Abstract
Background and objectives
In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy.
Design, setting, participants, & measurements
One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1–11.2) were analyzed for efficacy using three approaches: (1) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; (2) Stability of eGFR slopes with duration of follow-up; and (3) comparison of observed and predicted eGFRs at last follow-up.
Results
Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, −2.20±2.18 ml/min per 1.73 m2 per year) and from month 1 (mean±SD, −1.97±2.44 ml/min per 1.73 m2 per year) compared with controls (mean±SD, −3.50±2.09 ml/min per 1.73 m2 per year; P<0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment.
Conclusions
Follow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups.
Keywords: ADPKD; Benzazepines; chronic kidney disease; EGFR protein, human; Follow-Up Studies; glomerular filtration rate; Humans; polycystic kidney disease; Polycystic Kidney, Autosomal Dominant; Receptor, Epidermal Growth Factor; Renal Insufficiency, Chronic; Renal Replacement Therapy; TEMPO; Tolvaptan; vasopressin; Vasopressin Receptor Antagonist
Introduction
Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of ESKD in adults (1–3). Vasopressin-driven up-regulation of cAMP promotes kidney cyst development and growth through its effects on cell proliferation and fluid secretion (4,5). Suppression of vasopressin production, release, or action by means of hydration (6,7), V2 receptor blockade (8–13), or genetic mutation (14) reduce cyst burden, protect kidney function, and prolong survival in rodent models. Sustained suppression is critical to achieve this protective effect (13,14).
The success of V2 receptor antagonists, in rodent models of polycystic kidney disease (8–13), led to the initiation of clinical trials for ADPKD in 2004. Preliminary studies showed that split twice daily doses of tolvaptan were necessary to continuously suppress urine osmolality to <300 mOsm/kg, implying effective V2 receptor inhibition (15), and to balance efficacy and tolerability (16). Tolvaptan-induced aquaresis was accompanied by small reductions in GFR, without significant changes in kidney blood flow (17,18), likely due to activation of tubuloglomerular feedback (19–21). Changes in GFR reversed rapidly after discontinuation of tolvaptan (18).
In the double-blind Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 trial, 1445 patients aged 18–50 years, with total kidney volume (TKV) ≥750 ml, and estimated creatinine clearance ≥60 ml/min were randomized to tolvaptan or placebo (22). TKV increased 2.8% per year in the tolvaptan group and 5.5% per year in the placebo group. Tolvaptan reduced the decline in eGFR from 10.1 to 6.8 ml/min per 1.73 m2 over 3 years; the 3.3 ml/min per 1.73 m2 eGFR benefit was maintained for a further 2 years when all patients received tolvaptan in an open-label extension (TEMPO 4:4) (23). Transaminase elevations more than three times the upper limit of normal occurred in 4.4% of tolvaptan and 1% of placebo patients. Hepatocellular toxicity meeting Hy Law criteria occurred in three out of 1271 tolvaptan-treated patients (24). These results led to approval of tolvaptan for patients with ADPKD meeting diverse criteria to select for progressive disease in Japan, Canada, the European Union, Switzerland, Norway, and South Korea. In the United States, the Food and Drug Administration did not approve tolvaptan and asked for additional data.
The Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial, a phase three, randomized withdrawal, multicenter, placebo-controlled, double-blind trial, was designed to ascertain its efficacy in later stage ADPKD (25). After an 8-week prerandomization period including sequential placebo and tolvaptan run-in phases, 1370 patients able to tolerate a split dose of 60/30 mg (aged 18–55 years with eGFR 25–65 ml/min per 1.73 m2 or aged 56–65 years with eGFR 25–44 ml/min per 1.73 m2) were randomized to tolvaptan or placebo for 12 months, with monthly monitoring of serum creatinine, sodium, and liver tests. Three serum creatinine measurements were taken 7–40 days after stopping tolvaptan or placebo. The eGFR change from baseline was −2.34 ml/min per 1.73 m2 in the tolvaptan group and −3.61 ml/min per 1.73 m2 in the placebo group. Reversible transaminase elevations more than three times the upper limit of normal occurred in 5.6% of tolvaptan-treated patients and in 1.2% of placebo patients.
