Clin Exp Nephrol DOI 10.1007/s10157-014-1023-9
ORIGINAL ARTICLE
Responsiveness to erythropoiesis-stimulating agents and renal survival in patients with chronic kidney disease Michio Kuwahara • Shintaro Mandai • Yuri Kasagi • Keita Kusaka • Tomomi Tanaka Satomi Shikuma • Wataru Akita
•
Received: 24 April 2014 / Accepted: 9 August 2014 Ó Japanese Society of Nephrology 2014
Abstract Background Renal anemia of chronic kidney disease (CKD) is generally treated by erythropoiesis-stimulating agents (ESAs). However, there are individual differences in patients’ responsiveness to ESA, which may affect the prognosis of CKD. Methods The effect of ESAs on hemoglobin was followed in 297 CKD patients with renal anemia. Three types of ESA, epoetin alfa or beta, darbepoetin alfa, and epoetin beta pegol, were used in this study and dose of ESA was converted to that of epoetin using a dose conversion ratio (epoetin:darbepoetin alfa:epoetin beta pegol = 200:1:0.93). After initial 12-week administration of ESAs, the patients were divided into three groups: poor, intermediate, and good responders based on DHb/week/epoetin dose as an index. Hemoglobin values were followed for 144 weeks. Results Initial patient characteristics—including age, body mass index, hemoglobin, estimated glomerular filtration rate, transferrin saturation, ferritin, albumin, calcium, parathyroid hormone, C-reactive protein, and urine protein—were similar in the three responder groups, except phosphate in the poor responder group was significantly higher than in the other two groups. The period from ESA use to renal death (RD) was significantly shortest in the poor responder group, and the number of RD patients was fewer in the good responder group. Multivariate Cox regression revealed that low final DHb(DHb from ESA use to just before dialysis)/week/epoetin dose, and low Hb after
M. Kuwahara (&) S. Mandai Y. Kasagi K. Kusaka T. Tanaka S. Shikuma W. Akita Department of Nephrology, Shuuwa General Hospital, 1200 Yahara-Shinden, Kasukabe, Saitama 344-0035, Japan e-mail: [email protected]
12-week ESA use were significant factors related to responsiveness to ESA, suggesting that hyporesponsiveness to ESA was a risk factor for RD. Cox regression also found that hyperphosphatemia and diabetic nephropathy were risks for RD as well. Conclusions The study results suggest that hyporesponsiveness to ESA after the first 12-week administration as well as after 12 weeks is a risk for RD in pre-dialysis CKD patients. Furthermore, hyperphosphatemia and diabetic nephropathy are risk factors for RD. Keywords Renal anemia Responsiveness to ESA Renal death
Introduction Anemia frequently occurs in patients with chronic kidney disease (CKD) as renal function declines. Accumulating evidence indicates that anemia in CKD patients before dialysis advances renal dysfunction [1, 2] and leads to the development of cardiovascular disease (CVD) [3–6]. We have also reported that, among CKD patients before dialysis, the left ventricular ejection fraction was higher and left ventricular hypertrophy was lower in patients with hemoglobin (Hb) C11 g/dL compared with patients having Hb \11 g/dL [7]. Moreover, it has been reported that erythropoiesis-stimulating agents (ESAs) delay the progression of CKD [1, 2], and improve CVD [3, 6]. Administration of ESAs is the standard therapy for renal anemia. Epoetin alfa or beta (EPO), darbepoetin alfa (DPO), and epoetin beta pegol (EPObp) are currently widely used in Japanese CKD patients with anemia. Two randomized large trials of anemia correction in predialysis CKD patients were published in 2006: Cardiovascular
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Risk Reduction by Early Anemia Treatment with Epoetin (CREATE) [8] and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) [9]. Both studies aimed for higher Hb targets and found trends toward increased mortality risk and for other adverse outcomes. These results led to revise the target Hb level of CKD patients in United States. At present, several guidelines have set the target Hb level for anemic CKD patients before dialysis. Some examples are Hb C11 g/dL [10], 11–12 g/dL [11], and C11 g/dL [12] in the European, KDOQI, and Japanese Society for Dialysis Therapy (JSDT) guidelines, respectively. Meanwhile, the ESA dosage required to achieve the target Hb is different in individual patients. Because sustained anemia leads to adverse outcomes as described above, low response to ESAs may exacerbate the prognosis of anemic CKD patients. In fact, a number of studies indicated that a poor ESA response is associated with higher risk of morbidity and mortality in dialysis patients [13–16]. In contrast to patient on dialysis, only several studies investigated ESA hyporesponsiveness in pre-dialysis CKD patients as far as we know [17–20]. The purposes of the present study were to evaluate the effect of initial ESA treatment on Hb by calculating DHb/ week/ESA dose as an index in non-dialysis CKD patients, and to investigate the relationship between the effect of ESAs and risk of renal death.
