDNEY DISEASE
(range, 2.6 to 15.1 years). One hundred eleven patients were on antihypertensive medication therapy at their first visit; 165 patients, at their second visit; and 109 patients, at both visits. Only 51 patients were normotensive without medication at both visits. Mean initial systolic blood pressure was 127 ⫾ 12 mm Hg (range, 105 to 161 mm Hg), and mean initial diastolic blood pressure was 85 ⫾ 9 mm Hg (range, 65 to 110 mm Hg), for an MAP of 98 ⫾ 8 mm Hg (range, 80 to 125 mm Hg). Follow-up systolic blood pressure was 127 ⫾ 13 mm Hg (range, 99 to 165 mm Hg) and follow-up diastolic blood pressure was 82 ⫾ 8 mm Hg (range, 61 to 109 mm Hg), for a follow-up MAP of 97 ⫾ 9 mm Hg (range, 76 to 124 mm Hg). Follow-up diastolic blood pressure and MAP were significantly lower than initial values (P ⬍ 0.0001 and P ⬍ 0.001, respectively). Mean proteinuria at the initial visit was protein of 143 ⫾ 90 mg/24 h (range, 18 to 685 mg/24 h), and at the follow-up visit, 248 ⫾ 410 mg/24 h (range, 0 to 4,470 mg/24 h). Diabetes mellitus was diagnosed in one patient with nephrotic-range proteinuria. Initial mean renal volume was 561 ⫾ 354 cm3, with a wide range from normal-sized to very enlarged kidneys (range, 120 to 2,072 cm3). Follow-up mean renal volume was 942 ⫾ 597 cm3 (range, 136 to 3,038 cm3). Mean annual increase in renal volume for all subjects was 46 ⫾ 55 cm3. Initial mean GFR was 71 ⫾ 22 mL/min/1.73 m2 (0.68 ⫾ 0.21 mL/s/m2; range, 20 to 152 mL/min/1.73 m2), and follow-up mean GFR was 52 ⫾ 26 mL/min/1.73 m2 (0.50 ⫾ 0.25 mL/s/m2; range, 7 to 119 mL/min/ 1.73 m2). Effect of Sex Initial ages of men (37 ⫾ 8.7 years) and women (38 ⫾ 11.6 years) at entry onto the study were similar (P ⫽ not significant [NS]). However, there were several differences between male and female ADPKD populations. Initial renal volumes were much greater in men than in women (684 ⫾ 407 versus 490 ⫾ 299 cm3; P ⬍ 0.001). Renal growth rates were significantly greater for men than for women (65 ⫾ 63 versus 35 ⫾ 47 cm3/y; P ⬍ 0.005). Men had significantly greater systolic, diastolic, and MAPs at both baseline and follow-up than women (initial systolic blood pressure,
1129
131 ⫾ 10 versus 125 ⫾ 12 mm Hg; P ⬍ 0.0001; follow-up systolic blood pressure, 130 ⫾ 12 versus 126 ⫾ 13 mm Hg; P ⬍ 0.05; initial diastolic blood pressure, 90 ⫾ 9 versus 83 ⫾ 8 mm Hg; P ⬍ 0.0001; follow-up diastolic blood pressure, 84 ⫾ 9 versus 80 ⫾ 8 mm Hg; P ⬍ 0.005; initial MAP, 104 ⫾ 9 versus 97 ⫾ 9 mm Hg; P ⬍ 0.0001; and follow-up MAP, 99 ⫾ 9 versus 95 ⫾ 9 mm Hg; P ⬍ 0.005). A greater percentage of men than women were administered antihypertensive medications (P ⬍ 0.01). Although initial GFR values were similar in men (73 ⫾ 21 mL/min/1.73 m2; 0.70 ⫾ 0.20 mL/s/m2) and women (71 ⫾ 23 mL/min/1.73 m2; 0.68 ⫾ 0.22 mL/s/m2; P ⫽ NS), there was a significantly greater rate of decline in GFR in men (⫺2.99 mL/min/1.73 m2/y; ⫺0.029 mL/s/ m2/y) compared with women (⫺1.98 mL/min/ 1.73 m2/y; ⫺0.019 mL/s/m2/y; P ⬍ 