An editorial on the results of the REPRISE trial (25) accepted that the degree by which tolvaptan slowed the decline of eGFR (1.27 ml/min per 1.73 m2 per year) could be clinically important; however, it also pointed out that further studies were needed to ascertain whether it could meaningfully delay the need for kidney replacement (26). The purpose of this article is to describe the progression of ADPKD in 97 patients with ADPKD continuously treated at the Mayo Clinic for periods of time ranging from 1.1 to 11.2 years, compared with matched controls or predictive models of disease progression.
Materials and Methods
Study Patients
This study includes all patients who participated at the Mayo Clinic in clinical trials of tolvaptan for ADPKD: 156–04–250 (TEMPO 2:4, NCT00413777), 156–04–251 (TEMPO 3:4, NCT00428948), 156–06–260, 156–08–271 (TEMPO 4:4, NCT01214421), 156–09–285 (NCT01210560), 156–09–290 (NOCTURNE, NCT01451827), 156–13–210 (REPRISE, NCT02160145), 156–13–211 (NCT02251275). Brief descriptions of these clinical trials, eligibility criteria, and frequency of eGFR measurements are provided in the Supplemental Material. Protocols and informed consents for all of the studies were approved by the Mayo Clinic Institutional Review Board.
Study Design
Three strategies were used to determine whether the effect of tolvaptan on the decline in eGFR, observed in multicenter, randomized clinical trials of 1–3 years duration, is sustained and cumulative during more extended periods of follow-up. First, we compared eGFR slopes and outcome (33% reduction from baseline eGFR) in tolvaptan-treated patients compared with controls from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) observational study (27,28) and the HALT PKD Study B clinical trial (29), matched in a 1:2 ratio by sex, age, and baseline eGFR. The purpose of the present study was to determine whether administration of tolvaptan for periods of time ranging from 1.1 to 11.2 years lowers the rate of decline of eGFR regardless of duration of follow up. Second, we performed analyses of the eGFR slopes of patients with ADPKD treated with tolvaptan by duration of follow-up, with stratification by ADPKD severity and CKD stage, and comparison to reference populations (placebo-treated groups in the TEMPO 3:4 and REPRISE clinical trials). The purpose of the present study was to determine whether the annualized rate of eGFR decline in the tolvaptan-treated patients is stable over time and different from reference populations not treated with tolvaptan. Finally, we compared the observed and predicted (estimated using a validated predictive equation) (30) eGFR values at the last follow-up of the patients with ADPKD treated with tolvaptan. The purpose of the present study was to determine whether treatment with tolvaptan alters the predicted rate of eGFR decline and whether this results in an accumulating difference over time.
For all analyses, the last follow-up eGFR on treatment was used. Rates of eGFR decline and predicted last follow-up eGFRs were calculated using the baseline (off tolvaptan) or the month 1 (on tolvaptan) eGFR values, with the latter accounting for the acute hemodynamic effect of tolvaptan (17,18,31).
Control Population
Deidentified data for matched controls were provided by the National Institutes of Health-sponsored CRISP observational study (Clinicaltrials.gov identifier NCT01039987) (27,28) and by the HALT PKD Study B clinical trial (Clinicaltrials.gov identifier NCT01885559) (29). Sets of potential controls were first identified by matching sex for each tolvaptan-treated patient. Then, tolvaptan-treated patients were ordered randomly, and in this order, they were matched to participants in their set who had the smallest sum of percent absolute differences in age and baseline eGFR from their potential matches. Once identified, each control participant was used only once. Matching proceeded in a randomly selected order for tolvaptan-treated patients. The first control participant was matched to the first tolvaptan-treated patient, and then the second control was matched to the second tolvaptan-treated patient, and so on, until all had one match. The process then proceeded in reverse, selecting a second control participant for the tolvaptan-treated patient who was last matched, progressing to the first tolvaptan-treated patient in this order until all had two matches.
Study Assessments
The equation from the CKD Epidemiology Collaboration was used to determine the eGFR (32). Serum creatinine measurements used the isotope dilution mass spectrometry-traceable Roche enzymatic method (33).