Methods Patients The subjects of this study were outpatients in the clinics of the Department of Nephrology of Shuuwa General Hospital. The study was conducted between April 2005 and September 2013. During this period, at least one type of ESA was administered subcutaneously to 465 CKD patients with renal anemia. Of the 465 patients, 83 patients stopped attending our clinic due to change of address, change of hospital or other reasons; 20 patients began dialysis within 12 weeks after the first administration of ESA; 29 patients were complicated with potential diseases causing anemia such as hemorrhagic disease, hematological disease, or carcinoma; and 36 patients died before their CKD progressed to RD. These 168 patients were excluded from the study. Data from the remaining 297 patients were analyzed. No patients initiated dialysis before 24 weeks after the initial administration of ESA. Study design The study protocol was approved by the ethics committee of our hospital, and the study was performed in
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accordance with the Declaration of Helsinki guidelines regarding ethical principles for medical research involving human subjects (registration number: 2005-2-2). The target Hb level was C10 g/dL in the 2004 JSDT guideline and C11 g/dL in the 2008 JSDT guideline [12]. The target Hb level of our study also followed these guidelines. Several guidelines recommend starting iron supplementation in CKD patients with transferrin saturation \20 % and ferritin \100 ng/mL [10–12]. Therefore, we supplied iron as needed to prevent iron deficiency according to the above criteria. At the beginning of the study, clinical and laboratory parameters, including gender, age, body mass index (BMI) cause of CKD, past history of cardiovascular events (CVEs), blood pressure, Hb, estimated glomerular filtration rate (eGFR, calculated using the formula modified for the Japanese population [21]), transferrin saturation, ferritin, albumin, calcium (Ca), phosphate (P), intact parathyroid hormone (iPTH), C-reactive protein (CRP), and urine protein were measured. After the initial 12-week administration of ESA, Hb and BP were measured. The DHb/ week (g/dL/week)/ESA(U or lg/kg/week) was calculated and used as an index for the effect of ESAs on Hb. Patients were treated by the same kind of ESA during these 12 weeks. If patients did not visit the clinic exactly 12 weeks afterward, a putative DHb/week/ESA dose after 12 weeks was calculated from data taken on the visit date nearest to 12 weeks. Hb value after 12 weeks was actually obtained 12.5 ± 1.0 weeks (range 10.6–14.0 weeks) and thus patients’ visit day appeared not far from 12 weeks. The number of CVEs that occurred and the number of patients who started dialysis after administration of ESAs were also noted. Treatment of renal anemia was initiated using EPO, DPO, and EPObp in 158, 81, and 58 patients, respectively. In this study, we assumed that dose conversion ratio for EPO:DPO was 200 units:1 lg (suggested by the Japanese manufacturer information by Kirin Pharma Company) and that for DPO:EPObp was 1.08 lg:1 lg [22]. Thus, all ESA dose was converted to EPO dose using the above dose conversion ratio. After the initial 12-week administration of ESA, the patients were divided into three groups: poor responders (1st tertile), intermediate responders (2nd tertile), and good responders (3rd tertile), based on the value of DHb/ week/ESA. The timing of ESA use, dosage, and type of ESA administered were determined by the attending physician. Thereafter, the dosage of ESA was decided according to the patient’s Hb level. A part of patients were initiated dialysis during the study. This state was defined as renal death (RD) in this study. Risk factors for RD were analyzed using Cox proportional hazards model.
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Definition of terms The terms used in this study are defined as follows. CVEs include cardiac events, cerebrovascular events, and peripheral artery disease (PAD) events. Cardiac events include angina pectoris, hospitalization for heart failure, percutaneous coronary intervention, coronary artery bypass surgery, or acute myocardial infarction. Cerebrovascular events include hospitalization for stroke. PAD events include hospitalization for intervention or surgery of arteries distal to the common iliac artery range. Statistics Continuous variables are expressed as mean ± SD or median. Statistical significance was evaluated by unpaired t tests, the Chi-squared test, or analysis of variance (ANOVA). When statistical significance was detected among groups by ANOVA, significance between any two groups was examined by the Student–Newman–Keuls test. Hazard ratios (HR) and 95 % CIs for risk factors for RD were evaluated using Cox proportional hazards regression analysis. Renal survival rates were determined using the Kaplan–Meier method. Data were statistically analyzed using SPSS II for Windows, a software package based on SPSS 11.0 J for Windows (SPSS, Chicago, IL, USA). Values of P \ 0.05 were considered significant.