0.01). Degrees of proteinuria at baseline (protein, 167 ⫾ 114 versus 128 ⫾ 72 mg/24 h; P ⬍ 0.01) and follow-up (364 ⫾ 589 versus 180 ⫾ 229 mg/24 h; P ⬍ 0.005) also were greater in men than in women. Comparison of Characteristics of Patients With Versus Without GFR Decline Overall, the rate of decline in GFR was ⫺2.4 ⫾ 2.8 mL/min/1.73 m2/y (⫺0.023 mL/s/m2/y). A subgroup of 36 subjects (7 men, 29 women) did not experience a decline in renal function during a mean follow-up of 6.5 ⫾ 2.2 years, whereas 193 subjects (77 men, 116 women) had a decline in GFR during a mean follow-up of 8.1 ⫾ 3.2 years (Table 1). Subjects with stable GFRs over time had significantly smaller initial renal volumes and renal growth rates over time than patients in whom GFR declined over time. Although their initial systolic, diastolic, and MAPs were significantly lower at baseline, there was no difference in blood pressure at follow-up between the two groups. Proteinuria values were similar at baseline, but were significantly different at follow-up; subjects with a decline in GFR had significantly greater follow-up proteinuria. Of 56 subjects who were normotensive at both visits without medication, 18 subjects did not have a decline in GFR. This ratio (18 of 56 patients) is significantly greater than that for the rest of the population with hypertension (18 of 173 patients; P ⬍ 0.0001). After controlling for
1130
FICK-BROSNAHAN ET AL Table 1.
Comparison of Subjects With and Without GFR Decline During the Course of the Study
Initial age (y) Initial renal volume (cm3) Follow-up renal volume (cm3) Change in renal volume (cm3/y) Initial SBP (mm Hg) Follow-up SBP (mm Hg) Initial DBP (mm Hg) Follow-up DBP (mm Hg) Initial MAP (mm Hg) Follow-up MAP (mm Hg) Initial GFR (mL/min/1.73 m2)* Follow-up GFR (mL/min/1.73 m2)* Change in GFR (mL/min/1.73 m2)* Initial proteinuria (mg/24 h) Follow-up proteinuria (mg/24 h)
Subjects With Decline (n ⫽ 193)
Subjects Without Decline (n ⫽ 36)
P
38 ⫾ 11 598 ⫾ 368 1,017 ⫾ 605 49 ⫾ 57 128 ⫾ 12 127 ⫾ 13 86 ⫾ 9 82 ⫾ 9 100 ⫾ 9.4 97 ⫾ 9.4 71 ⫾ 23 46 ⫾ 22 ⫺3.18 ⫾ 1.97 144 ⫾ 93 274 ⫾ 442
34 ⫾ 11 366 ⫾ 168 537 ⫾ 342 30 ⫾ 41 123 ⫾ 10 128 ⫾ 12 83 ⫾ 9 82 ⫾ 7 96 ⫾ 8.6 96 ⫾ 8.6 73 ⫾ 16 85 ⫾ 19 ⫺2.09 ⫾ 2.41 133 ⫾ 81 113 ⫾ 78
0.0185 ⬍0.0001 ⬍0.0001 0.0167 0.0283 0.7698 0.0478 0.9747 0.0295 0.8770 0.5801 ⬍0.0001 ⬍0.0001 0.4754 ⬍0.0001
NOTE. Values expressed as mean ⫾ SD. Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; GFR, calculated by MDRD (Modification of Diet in Renal Disease) formula. *To convert GFR values to milliliters per second per square meter, divide by 34.7.
age and sex, subjects with a diagnosis of hypertension at any point in the study had larger kidneys at baseline (P ⫽ 0.0002) and follow-up (P ⬍ 0.0001), faster renal volume growth rate (P ⫽ 0.001), similar GFR at baseline (P ⫽ NS), but worse GFR at follow-up (P ⬍ 0.0001), and a faster rate of decline in GFR (P ⫽ 0.0024) than subjects without a diagnosis of hypertension (data not shown).