To compare observed and predicted eGFRs, we used an equation derived in a cohort of Mayo Clinic patients with ADPKD using a multivariable, longitudinal, linear mixed-effects analysis with baseline predictors of sex, age, image class, and eGFR, along with follow-up years from baseline to subsequent visits (30). The equation was validated using an internal Mayo Clinic cohort and an external cohort from the CRISP study (30). All of the patients had typical ADPKD (bilateral and diffuse distribution of the cysts) and had been classified according to the yearly kidney growth rate (estimated from their age and height-adjusted TKV at baseline and from a theoretical starting height-adjusted TKV of 150 ml/m) into class A (<1.5% per year), B (1.5%–3% per year), C (3%–4.5% per year), D (4.5%–6% per year), or E (>6% per year) (30).
Statistical Analyses
Comparison statistics were generated to assess whether the groups of interest were significantly different. A standard t test was used to compare eGFR slopes in tolvaptan-treated patients with eGFR slopes in controls, and a paired t test was used to compare observed versus predicted final eGFR values in each tolvaptan-treated patient. The least squares method was used for estimation of eGFR slopes. The Kaplan–Meier method was used to determine times to a 33% reduction from baseline eGFRs. Significance between tolvaptan-treated patients and controls was determined using the log-rank test. Risk ratios were estimated on the basis of the Cox model and are presented along with 95% confidence intervals. Schoenfeld residuals were used to confirm the assumption of proportional hazard.
Results
Tolvaptan-Treated Patients
A total of 128 patients with ADPKD participated in at least one study of tolvaptan at the Mayo Clinic (Figure 1). At the end of each study, all had the opportunity to enroll into an open-label extension trial. Of 45 patients who participated in 1–8 week studies, 13 declined enrollment. Seven additional patients who received placebo in randomized, clinical trials also declined enrollment. The remaining 108 patients were included in the current analysis for tolerability and safety. Eleven patients had received tolvaptan for <1 year (Supplemental Table 1); seven of the 11 patients had been assigned to placebo in the REPRISE trial and had started tolvaptan <1 year before the current analysis; one patient did not restart tolvaptan after a long recovery from an elective surgery; the other three patients withdrew from the study during the first year for reasons listed in Supplemental Tables 1–3. The remaining 97 patients were included in the efficacy analysis. Baseline eGFR was available in all patients. Baseline TKV was only available in 74 patients because TKV measurements were not required in the REPRISE trial.
Figure 1.
The flow chart of the study population describes the study sources, enrollment into an open label extension, overall duration of follow-up, and approaches used to evaluate the long-term efficacy of treatment with tolvaptan.
Baseline characteristics by availability of TKV at baseline and duration of follow-up of the patients in the efficacy analysis are shown in Table 1. Most patients without available baseline TKV had participated in the REPRISE trial and had more advanced CKD compared with patients with available baseline TKV.
Table 1.
Baseline characteristics of the 97 patients treated with tolvaptan for at least 1 year and of 194 control patients matched by sex, age, and baseline eGFR