Results The baseline characteristics of the study patients are presented in Table 1. The proportion of males was 57.2 %, age was 66.3 ± 13.7 years, and BMI was 23.4 ± 3.9 kg/m2. The causes of CKD were chronic glomerulonephritis and diabetic nephropathy in 46.1 and 42.1 %, respectively. Seventy-three patients (24.6 %) had a history of CVEs. More than 70 % of patients were prescribed an ACEI/ARB and/or calcium channel blocker. Iron was supplied to 23.6 % of the patients. The Hb value prior to ESA use was 9.00 ± 1.02 g/dL, and 37.7 % of the patients had Hb \9.00 g/dL. Among the patients who had Hb \9.00 g/dL, 87.5 % of the patients had their first visit to our clinics. Most patients who have been introduced for the first time in our clinic had not received medical examinations of nephrologists. The presence of these patients was considered to cause a low Hb value before treatment with ESA in our study. The eGFR was 16.7 ± 9.5 mL/min/1.73 m2. At the beginning of the study, 12.8 % of the patients had TSAT \20 % and ferritin \100 ng/mL. These patients were immediately supplied oral iron; only 0.7 % of
patients had potential iron deficiency during management by ESA. The albumin was 3.5 ± 0.6 g/dL; with 4.7 % of patients’ albumin \2.5 g/dL. The iPTH was 218.6 ± 162.4 pg/mL, with 5.1 % of patients’ iPTH exceeding 500 pg/mL. CRP was positive ([0.3 mg/dL) in 23.6 % of the patients at baseline. However, patients with sustained positive CRP comprised 7.4 % during ESA therapy. The patients were then divided into three groups of equal numbers: poor, intermediate, and good responders, depending on their initial 12-week response to ESA by calculating DHb/week (g/dL/week)/ESA(U/ kg/week). The parameters were not significantly different among three groups, except that the P level in the poor responder group was higher than that of other two groups (Table 1). Table 2 provides the follow-up data of the patients. After the first 12 weeks of ESA use, Hb and DHb/week/ EPO were observed as good responders [intermediate responders [poor responders. Blood pressure was similar in the three groups. During entire study period, final Hb [Hb value just before starting dialysis (renal death patients) or at the end of study (non-renal death patients)] and final DHb/week/EPO were significantly higher in good responders than those in other two responder groups. Cardiovascular events occurred in 15.1 % of the total number of patients; two kinds of events occurred in seven patients. The prevalence of CVEs during the study period was similar in the three groups. The number of patients who required dialysis during the study was fewer in good responders compared to other two responders. Hb before ESA use was not significantly different between RD patients group (8.95 ± 0.84 g/dL, n = 160) and non-RD patients group (9.08 ± 0.92 g/dL, n = 137). When the period from the beginning of ESA treatment to RD was compared, the period of the poor responders was shorter than those of the other two responder groups. These results were consistent with the renal survival probability depicted in Fig. 1 (P = 0.019 by log rank). The above observations suggested that responsiveness to ESA predicts renal survival. However, it might be possible that factors other than ESA responsiveness affect renal survival. Therefore, Cox regression was performed to determine risk factors for RD (Table 3). Univariate analysis significantly correlated with diabetic nephropathy, Ca, P, urine protein, Hb after 12-week ESA use, DHb/week/ EPO dose (after 12 weeks), and final DHb/week/EPO dose. Significant parameters determined by univariate analysis were subsequently evaluated into a forward stepwise multivariate Cox analysis. The results indicated that hyperphosphatemia, diabetic nephropathy, low final DHb/ week/ESA dose, and low Hb after 12-week ESA use were significant factors.
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Clin Exp Nephrol Table 1 Baseline characteristics of the total patients and the three patient groups categorized by responsiveness to 12 weeks of ESA treatment Characteristics
Total
1st tertile (poor responders)
2nd tertile (intermediate responders)
3rd tertile (good responders)
P
Number of patients
297
99
99
99
Male gender (%)
57.2
51.5
63.6
56.6
0.18
Age (years)
66.3 ± 13.7
67.4 ± 12.8
65.7 ± 13.4
65.8 ± 14.1
0.63
Body mass index (kg/m2)
23.4 ± 3.9
22.8 ± 3.4
23.4 ± 4.2
23.8 ± 4.0
0.15
Hypertension (%)
90.2
90.9
90.9
87.9
0.72
Chronic glomerulonephritis (%) Diabetes nephropathy (%)
46.1 42.1
52.5 37.4
45.5 42.4
40.4 46.5
0.23 0.43
Nephrosclerosis
6.7
7.1
6.1
7.1
0.95
Others
5.1
3.0
6.0
6.0
0.23
24.6
24.2
25.2
24.2
0.93
Cardiac events (%)
16.8
18.2
19.2
13.2
0.48
Cerebrovascular events (%)
6.1
4.0
6.1
8.1
0.50
Peripheral artery disease events (%)
2.0
2.0
2.0
2.0
1.00
Causes of chronic kidney disease
History of cardiovascular events (%)
Systolic blood pressure (mmHg)
138 ± 19
138 ± 19
140 ± 20
137 ± 18
0.36
Diastolic blood pressure (mmHg)
75 ± 13
77 ± 13
75 ± 13
75 ± 12
0.39
Antihypertensive medications ACEI and/or ARB (%)
74.4
69.7
82.8
74.8
0.07
Calcium channel blocker (%)
77.8
83.8
74.8
74.8
0.21
b-blocker (%)
21.2
24.2
16.2
23.2
0.32
Use of iron supplement (%)
23.6
20.2
25.3
25.3
0.63
Laboratory measurements Hb before ESA use (g/dL)
9.00 ± 1.02
9.20 ± 0.98
8.90 ± 1.02
8.94 ± 1.03
0.08
eGFR (ml/min/1.73 m2)
16.7 ± 9.5
16.2 ± 9.8
16.5 ± 9.7
17.3 ± 7.3
0.66
Transferrin saturation (%)
26.8 ± 12.5
25.9 ± 12.1