Correlation and Multiple Linear Regression Analyses Correlational analyses using all data points showed that GFR correlated significantly with renal volume (R ⫽ ⫺0.53; P ⬍ 0.0001), initial age (R ⫽ ⫺0.44; P ⬍ 0.0001), and proteinuria (R ⫽ ⫺0.30; P ⬍ 0.0001), but not blood pressure (R ⫽ ⫺0.02; P ⫽ NS). Figure 1 shows the
Fig 1. Relationship between GFR and renal volume in 229 subjects with ADPKD over the course of the study using all data points for each subject. *GFR calculated by MDRD formula.
RENAL VOLUME GROWTH AND POLYCYSTIC KIDNEY DISEASE
1131
Fig 2. Relationship between rate of change in GFR and renal volume growth rate in 229 subjects with ADPKD.
relationship between GFR and renal volume during the course of the study. Rate of decline in GFR correlated with renal volume growth rate (Fig 2), initial age, initial renal volume, follow-up renal volume, initial proteinuria, follow-up proteinuria, and initial MAP, but not follow-up MAP (Table 2). Follow-up GFR also correlated with age at study entry, initial renal volume, MAP and proteinuria, as well as follow-up renal volume and proteinuria, and renal volume growth rate (Table 2). Analyses by sex showed that for men, GFR Table 2. Correlations of Follow-Up GFR and Change in GFR With Characteristics of 229 Patients With ADPKD Follow-Up GFR
Initial age Renal volume growth rate Initial renal volume Follow-up renal volume Initial MAP Follow-up MAP Initial proteinuria Follow-up proteinuria
Change in GFR
r
P
r
P
⫺0.48
⬍0.0001
⫺0.16
⬍0.05
⫺0.24
⬍0.0005
⫺0.20
⬍0.005
⫺0.45
⬍0.0001
⫺0.25
⬍0.0001
⫺0.50 ⫺0.18 0.12 ⫺0.29
⬍0.0001 ⬍0.01 NS ⬍0.0001
⫺0.29 ⫺0.17 ⫺0.01 ⫺0.18
⬍0.0001 ⬍0.05 NS ⬍0.01
⫺0.32
⬍0.0001
⫺0.25
⬍0.005
correlated significantly with renal volume (R ⫽ ⫺0.61; P ⬍ 0.0001), age at entry (R ⫽ ⫺0.40; P ⬍ 0.0001), and proteinuria (R ⫽ ⫺0.35; P ⬍ 0.0001), but not blood pressure (R ⫽ ⫺0.09; P ⫽ NS). For men, decline in GFR correlated with change in renal volume (R ⫽ ⫺0.25; P ⬍ 0.05), level of initial proteinuria (R ⫽ ⫺0.22; P ⬍ 0.05), and follow-up proteinuria (R ⫽ ⫺0.30; P ⬍ 0.01). For women, GFR correlated significantly with renal volume (R ⫽ ⫺0.49; P ⬍ 0.0001), age (R ⫽ ⫺0.47; P ⬍ 0.0001), and proteinuria (R ⫽ ⫺0.30; P ⬍ 0.0001), but not blood pressure (R ⫽ ⫺0.06; P ⫽ NS). Additionally, in women, change in GFR correlated with initial renal volume (R ⫽ ⫺0.26; P ⬍ 0.01), initial age (R ⫽ ⫺0.20; P ⬍ 0.05), initial MAP (R ⫽ ⫺0.16; P ⬍ 0.05), and follow-up proteinuria (R ⫽ ⫺0.17; P ⬍ 0.05), but not rate of change in renal volume or initial proteinuria. The number of pregnancies in women did not correlate with GFR or rate of decline in GFR. Multiple linear regression analyses with 229 subjects showed that renal volume growth rate (P ⬍ 0.01), initial renal volume (P ⫽ 0.001), initial age (P ⬍ 0.0001), baseline GFR (P ⬍ 0.0001), and proteinuria (P ⫽ 0.0004) were significantly related to change in GFR, whereas sex (P ⫽ NS) and blood pressure (P ⫽ NS) were not. Multiple linear regression by sex showed
1132
FICK-BROSNAHAN ET AL
that for men, change in GFR was significantly related to renal volume growth rate (P ⬍ 0.01), baseline GFR (P ⬍ 0.05), and proteinuria (P ⬍ 0.005), but not to initial age (P ⫽ NS), blood pressure (P ⫽ NS), or initial renal volume (P ⫽ NS). For women, change in GFR was significantly related to initial age, initial renal volume, initial GFR, and proteinuria (P ⬍ 0.05), but not to renal volume growth rate (P ⫽ NS), blood pressure (P ⫽ NS), or number of pregnancies (P ⫽ NS). DISCUSSION