| Characteristics | Patients Treated with Tolvaptan for >1 yr,a n=97 | Controls, n=194 | |||
|---|---|---|---|---|---|
| With Baseline MRI, n=74 | Without Baseline MRI, n=23 | All, n=97 | |||
| 1–5 yr Follow-Up, n=38 | >5 yr Follow-Up, n=36 | ||||
| Men, n (%) | 15 (39) | 12 (33) | 9 (39) | 36 (37) | 72 (37) |
| Age, yr, mean±SD | 43±10 | 42±9 | 49±9 | 44±10 | 44±9 |
| Genetic analysis, n (%) | 30 (79) | 35 (97) | 22 (96) | 87 (90) | 191 (99) |
| No mutation detected, n/N (%)b | 2/30 (7) | 0/35 (0) | 0/22 (0) | 2/87 (2) | 7/191 (4) |
| PKD1 mutation, n/N (%)b | 23/30 (77) | 29/35 (83) | 17/22 (77) | 69/87 (79) | 156/191 (82) |
| Truncating | 15/30 (50) | 18/35 (51) | 14/22 (64) | 47/87 (54) | 96/191 (50) |
| Nontruncating | 8/30 (27) | 11/35 (31) | 3/22 (14) | 22/87 (25) | 60/191 (31) |
| PKD2 mutation, n/N (%)b | 5/30 (17) | 6/35 (17) | 5/22 (23) | 16/87 (18) | 28/191 (15) |
| Source study, n (%) | |||||
| 156–06–260 (17) | 5 (13) | 4 (11) | 0 (0) | 9 (9) | — |
| TEMPO 2:4, 156–04–250 (16) | 4 (11) | 6 (17) | 0 (0) | 10 (10) | — |
| TEMPO 3:4, 156–04–251 (22) | 14 (37) | 18 (50) | 1 (4) | 33 (34) | — |
| REPRISE, 156–13–210 (25) | 6 (16) | 0 (0) | 19 (83) | 25 (26) | — |
| NOCTURNE, 156–09–290 (NCT01451827) | 8 (21) | 5 (14) | 0 (0) | 13 (13) | — |
| 156–09–285 (NCT01210560) | 1 (3) | 3 (8) | 3 (13) | 7 (7) | — |
| CRISP (27,28) | — | — | — | — | 78 (40) |
| HALT PKD study B (29) | — | — | — | — | 116 (60) |
| eGFR, ml/min per 1.73 m2, mean±SD | 66±27 | 78±20 | 48±23 | 65±25 | 64±25 |
| Total kidney volume, ml, mean±SD | 2020±1881 | 1444±759 | — | — | — |
| Irazabal classification (30), n (%) | |||||
| 1A | 1 (3) | 0 (0) | — | — | — |
| 1B | 7 (18) | 9 (25) | — | — | — |
| 1C | 13 (34) | 16 (44) | — | — | — |
| 1D | 12 (32) | 7 (19) | — | — | — |
| 1E | 5 (13) | 4 (11) | — | — | — |
| CKD stage, n (%) | |||||
| 1, eGFR>90 ml/min per 1.73 m2 | 7 (18) | 8 (22) | 3 (13) | 18 (19) | 32 (17) |
| 2, eGFR 60–89 ml/min per 1.73 m2 | 13 (34) | 18 (50) | 3 (13) | 34 (35) | 69 (36) |
| 3, eGFR 30–59 ml/min per 1.73 m2 | 14 (37) | 10 (28) | 13 (57) | 37 (38) | 80 (41) |
| 4, eGFR 15–29 ml/min per 1.73 m2 | 4 (11) | 0 (0) | 4 (17) | 8 (8) | 13 (7) |
MRI, magnetic resonance imaging; —, not applicable; TEMPO, Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes; REPRISE, Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD; CRISP, Consortium for Radiologic Imaging Studies of PKD.
Eleven patients on tolvaptan for <1 year are shown in Supplemental Table 1.
Percentage is on the basis of the total number of patients for each class with genetic analysis.
Of the 108 patients in the study, 53 are still treated with tolvaptan in the open-label extension study at the Mayo Clinic and 15 were transferred to a research site closer to home to continue the open-label extension trial. Sixteen patients withdrew from the study because of inability to comply with required travel demands and absences from work: two because of plans for pregnancy, one moved to another country, nine because of disease progression and preparation for kidney transplantation (Supplemental Table 2), one because of anxiety, and three because of incidental illnesses thought to be unrelated to the administration of tolvaptan (chronic myeloid leukemia, eosinophilic fasciitis, and bowel obstruction after hernia repair). Eight patients withdrew because of adverse events from tolvaptan (four because of polyuria, two because of chronic fatigue, and two because of reversible transaminase elevations; Supplemental Table 3). No patient was lost to follow-up.