27.8 ± 12.8
26.7 ± 12.7
0.59
Ferritin (ng/mL)
189.4 ± 161.6
178.8 ± 155.5
189.6 ± 159.8
200.3 ± 170.5
0.66
Albumin (g/dL)
3.50 ± 0.56
3.57 ± 0.55
3.46 ± 0.48
3.45 ± 0.54
0.21
Ca (mg/dL)
8.54 ± 0.73
8.59 ± 0.69
8.47 ± 0.73
8.56 ± 0.78
P (mg/dL)
4.07 ± 0.89
4.32 ± 0.89
4.03 ± 0.93*
3.86 ± 0.78*
0.78 \0.01
iPTH (pg/mL)
218.6 ± 162.4
231.4 ± 194.1
229.9 ± 141.2
193.6 ± 126.0
CRP (mg/dL)
0.09 (0.27)
0.07 (0.25)
0.10 (0.30)
0.09 (0.26)
0.20 0.40
Urine protein (g/gCr)
3.09 ± 3.51
2.75 ± 2.64
3.333 ± 3.31
3.21 ± 3.95
0.45
Categorical and continuous values are expressed as % and mean ± SD, respectively. Because the distribution of CRP was non-parametric, data are expressed as median and interquartile range (in parenthesis) ESA erythropoiesis-stimulating agent, ACEI angiotensin-converting-enzyme inhibitor, ARB angiotensin-receptor blocker, eGFR estimated glomerular filtration rate * P \ 0.05 compared to poor responder group by analysis of variance (ANOVA)
Discussion The period from the start of ESA treatment to dialysis in the poor responder group was significantly shorter than in the other two responder groups, suggesting that Hb response after 12 weeks of ESA administration might predict the prognosis of CKD. This finding was basically consistent with the previous results [20], where poor responsiveness to ESA was shown to be associated with higher risk for RD
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using multivariable Cox proportional hazards analysis (hazard ratio 2.49, 95 % CI 1.28–4.84). The Hb level was consistently lower in the RD patients than in the non-RD patients. Anemia is known to be a factor in the progression of CKD [1, 2]. Prevalence of CVE history, onset frequency of CVE during the study period, and blood pressure level at the beginning and at 12 weeks after ESA use were not statistically different among the three responder groups. Therefore, we speculate that hyporesponsiveness to ESA
Clin Exp Nephrol Table 2 Follow-up data of patients after administration of ESA Characteristics
1st tertile (poor responders)
2nd tertile (intermediate responders)
3rd tertile (good responders)
P
9.45 ± 1.00
10.09 ± 1.00*
10.76 ± 0.89**
\0.01
2.74 ± 6.11
17.29 ± 4.66*
48.36 ± 24.9**
\0.01
After 12 weeks Hb after ESA use (g/dL) DHb/week (g/dL/week) 9104/EPO dose (U/kg/week) Administered ESA EPO (%)
57.6
55.6
43.4
DPO (%)
22.2
27.3
34.2
20.2
16.1
22.2
Systolic blood pressure (mmHg)
EPObp (%)
139 ± 18
140 ± 18
135 ± 17
0.15
Diastolic blood pressure (mmHg)
77 ± 8
75 ± 10
75 ± 10
0.18
During entire study period Final Hba
9.83 ± 1.23
10.10 ± 1.18
10.44 ± 0.95**
\0.01
Final DHb/week (g/dL/week) 9 104/EPO dose (U/kg/week)
1.42 ± 2.54
2.23 ± 3.30
4.98 ± 6.97**
\0.01
Cardiovascular events after ESA use (%)
17.2
17.1
11.1
0.39
11.1 5.1
11.1 4.1
9.1 4.1
0.93 0.926
Cardiac events (%) Cerebrovascular events (%)
2.0
2.0
2.0
Number of renal death patients (n)
Peripheral artery disease events (%)
61
64
35**
Period from ESA use to renal death (days)
438 ± 328
602 ± 444*
637 ± 471*
1.00 \0.01 0.03
Categorical and continuous values are expressed as % and mean ± SD, respectively ESA erythropoiesis-stimulating agent, EPO, epoetin beta, DPO darbepoetin alfa, EPObp epoetin beta pegol * P \ 0.05 and ** P \ 0.05 compared to poor responders and both poor and intermediate responders, respectively, by analysis of variance (ANOVA) a Hb value just before starting dialysis (renal death patients) or Hb value at the end of study (non-renal death patients)
Fig. 1 Renal survival rate of patients who started dialysis after ESA use. Data are presented according to ESA response separately: in poor responders (n = 61), intermediate responders (n = 64), and good responders (n = 35)
was mainly responsible for the shorter period of renal survival in the poor responders. In baseline data, only the P level in the poor responders was significantly higher than in the other two responder groups. In spite of the lack of a relationship between hyperphosphatemia and responsiveness
to ESA in pre-dialysis patients as far as we know, hyperphosphatemia has been known as a risk factor for decline in renal function in CKD patients before dialysis [23, 24]. Thus, hyperphosphatemia might also influence shortened renal survival to some extent, which was also supported by our following analysis. We performed Cox regression to precisely determine factors associated with RD. Univariate analysis found seven significant factors associated with RD. Further multivariate analysis detected four significant risk factors: hyperphosphatemia, diabetic nephropathy, low final DHb/week/EPO dose, and low Hb after 12-week ESA use. Of these, low Hb after 12-week ESA use was a clearly significant factor related to hyporesponsiveness to ESA because Hb before ESA use did not significantly differ in RD patients and non-RD patients. Low final DHb/week// EPO dose was also related to ESA responsiveness, suggesting again a close relationship between hyporesponsiveness to ESA and decline of kidney function. Our finding that diabetic nephropathy is a risk factor is in accordance with a previous observation [17]. Hyporesponsiveness to ESA is known to be caused by numerous factors such as iron deficiency, inflammation,
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Clin Exp Nephrol Table 3 Predictors of renal survival using Cox proportional hazards model Parameters
Univariate HR (95 %CI)
Multivariate P value
Male gender
0.992 (0.697–1.434)