This longitudinal study shows that GFR and rate of decline in GFR in patients with ADPKD correlate with renal volume and rate of increase in renal volume, and men have greater increases in renal volume and declines in GFR than women of similar ages. Two other studies have examined the relationship between renal volume growth and decline in GFR by means of computed tomography with contrast media.9,12 However, both studies were small, including only 10 and 9 patients, whereas we present longitudinal data for 229 subjects followed up for a mean of 7.8 years (range, 2.6 to 15.1 years). Similar to the computed tomographic studies, the majority of our patients had preserved renal function at baseline. Initial and follow-up renal volumes varied widely among patients on all three studies. However, overall renal volume growth rates were similar (46 ⫾ 55 cm3/y/kidney in the current study, 24 ⫾ 22 cm3/y/kidney in the study by King et al,9 and 54 ⫾ 10 cm3/y/kidney in the study by Sise et al12). Whereas Sise et al12 did not report annual change in GFR, the mean rate of decline in GFR in the study by King et al9 (2.8 ⫾ 2.8 mL/min/1.73 m2/y; 0.027 mL/s/m2/y) was similar to that on our study (2.4 ⫾ 2.8 mL/min/1.73 m2/y; 0.023 mL/s/m2/y). Importantly, King et al9 found a significant correlation between increase in renal cyst volume and decline in GFR. This is similar to our finding of a significant correlation between increase in total renal volume and decline in GFR because the increase in total renal volume is caused by the increase in cyst volume. Because our study included 229 patients with ADPKD, we also were able to determine the impact of sex and blood pressure on renal volume growth rate and identify characteristics of
patients with no decline in GFR during follow-up compared with those with a decline in GFR. In previous studies, men were found to enter ESRD an average of 5 to 6 years earlier than women.8,13-15 In the present study, men had more severe disease than women of similar age. Specifically, they had larger kidneys at baseline, faster renal enlargement, faster declines in GFR, and higher blood pressures despite antihypertensive medication. However, the rate of change in GFR in men was linearly related to only change in renal volume, level of initial proteinuria, and follow-up proteinuria, not initial or follow-up MAP. The strongest correlation (R ⫽ ⫺0.61) was between renal volume and GFR, suggesting that effects of renal volume growth, ie, renal cyst expansion, are the most important measurable determinants of GFR decline in men with ADPKD. For women, the rate of change in GFR was linearly related to initial renal volume, initial age, initial MAP, and follow-up proteinuria. As in men, the strongest correlation (R ⫽ ⫺0.49) was between renal volume and GFR, suggesting a relationship between renal volume increase and decline in GFR in women, as well. Why men with ADPKD have more severe disease than women with ADPKD cannot be answered by this study. Subjects with ADPKD who did not experience a decline in GFR over the short term (follow-up, 6.5 years) were young; had relatively small kidneys, slow renal growth rates, and normal blood pressures; and most were not administered medication. This is important prognostic information for the natural history of ADPKD and for planning intervention studies. A previous cross-sectional study showed that overt proteinuria (protein ⬎ 300 mg/d) was associated with larger renal volumes, higher blood pressures, and lower creatinine clearances in patients with ADPKD.16 The computed tomographic study of King et al involving nine patients with ADPKD showed that subjects with greater initial proteinuria had a significantly larger increase in renal volume and decline in GFR than those with less proteinuria.9 The present study confirms these results. Overall, the present study shows that renal growth, hypertension, proteinuria, and decline in GFR are interrelated. However, the degree of