Comparison of eGFR Slopes and Outcomes to Matched Controls
The effect of tolvaptan on the decline of eGFR was ascertained by comparing each treated patient (n=97) with two matched controls (n=194; 78 from the CRISP study, 116 from HALT PKD study B). Baseline characteristics were well balanced (Table 1). Rates of eGFR decline in the tolvaptan-treated patients, calculated from the baseline eGFR values (mean±SD, −2.20±2.18 ml/min per 1.73 m2 per year) and from month 1 after starting tolvaptan (mean±SD, −1.97±2.44 ml/min per 1.73 m2 per year), were significantly (P<0.001) slower than those in the controls (mean±SD, −3.50±2.09 ml/min per 1.73 m2 per year; Table 2), across all CKD stages. Because the duration of follow-up was less in the tolvaptan-treated patients than in the controls, for each couple of matched controls we selected the one with the duration of follow-up closer to that of the corresponding tolvaptan-treated patient. The rate of eGFR decline in this adjusted control group was also significantly higher (mean±SD, −3.84 ml/min per 1.73 m2 per year) than in the tolvaptan-treated patients (P<0.001; Table 2). In other analyses we used the follow-up visits best matching the duration of follow-up of the tolvaptan-treated patients as the last follow-up visit of the control patients. This had no effect on the results (Supplemental Table 4). Finally, we compared the eGFR slopes of the patients treated with tolvaptan for ≥3 years or for ≥5 years to their respective controls. In both cases, they were slower than those in the controls across CKD stages 1–3b (Supplemental Table 5). Kaplan–Meier analysis showed that the risks of a 33% reduction of eGFR from baseline or from month 1 value were significantly less in the patients treated with tolvaptan than in the controls, with risk ratios of 0.63 (95% confidence interval [95% CI], 0.38 to 0.98) and 0.53 (95% CI, 0.31 to 0.85), respectively (Figure 2, A and B).
Table 2.
Annualized eGFR slopes (ml/min per 1.73 m2 per year) for tolvaptan-treated patients versus controls
| CKD Stage | Tolvaptan-Treated Patients | Controls | ||||
|---|---|---|---|---|---|---|
| Baseline eGFR | eGFR Slope | Baseline eGFR | eGFR Slope | |||
| Baseline, Last Follow-Up, n=97 | 1 Mo, Last Follow-Up, n=97 | All, n=194 | Best Matched Follow-Up, n=97a | |||
| 1 | 102±10 | −1.49±2.88 | −0.72±3.77b,c | 102±13 | −2.68±1.95 | −2.72±2.34 |
| [18] | [18] | [18] | [36] | [36]d | [18] | |
| 2 | 75±9 | −1.77±2.05e,f | −1.77±2.10e,f | 74±9 | −3.62±2.42 | −3.88±2.47 |
| [34] | [34] | [34] | [68] | [68]d | [34] | |
| 3 | 46±10 | −2.68±1.96e,f | −2.53±1.86e,f | 46±10 | −3.78±1.88 | −4.20±1.59 |
| [37] | [37] | [37] | [74] | [74]d | [37] | |
| 4 | 25±3 | −3.25±0.91c | −3.02±1.06c | 28±2 | −3.63±1.37 | −4.43±1.06 |
| [8] | [8] | [8] | [16] | [16]d | [8] | |
| Total | 64±25 | −2.20±2.18g,h | −1.97±2.44g,h | 64±25 | −3.50±2.09 | −3.84±2.09 |
| [97] | [97] | [97] | [194] | [194]d | [97] | |
| Follow-up, yr | — | 4.64±2.79g,h | 4.55±2.80g,h | — | 7.91±3.97 | 6.97±3.56 |
Values are expressed as mean±SD. Numbers in brackets represent the numbers of patients. —, not applicable.
The control with a duration closest to the matched patient was chosen in the adjusted control group.
Significantly different from controls (all) at a P value of <0.05.
Significantly different from controls (matched) at a P value of <0.05.
Characterization of the controls is on the basis of CKD of its matched patient.
Significantly different from controls (all) at a P value of <0.02.
Significantly different from controls (matched) at a P value of <0.02.
Significantly different from controls (all) at a P value of <0.001.
Significantly different from controls (matched) at a P value of <0.001.
Figure 2.