Age (1/year increase)
1.006 (0.999–1.013)
0.10
Body mass index (/1 kg/m2 increase)
1.036 (0.997–1.076)
0.07
HR (95 %CI)
P value
1.665 (1.189–2.331)
0.003
1.530 (1.244–1.881)
\0.001
0.804 (0.688–0.940)
0.006
0.992 (0.871–0.976)
0.005
0.97
Cause of chronic kidney disease Chronic glomerulonephritis
0.755 (0.567–1.059)
0.11
Diabetic nephropathy
1.541 (1.121–2.117)
0.01
1.006 (0.997–1.015) 1.007 (0.995–1.019)
0.21 0.27
Systolic BP (/1 mmHg increase) Diastolic BP (/1 mmHg increase) Antihypertensive medications ACEI and/or ARB (%)
1.059 (0.734–1.527)
0.76
Calcium channel blocker (%)
1.711 (1.073–2.716)
0.23
b-blocker (%)
0.646 (0.448–0.932)
0.19
1.220 (0.801–1.748)
0.28
Cardiac events
0.950 (0.662–1.541)
0.81
Cerebrovascular events
1.249 (0.705–2.211)
0.50
Peripheral artery disease events
0.678 (0.299–1.540)
0.36
0.995 (0.691–1.433)
0.98
0.898 (0.761–1.060)
0.20
eGFR (/1 mL/min/1.73 m increase)
0.988 (0.965–1.012)
0.34
Transferrin saturation (/1 % increase)
1.001 (0.988–1.014)
0.81
Ferritin (/1 ng/mL increase) Albumin (/1 g/dL increase)
1.001 (0.999–1.002) 0.747 (0.528–1.508)
0.30 0.10
Ca (/1 mg/dL increase)
0.729 (0.561–0.946)
0.02
P (/1 mg/dL increase)
1.766 (1.452–2.149)
\0.01
iPTH (/1 pg/mL increase)
1.000 (0.999–1.001)
0.72
Urine protein (/1 g/gCr increase)
1.087 (1.033–1.143)
\0.01
CRP (/1 mg/dL increase)
1.154 (0.879–1.515)
0.30
Hemoglobin after 12-week ESA use (/1 g/dL increase)
0.788 (0.674–0.820)
\0.01
DHb/week (g/dL/week) 9104/EPO dose (U/kg/week)
0.988 (0.977–1.000)
0.05
0.929 (0.809–1.066)
0.29
0.903 (0.856–0.953)
\0.01
History of cardiovascular events
Use of iron supplement Laboratory measurements Initial hemoglobin (/1 g/dL increase) 2
Follow-up data After 12 weeks
During entire study period Final Hb (/1 g/dL increase)a 4
Final DHb/week (g/dL/week) 9 10 /EPO dose (U/kg/week)
ESA erythropoiesis-stimulating agent, ACEI angiotensin-converting-enzyme inhibitor, ARB angiotensin-receptor blocker, eGFR estimated glomerular filtration rate a
Hb value just before starting dialysis
chronic blood loss, malignancies, severe hyperparathyroidism, malnutrition, use of ACEI/ARB, vitamin deficiencies, and carnitine deficiency [10–12]. During the initial 12-week treatment with ESA, possible iron deficiency hardly existed, and patients with sustained positive CRP constituted only 7.4 % in our study. Patients with potential chronic blood loss and malignancies were excluded from the study in advance. Severe
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hyperparathyroidism, if defined as iPTH [500 pg/mL, was observed in 5.1 % of the study patients. The patients with \2.5 g/dL albumin constituted 4.7 % of the total number of study patients. Thus, the numbers of patients complicated with potential iron deficiency, chronic inflammation, severe hyperparathyroidism, and malnutrition were low, and laboratory data accounting for these factors were similar in the three responder groups. The frequency of use
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of ACEI/ARB was also similar in the three responder groups. Vitamins and carnitine were unmeasured in the present study. However, we speculate that the effect on anemia of these deficiencies appeared small because almost all patients were able to eat well nutritiously. A previous study indicated that older age, BMI, pretreatment Hb, use of ACEI/ARB, and diabetic nephropathy were associated with increased EPO requirement to normalize (Hb 13–15 g/dL) in anemic CKD patients not on dialysis [17]. Another study found that female gender, history of cardiovascular disease, and inflammation are factors associated with a higher ESA/Hb index in patients before dialysis [19]. These findings were partially inconsistent with our results. The exact reasons for discrepancies between their and our results were undetected. It might be possible that differences in target Hb level, index of responsiveness to ESA, methods of data analysis, and races account for the discrepancies. In CKD patients with type II diabetes, a low initial response to DPO was shown to cause an increased risk of death or cardiovascular events [18]. Because our diabetic patients’ group treated with DPO was too small to obtain a meaningful analysis, we failed to validate the above finding. The present study had several limitations. First, the number of study patients was small. Second, three different types of ESA were used and ESA dose was converted based on a dose conversion ratio. However, we were unable to verify whether the ratio was reasonable. Third, the follow-up period was not enough long. Therefore, the findings of the present study might not be definitive. A larger sample group and a longer follow-up period are necessary to confirm our findings. In conclusion, we observed that response to the initial 12-week treatment with ESAs is associated with a risk for RD in pre-dialysis CKD patients. Our analysis also suggests hyporesponsiveness to ESA a risk factor for RD even after 12 weeks. In addition, we found that hyperphosphatemia and diabetic nephropathy are potent risks for RD in CKD patients before dialysis. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Roth D, Smith RD, Schulman G, Steinman TI, Hatch FE, Rudnick MR, et al. Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients. Am J Kidney Dis. 1994;24:777–84. 2. Kuriyama S, Tomonari H, Yoshida H, Hashimoto T, Kawaguchi Y, Sakai O. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron. 1997;77:176–85.