RENAL VOLUME GROWTH AND POLYCYSTIC KIDNEY DISEASE
correlations suggests that other unidentified factors also are likely determinants of renal function decline in ADPKD. Activation of the reninangiotensin-aldosterone system has been implicated in ADPKD,17 presumably secondary to renal cyst expansion and local ischemia. Because angiotensin II is a known stimulator of growth factor and fibrosis5,18-20 and aldosterone is known to stimulate fibrosis,21 a role of the reninangiotensin-aldosterone system in cyst formation, interstitial fibrosis, and hypertension has been proposed.5,22,23 Animal experiments and histological studies suggest that inflammatory cytokines and apoptosis of normal tubules24 may contribute to progressive tubular atrophy, glomerulosclerosis, and interstitial fibrosis.23 These processes likely are linked to the expanding cysts, which contain numerous growth factors and inflammatory cytokines.23 At present, the progressive renal parenchymal remodeling in ADPKD cannot be quantified using an imaging method. Therefore, total renal volume or renal cyst volume must be used to assess the progression of ADPKD at a stage when GFR is preserved. In this stage, slowing renal cyst growth and preventing a future decline in renal function may be most effective. In conclusion, the present results indicate that renal volume measurements can be used to follow-up progression of ADPKD. Because the optimal goal in ADPKD treatment is ESRD prevention, rather than just slowing the time to ESRD, early intervention to prevent progressive cyst enlargement may be necessary. Whether controlling blood pressure and reducing proteinuria in patients with ADPKD can slow renal volume growth is unclear. However, blood pressure control is important because cardiovascular complications are now the major cause of death in these individuals.25,26 Our recent 7-year randomized study of patients with ADPKD showed that rigorous antihypertensive therapy with a blood pressure goal of less than 120/80 mm Hg can reverse left ventricular hypertrophy, an important cardiovascular risk factor, significantly better than standard therapy with a blood pressure goal of 135 to 140/85 to 90 mm Hg.27 In regard to kidneys, it appears that therapies aimed at inhibiting cyst expansion may have the best potential to preserve renal function. Such therapies are now being developed.28
1133
REFERENCES 1. US Renal Data System: USRDS 2000 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Baltimore, MD, 2000 2. Franz KA, Reubi FC: Rate of functional deterioration in polycystic kidney disease. Kidney Int 23:526-529, 1983 3. Klahr S, Breyer JA, Beck GJ, et al: Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group [published erratum in J Am Soc Nephrol 6:1318, 1995]. J Am Soc Nephrol 5:2037-2047, 1995 4. Fick-Brosnahan GM, Ecder T, Schrier R: Polycystic kidney disease, in Schrier R (ed): Diseases of the Kidney and Urinary Tract. Philadelphia, PA, Lippincott, Williams and Wilkins, 2001, pp 547-588 5. Ecder T, Schrier RW: Hypertension in autosomaldominant polycystic kidney disease: Early occurrence and unique aspects. J Am Soc Nephrol 12:194-200, 2001 6. Chapman AB, Schrier RW: Pathogenesis of hypertension in autosomal dominant polycystic kidney disease. Semin Nephrol 11:653-660, 1991 7. Gabow PA, Chapman AB, Johnson AM, et al: Renal structure and hypertension in autosomal dominant