Tolvaptan slows the rate of eGFR decline and its effect is sustained and cumulative over time. (A and B) Kaplan–Meier analysis showed that the risks of a 33% reduction of eGFR from baseline (BL) or month 1 (Mo1) value were significantly less in the patients treated with tolvaptan than in the controls, with risk ratios of 0.63 (95% CI, 0.38 to 0.98) and 0.53 (95% CI, 0.31 to 0.85), respectively. (C) The annualized eGFR slopes of tolvaptan-treated patients plotted against duration of follow-up were consistent between year 1 and year 11; the slope of regression line was −0.11 ml/min per 1.73 m2 per year (95% CI, −0.32 to 0.09). (D) Observed–predicted eGFR at the last follow-up plotted against duration of follow-up; as the duration of follow-up increases, the observed eGFRs became increasingly higher than the predicted eGFRs. The slope of the regression line with a zero y-intercept is 0.96 ml/min per 1.73 m2 per year (95% CI, 0.47 to 1.45).
Analysis of eGFR Slopes by Duration of Treatment
To determine whether the effect of tolvaptan on the rate of decline of eGFR wanes with the duration of follow-up, we compared the eGFR slopes (both including and excluding the baseline eGFR before starting tolvaptan) in the patients treated between 1 and 5 years (mean±SD, −2.28±2.53 and 1.96±2.89 ml/min per 1.73 m2) and those treated for >5 years (mean±SD, −2.08±1.55 and −1.97±1.57 ml/min per 1.73 m2). The eGFR slopes were similar in both groups of patients, overall and across CKD stages and disease severity classes, and lower than those in the placebo patients of the TEMPO 3:4 and REPRISE trials (Table 3). Plots of eGFR slopes against duration of follow-up confirmed the stability of the annual rate of eGFR decline in the tolvaptan-treated patients (Figure 2C) and in the controls (Supplemental Figure 1).
Table 3.
Annualized eGFR slopes (ml/min per 1.73 m2 per year) according to duration of follow-up and by CKD stage or image classification
| 1–5 yr Follow-Up, n=58 | >5 yr Follow-Up, n=39 | Reference Populations | ||||
|---|---|---|---|---|---|---|
| Classification | Baseline to Last Follow-Up | Month 1 to Last Follow-Up | Baseline to Last Follow-Up | Month 1 to Last Follow-Up | TEMPO 3:4 Placeboa | REPRISE Placeboa |
| CKD stage | ||||||
| 1 | −1.22±4.13 [8] | 0.19±5.39 [8] | −1.69±1.52 [10] | −1.44±1.70 [10] | −2.55 (−3.20 to −1.90)b [162] | — |
| 2 | −1.36±2.50 [15] | −1.20±2.50 [15] | −2.27±1.68 [19] | −2.42±1.46 [19] | −3.9 (−4.42 to −3.37)b [216] | −4.65 (−6.24 to −3.05)b [38] |
| 3 | −2.80±2.11 [27] | −2.72±2.02 [27] | −2.09±1.39 [10] | −2.02±1.29 [10] | −5.36 (−6.19 to −4.53)b [84] | −4.16 (−4.50 to −3.81)b [500] |
| 4 | −3.25±0.91 [8] | −3.02±1.06 [8] | — | — | — | −4.60 (−5.09 to −4.12)b [125] |
| Total | −2.28±2.53 [58] | −1.96±2.89 [58] | −2.08±1.55 [39] | −1.97±1.57 [39] | −3.69 [462] | −3.61±0.24 [663] |
| Follow-up, yr | 2.65±1.42 | 2.56±1.10 | 7.60±1.74 | 7.51±1.73 | 3 | 1 |
| Age, yr | 46±9 | 46±9 | 41±9 | 41±9 | 39±7 | 47±8 |
| Men, n (%) | 24 (41) | 24 (41) | 12 (31) | 12 (31) | 248 (54) | 322 (49) |
| Irazabal image classc | ||||||
| 1A | 0.96 [1] | 2.47 [1] | — | — | — | — |
| 1B | −1.42±3.59 [7] | −1.53±2.99 [7] | −1.71±1.14 [9] | −1.62±1.14 [9] | −1.79 (−3.08 to −0.51)b [31] | — |
| 1C | −2.35±1.42 [13] | −1.80±2.00 [13] | −2.13±1.76 [16] | −2.05±1.75 [16] | −3.59 (−4.18 to −3.00)b [191] | — |
| 1D | −2.98±1.73 [12] | −2.59±1.70 [12] | −2.26±1.27 [7] | −2.16±1.30 [7] | −3.89 (−4.54 to −3.24)b [161] | — |
| 1E | −0.32±4.90 [5]d | 0.71±6.73[5]d | −2.74±1.95 [4] | −2.7±1.96 [4] | −4.93 (−5.87 to −3.99)b [82] | — |
| Total | −2.02±2.69 [38] | −1.56±3.16 [38] | −2.12±1.50 [36] | −2.04±1.50 [36] | — | — |
| Follow-up, yr | 2.9±1.2 | 2.8±1.2 | 7.7±1.8 | 7.6±1.8 | 3 | — |
| Age, yr | 43±9 | 43±9 | 42±9 | 42±9 | 39d | — |
| Men, n (%) | 15 (39) | 15 (39) | 12 (33) | 12 (33) | 248 (53) | — |
Values are expressed as mean±SD. Numbers in brackets represent the numbers of patients. TEMPO, Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes; REPRISE, Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD; —, not applicable.