3. Roger SD, McMahon LP, Clarkson A, Disney A, Harris D, Hawley C, et al. Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. J Am Soc Nephrol. 2004;15:148–56. 4. Silverberg DS, Wexler D, Blum M, Tchebiner JZ, Sheps D, Keren G, et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant. 2003;18:141–6. 5. Go AS, Yang J, Ackerson LM, Lepper K, Robbins S, Massie BM, et al. Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the anemia in chronic heart failure: outcomes and resource utilization (ANCHOR) study. Circulation. 2006;113:2713–23. 6. Walker AM, Schneider G, Yeaw J, Nordstrom B, Robbins S, Pettitt D. Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. J Am Soc Nephrol. 2006;17:2293–8. 7. Kuwahara M, Iimori S, Kuyama T, Akita W, Mori Y, Asai T, et al. Effect of anemia on cardiac disorders in pre-dialysis immediately before starting hemodialysis. Clin Exp Nephrol. 2011;15:121–5. 8. Dru¨eke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355: 2071–84. 9. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98. 10. Locatelli F, Aljama P, Ba´ra´ny P, Canaud B, Carrera F, Eckardt KU, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19(Suppl 2):21–47. 11. KDOQI. KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease update of hemoglobin target. Am J Kidney Dis. 2007;2007(50):471–530. 12. Tsubakihara Y, Nishi S, Akiba T, Hirakata H, Iseki K, Kubota M, et al. 2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial. 2010;14:240–75. 13. Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ. Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis. 2004;44:866–76. 14. Locatelli F, Pisoni RL, Combe C, Bommer J, Andreucci VE, Piera L, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19:121–32. 15. Robinson BM, Joffe MM, Berns JS, Pisoni RL, Port FK, Feldman HI. Anemia and mortality in hemodialysis patients: accounting for morbidity and treatment variables updated over time. Kidney Int. 2005;68:2323–30. 16. Panichi V, Rosati A, Bigazzi R, Paoletti S, Mantuano E, Beati S, et al. Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant. 2011;26: 2641–8. 17. Rossert J, Gassmann-Mayer C, Frei D, McClellan W. Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients. Nephrol Dial Transplant. 2007;22: 794–800. 18. Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363:1146–55.
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Clin Exp Nephrol 19. de Lurdes Agostinho Cabrita A, Pinho A, Malho A, Morgado E, Faı´sca M, Carrasqueira H, et al. Risk factors for high erythropoiesis stimulating agent resistance index in pre-dialysis chronic kidney disease patients, stages 4 and 5. Int Urol Nephrol. 2011;43:835–40. 20. Minutolo R, Conte G, Cianciaruso B, Bellizzi V, Camocardi A, De Paola L, et al. Hyporesponsiveness to erythropoiesis-stimulating agents and renal survival in non-dialysis CKD patients. Nephrol Dial Transplant. 2012;27:2880–6. 21. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.
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22. Kuwahara M, Hasumi S, Mandai S, Tanaka T, Shikuma S, Akita W, et al. Effects of three kinds of erythropoiesis-stimulating agents on renal anemia in Japanese non-dialysis chronic kidney disease patients. Clin Exp Nephrol. 2013 [Epub ahead of print]. 23. Voormolen N, Noordzij M, Grootendorst DC, Beetz I, Sijpkens YW, van Manen JG, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant. 2007;22:2909–16. 24. Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:825–31.
ORIGINAL ARTICLE
Responsiveness to erythropoiesis-stimulating agents and renal survival in patients with chronic kidney disease Michio Kuwahara • Shintaro Mandai • Yuri Kasagi • Keita Kusaka • Tomomi Tanaka Satomi Shikuma • Wataru Akita
•
Received: 24 April 2014 / Accepted: 9 August 2014 Ó Japanese Society of Nephrology 2014
Abstract Background Renal anemia of chronic kidney disease (CKD) is generally treated by erythropoiesis-stimulating agents (ESAs). However, there are individual differences in patients’ responsiveness to ESA, which may affect the prognosis of CKD. Methods The effect of ESAs on hemoglobin was followed in 297 CKD patients with renal anemia. Three types of ESA, epoetin alfa or beta, darbepoetin alfa, and epoetin beta pegol, were used in this study and dose of ESA was converted to that of epoetin using a dose conversion ratio (epoetin:darbepoetin alfa:epoetin beta pegol = 200:1:0.93). After initial 12-week administration of ESAs, the patients were divided into three groups: poor, intermediate, and good responders based on DHb/week/epoetin dose as an index. Hemoglobin values were followed for 144 weeks. Results Initial patient characteristics—including age, body mass index, hemoglobin, estimated glomerular filtration rate, transferrin saturation, ferritin, albumin, calcium, parathyroid hormone, C-reactive protein, and urine protein—were similar in the three responder groups, except phosphate in the poor responder group was significantly higher than in the other two groups. The period from ESA use to renal death (RD) was significantly shortest in the poor responder group, and the number of RD patients was fewer in the good responder group. Multivariate Cox regression revealed that low final DHb(DHb from ESA use to just before dialysis)/week/epoetin dose, and low Hb after
M. Kuwahara (&) S. Mandai Y. Kasagi K. Kusaka T. Tanaka S. Shikuma W. Akita Department of Nephrology, Shuuwa General Hospital, 1200 Yahara-Shinden, Kasukabe, Saitama 344-0035, Japan e-mail: [email protected]
12-week ESA use were significant factors related to responsiveness to ESA, suggesting that hyporesponsiveness to ESA was a risk factor for RD. Cox regression also found that hyperphosphatemia and diabetic nephropathy were risks for RD as well. Conclusions The study results suggest that hyporesponsiveness to ESA after the first 12-week administration as well as after 12 weeks is a risk for RD in pre-dialysis CKD patients. Furthermore, hyperphosphatemia and diabetic nephropathy are risk factors for RD. Keywords Renal anemia Responsiveness to ESA Renal death