polycystic kidney disease. Kidney Int 38:1177-1180, 1990 8. Gabow PA, Johnson AM, Kaehny WD, et al: Factors affecting the progression of renal disease in autosomaldominant polycystic kidney disease. Kidney Int 41:13111319, 1992 9. King BF, Reed JE, Bergstralh EJ, Sheedy PF II, Torres VE: Quantification and longitudinal trends of kidney, renal cyst, and renal parenchyma volumes in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 11:1505-1511, 2000 10. Levey AS, Bosch JP, Breyer-Lewis J, Greene T, Rogers N, Roth D, for the Modification of Diet in Renal Disease Study Group: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130:461-470, 1999 11. Hadimeri H, Johansson AC, Haraldsson B, Nyberg G: CAPD in patients with autosomal dominant polycystic kidney disease. Perit Dial Int 18:429-432, 1998 12. Sise C, Kusaka M, Wetzel LH, et al: Volumetric determination of progression in autosomal dominant polycystic kidney disease by computed tomography. Kidney Int 58:2492-2501, 2000 13. Gretz N, Zeier M, Geberth S, Strauch M, Ritz E: Is gender a determinant for evolution of renal failure? A study in autosomal dominant polycystic kidney disease. Am J Kidney Dis 14:178-183, 1989 14. Stewart JH: End-stage renal failure appears earlier in men than in women with polycystic kidney disease. Am J Kidney Dis 24:181-183, 1994 15. Choukroun G, Itakura Y, Albouze G, et al: Factors influencing progression of renal failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 6:16341642, 1995 16. Chapman AB, Johnson AM, Gabow PA, Schrier RW: Overt proteinuria and microalbuminuria in autosomal domi-
1134
nant polycystic kidney disease. J Am Soc Nephrol 5:13491354, 1994 17. Chapman AB, Johnson A, Gabow PA, Schrier RW: The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N Engl J Med 323:10911096, 1990 18. Peters H, Noble NA: Angiotensin II and I-arginine in tissue fibrosis: More than blood pressure. Kidney Int 52:14971510A, 1997 (abstr) 19. Pimentel JL, Sundell CL, Wang S, Kopp JB, Montero A, Martinez-Maldonado M: Role of angiotensin II in the expression and regulation of transforming growth factor-beta in obstructive nephropathy. Kidney Int 48:1233-1246, 1995 20. Peters H, Border WA, Noble NA: Targeting TGF-beta overexpression in renal disease: Maximizing the antifibrotic action of angiotensin II blockade. Kidney Int 54:1570-1580, 1998 21. Hostetter T: Aldosterone in renal disease. Curr Opin Nephrol Hypertens 10:105-110, 2001 22. Ecder T, Edelstein CL, Fick G, Johnson CM, Gabow PA, Schrier RW: Diuretics versus angiotensin-converting enzyme inhibitors in autosomal dominant polycystic kidney disease. Am J Nephrol 21:98-103, 2001
FICK-BROSNAHAN ET AL
23. Grantham JJ: Mechanisms of progression in autosomal dominant polycystic kidney disease. Kidney Int 52:S93S97, 1997 (suppl 63) 24. Ecder T, Melnikov V, Korular D, Lucia MS, Schrier RW, Edelstein C: Caspases, Bcl-2 proteins and apoptosis in autosomal dominant polycystic kidney disease. Kidney Int 61:1220-1230, 2002 25. Iglesias CG, Torres VE, Offord KP, Holley KE, Beard CM, Kurland LT: Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980. Am J Kidney Dis 2:630-639, 1983 26. Fick GM, Johnson AM, Hammond WS, Gabow PA: Causes of death in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 5:2048-2056, 1995 27. Schrier R, McFann K, Johnson A, et al: Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal dominant polycystic kidney disease: Results of a seven-year prospective randomized study. J Am Soc Nephrol (in press) 28. Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED: Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int 57:33-40, 2000