eGFR data in the reference populations are reported at annualized means instead of slopes.
95% confidence interval.
Patients without baseline total kidney volume were included in the above CKD classification dataset but were not included in the image class dataset. Duration of follow-up, age, and sex are reported for each dataset.
One of the five patients in the 1–5 year 1E subgroup was a young patient with a relatively high baseline eGFR and a positive eGFR slope. This raised to average eGFR slope for that group (see Supplemental Figure 2).
Comparison of Observed and Predicted eGFRs at the Last Follow-Up
To determine whether the effect of tolvaptan on eGFR increases with duration of follow-up, we used a validated predictive equation (30) to estimate the difference between observed and predicted eGFR values at the end of follow-up. To adjust for the acute hemodynamic effect of tolvaptan on eGFR, we used the serum creatinine value on tolvaptan at 1 month, in addition to the baseline value before starting tolvaptan. The difference between the observed and the predicted value was greater when the month 1 serum creatinine was used for the calculation (Table 4). In addition, this difference increased with the duration of follow-up (slopes 0.63 ml/min per 1.73 m2 per year; 95% CI, 0.19 to 1.07; P=0.006, using the baseline value; and 0.96 ml/min per 1.73 m2 per year; 95% CI, 0.47 to 1.45; P<0.001, using month 1 eGFR) (Figure 2D, Table 4).
Table 4.
Observed versus predicted eGFR (ml/min per 1.73 m2) values at the last follow-up in the patients treated with tolvaptan
| Patients | Follow-Up, yr | Observed eGFR | Baseline eGFR Used for Prediction | Month 1 eGFR Used for Prediction | ||||
|---|---|---|---|---|---|---|---|---|
| Predicted eGFR | P Value versus Observed | Observed–Predicted eGFR | Predicted eGFR | P Value versus Observed | Observed–Predicted eGFR | |||
| All (n=74) | 5.2±2.8 | 56.2±26.3 | 53.1±24.6 | 0.02 | 3.1±11.4 | 51.6±24.6 | 0.003 | 4.6±12.7 |
| Follow-up >3 yr (n=58)a | 6.2±2.4b | 55.9±24.6 | 51.4±23.0 | 0.006 | 4.5±12.1 | 50.1±24.0 | 0.001 | 5.8±13.0 |
| Follow-up >5 yr (n=36)a | 7.7±1.8b | 54.8±25.6 | 49.1±21.5 | 0.02 | 5.7±14.0 | 46.5±22.5 | 0.002 | 8.3±14.6 |
Values are expressed as mean±SD.
The >3 and >5 year follow-up groups were the same for the baseline to last follow-up and 1 month follow-up to last follow-up, and were assigned to the appropriate duration group on the basis of baseline to final follow-up duration.
Duration of follow-up was roughly 1 month shorter in the month 1 prediction group compared with the baseline prediction group.
Discussion
ADPKD, the most common Mendelian cause of ESKD, has for centuries been a disease without cure (34). Treatment of hypertension has improved the kidney and cardiovascular outcomes (35–38), but there is little evidence that kidney survival has improved in the past two decades (39). Other potentially modifiable factors of disease progression have been identified (40–42). Until now, no treatment has directly targeted the mechanisms responsible for the development and growth of the cysts. Vasopressin V2 receptor antagonists may be the first such treatment.