Introduction Anemia frequently occurs in patients with chronic kidney disease (CKD) as renal function declines. Accumulating evidence indicates that anemia in CKD patients before dialysis advances renal dysfunction [1, 2] and leads to the development of cardiovascular disease (CVD) [3–6]. We have also reported that, among CKD patients before dialysis, the left ventricular ejection fraction was higher and left ventricular hypertrophy was lower in patients with hemoglobin (Hb) C11 g/dL compared with patients having Hb \11 g/dL [7]. Moreover, it has been reported that erythropoiesis-stimulating agents (ESAs) delay the progression of CKD [1, 2], and improve CVD [3, 6]. Administration of ESAs is the standard therapy for renal anemia. Epoetin alfa or beta (EPO), darbepoetin alfa (DPO), and epoetin beta pegol (EPObp) are currently widely used in Japanese CKD patients with anemia. Two randomized large trials of anemia correction in predialysis CKD patients were published in 2006: Cardiovascular
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Risk Reduction by Early Anemia Treatment with Epoetin (CREATE) [8] and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) [9]. Both studies aimed for higher Hb targets and found trends toward increased mortality risk and for other adverse outcomes. These results led to revise the target Hb level of CKD patients in United States. At present, several guidelines have set the target Hb level for anemic CKD patients before dialysis. Some examples are Hb C11 g/dL [10], 11–12 g/dL [11], and C11 g/dL [12] in the European, KDOQI, and Japanese Society for Dialysis Therapy (JSDT) guidelines, respectively. Meanwhile, the ESA dosage required to achieve the target Hb is different in individual patients. Because sustained anemia leads to adverse outcomes as described above, low response to ESAs may exacerbate the prognosis of anemic CKD patients. In fact, a number of studies indicated that a poor ESA response is associated with higher risk of morbidity and mortality in dialysis patients [13–16]. In contrast to patient on dialysis, only several studies investigated ESA hyporesponsiveness in pre-dialysis CKD patients as far as we know [17–20]. The purposes of the present study were to evaluate the effect of initial ESA treatment on Hb by calculating DHb/ week/ESA dose as an index in non-dialysis CKD patients, and to investigate the relationship between the effect of ESAs and risk of renal death.
Methods Patients The subjects of this study were outpatients in the clinics of the Department of Nephrology of Shuuwa General Hospital. The study was conducted between April 2005 and September 2013. During this period, at least one type of ESA was administered subcutaneously to 465 CKD patients with renal anemia. Of the 465 patients, 83 patients stopped attending our clinic due to change of address, change of hospital or other reasons; 20 patients began dialysis within 12 weeks after the first administration of ESA; 29 patients were complicated with potential diseases causing anemia such as hemorrhagic disease, hematological disease, or carcinoma; and 36 patients died before their CKD progressed to RD. These 168 patients were excluded from the study. Data from the remaining 297 patients were analyzed. No patients initiated dialysis before 24 weeks after the initial administration of ESA. Study design The study protocol was approved by the ethics committee of our hospital, and the study was performed in
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accordance with the Declaration of Helsinki guidelines regarding ethical principles for medical research involving human subjects (registration number: 2005-2-2). The target Hb level was C10 g/dL in the 2004 JSDT guideline and C11 g/dL in the 2008 JSDT guideline [12]. The target Hb level of our study also followed these guidelines. Several guidelines recommend starting iron supplementation in CKD patients with transferrin saturation \20 % and ferritin \100 ng/mL [10–12]. Therefore, we supplied iron as needed to prevent iron deficiency according to the above criteria. At the beginning of the study, clinical and laboratory parameters, including gender, age, body mass index (BMI) cause of CKD, past history of cardiovascular events (CVEs), blood pressure, Hb, estimated glomerular filtration rate (eGFR, calculated using the formula modified for the Japanese population [21]), transferrin saturation, ferritin, albumin, calcium (Ca), phosphate (P), intact parathyroid hormone (iPTH), C-reactive protein (CRP), and urine protein were measured. After the initial 12-week administration of ESA, Hb and BP were measured. The DHb/ week (g/dL/week)/ESA(U or lg/kg/week) was calculated and used as an index for the effect of ESAs on Hb. Patients were treated by the same kind of ESA during these 12 weeks. If patients did not visit the clinic exactly 12 weeks afterward, a putative DHb/week/ESA dose after 12 weeks was calculated from data taken on the visit date nearest to 12 weeks. Hb value after 12 weeks was actually obtained 12.5 ± 1.0 weeks (range 10.6–14.0 weeks) and thus patients’ visit day appeared not far from 12 weeks. The number of CVEs that occurred and the number of patients who started dialysis after administration of ESAs were also noted. Treatment of renal anemia was initiated using EPO, DPO, and EPObp in 158, 81, and 58 patients, respectively. In this study, we assumed that dose conversion ratio for EPO:DPO was 200 units:1 lg (suggested by the Japanese manufacturer information by Kirin Pharma Company) and that for DPO:EPObp was 1.08 lg:1 lg [22]. Thus, all ESA dose was converted to EPO dose using the above dose conversion ratio. After the initial 12-week administration of ESA, the patients were divided into three groups: poor responders (1st tertile), intermediate responders (2nd tertile), and good responders (3rd tertile), based on the value of DHb/ week/ESA. The timing of ESA use, dosage, and type of ESA administered were determined by the attending physician. Thereafter, the dosage of ESA was decided according to the patient’s Hb level. A part of patients were initiated dialysis during the study. This state was defined as renal death (RD) in this study. Risk factors for RD were analyzed using Cox proportional hazards model.