In two large clinical trials in patients with early disease over a 3-year period (TEMPO 3:4) and with advanced disease over a 1-year period (REPRISE), tolvaptan slowed the decline of eGFR in ADPKD. TEMPO 4:4 was an open-label extension and therefore not controlled. Our analysis compares the rate of eGFR decline in tolvaptan-treated patients to that observed in matched controls for periods of time up to 11.2 years. In our study, we used three different approaches to examine whether the effect of tolvaptan on the rate of eGFR decline was sustained, cumulative over time, and therefore likely to delay the need for kidney replacement.
First, we found that tolvaptan-treated patients had lower rates of eGFR decline and 33% reduction from the baseline eGFR compared with matched controls from the CRISP and HALT PKD study B studies, regardless of CKD stage. Second, the reduced annualized rates of eGFR decline did not wane over the duration of the follow-up and were consistently lower than in the placebo-treated patients from the TEMPO 3:4 and REPRISE trials. Finally, the difference between the observed and the predicted (30) eGFR values at the last follow-up on tolvaptan increased with the duration of follow-up. Using the three approaches, the tolvaptan-induced benefit was larger when the eGFR slopes and predicted eGFR values at last follow-up were estimated from month 1 one after starting tolvaptan rather than from baseline before starting tolvaptan. These estimates are likely more accurate because they eliminate the reversible, initial effect of tolvaptan on eGFR (17,18,31). The estimated benefit of 8.3 ml/min per 1.73 m2 over an average follow-up of 7.6 years represents an annual effect of 1.09 ml/min per 1.73 m2, consistent with the effects observed in the TEMPO 3:4 and REPRISE studies. Therefore, these results suggest that the effect of tolvaptan on the rate of decline of eGFR is sustained and cumulative over time.
The administration of tolvaptan was overall well tolerated and safe. None of the 108 patients in our study was lost to follow-up. Only eight discontinued the drug because of adverse events related to tolvaptan. Only one of 39 patients with a follow-up extending beyond 5 years discontinued tolvaptan because of an adverse event thought to be likely related to the drug (fatigue).
The main strength of this study is the large number of patients who have been treated with tolvaptan for extended periods of time at a single center and the utilization of several analytical approaches to confirm the consistency of the results. The limitations are those of a retrospective analysis, the use of historical controls, and the inclusion of patients from studies and trials with different entry criteria performed at different time periods. Nevertheless, the entry criteria in these trials were selected to enrich for patients with rapidly progressive disease. It is unlikely that the motivation or lifestyle of the matched controls from the CRISP and HALT PKD studies differed from those of the patients in the tolvaptan trials. This, however, could have affected the comparison of observed versus predicted follow-up eGFRs because the equation to predict future eGFR had been derived from a clinical cohort of patients followed at the Mayo Clinic, who might have been less motivated than participants in clinical trials. We have accounted for all of the patients treated with tolvaptan in our center and the reasons for discontinuing treatment to reveal any biases that could have affected the results. All 108 patients were included in the safety analysis. Eleven patients who had a follow-up of <1 year were not included in the efficacy analysis. All remaining 97 patients, including those who discontinued treatment were included in the efficacy analysis.
In summary, our study strongly suggests that the effect of tolvaptan on eGFR in patients with ADPKD is sustained, cumulative, and consistent with potentially delaying the need of kidney replacement.
Disclosures
V.E.T. is a member of the steering committees for the TEMPO and REPRISE clinical trials, has received research support from Otsuka Pharmaceutical, and is a consultant for Vertex, Sanofi, and Palladio. F.S.C. is an employee of Otsuka Pharmaceuticals.
Supplementary Material
Acknowledgments
We thank the patients involved in the clinical trials of tolvaptan for autosomal dominant polycystic kidney disease included in this analysis, the participants in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) and HALT PKD studies that we have used as controls, and the CRISP and HALT PKD study investigators and coordinators.
This study has been supported in part by the Mayo Clinic Robert M. and Billie Kelley Pirnie Translational Polycystic Kidney Disease Center and the National Institute of Diabetes and Digestive and Kidney Diseases grant DK090728.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.01520218/-/DCSupplemental.
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