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Definition of terms The terms used in this study are defined as follows. CVEs include cardiac events, cerebrovascular events, and peripheral artery disease (PAD) events. Cardiac events include angina pectoris, hospitalization for heart failure, percutaneous coronary intervention, coronary artery bypass surgery, or acute myocardial infarction. Cerebrovascular events include hospitalization for stroke. PAD events include hospitalization for intervention or surgery of arteries distal to the common iliac artery range. Statistics Continuous variables are expressed as mean ± SD or median. Statistical significance was evaluated by unpaired t tests, the Chi-squared test, or analysis of variance (ANOVA). When statistical significance was detected among groups by ANOVA, significance between any two groups was examined by the Student–Newman–Keuls test. Hazard ratios (HR) and 95 % CIs for risk factors for RD were evaluated using Cox proportional hazards regression analysis. Renal survival rates were determined using the Kaplan–Meier method. Data were statistically analyzed using SPSS II for Windows, a software package based on SPSS 11.0 J for Windows (SPSS, Chicago, IL, USA). Values of P \ 0.05 were considered significant.
Results The baseline characteristics of the study patients are presented in Table 1. The proportion of males was 57.2 %, age was 66.3 ± 13.7 years, and BMI was 23.4 ± 3.9 kg/m2. The causes of CKD were chronic glomerulonephritis and diabetic nephropathy in 46.1 and 42.1 %, respectively. Seventy-three patients (24.6 %) had a history of CVEs. More than 70 % of patients were prescribed an ACEI/ARB and/or calcium channel blocker. Iron was supplied to 23.6 % of the patients. The Hb value prior to ESA use was 9.00 ± 1.02 g/dL, and 37.7 % of the patients had Hb \9.00 g/dL. Among the patients who had Hb \9.00 g/dL, 87.5 % of the patients had their first visit to our clinics. Most patients who have been introduced for the first time in our clinic had not received medical examinations of nephrologists. The presence of these patients was considered to cause a low Hb value before treatment with ESA in our study. The eGFR was 16.7 ± 9.5 mL/min/1.73 m2. At the beginning of the study, 12.8 % of the patients had TSAT \20 % and ferritin \100 ng/mL. These patients were immediately supplied oral iron; only 0.7 % of
patients had potential iron deficiency during management by ESA. The albumin was 3.5 ± 0.6 g/dL; with 4.7 % of patients’ albumin \2.5 g/dL. The iPTH was 218.6 ± 162.4 pg/mL, with 5.1 % of patients’ iPTH exceeding 500 pg/mL. CRP was positive ([0.3 mg/dL) in 23.6 % of the patients at baseline. However, patients with sustained positive CRP comprised 7.4 % during ESA therapy. The patients were then divided into three groups of equal numbers: poor, intermediate, and good responders, depending on their initial 12-week response to ESA by calculating DHb/week (g/dL/week)/ESA(U/ kg/week). The parameters were not significantly different among three groups, except that the P level in the poor responder group was higher than that of other two groups (Table 1). Table 2 provides the follow-up data of the patients. After the first 12 weeks of ESA use, Hb and DHb/week/ EPO were observed as good responders [intermediate responders [poor responders. Blood pressure was similar in the three groups. During entire study period, final Hb [Hb value just before starting dialysis (renal death patients) or at the end of study (non-renal death patients)] and final DHb/week/EPO were significantly higher in good responders than those in other two responder groups. Cardiovascular events occurred in 15.1 % of the total number of patients; two kinds of events occurred in seven patients. The prevalence of CVEs during the study period was similar in the three groups. The number of patients who required dialysis during the study was fewer in good responders compared to other two responders. Hb before ESA use was not significantly different between RD patients group (8.95 ± 0.84 g/dL, n = 160) and non-RD patients group (9.08 ± 0.92 g/dL, n = 137). When the period from the beginning of ESA treatment to RD was compared, the period of the poor responders was shorter than those of the other two responder groups. These results were consistent with the renal survival probability depicted in Fig. 1 (P = 0.019 by log rank). The above observations suggested that responsiveness to ESA predicts renal survival. However, it might be possible that factors other than ESA responsiveness affect renal survival. Therefore, Cox regression was performed to determine risk factors for RD (Table 3). Univariate analysis significantly correlated with diabetic nephropathy, Ca, P, urine protein, Hb after 12-week ESA use, DHb/week/ EPO dose (after 12 weeks), and final DHb/week/EPO dose. Significant parameters determined by univariate analysis were subsequently evaluated into a forward stepwise multivariate Cox analysis. The results indicated that hyperphosphatemia, diabetic nephropathy, low final DHb/ week/ESA dose, and low Hb after 12-week ESA use were significant factors.
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Clin Exp Nephrol Table 1 Baseline characteristics of the total patients and the three patient groups categorized by responsiveness to 12 weeks of ESA treatment Characteristics
Total
1st tertile (poor responders)
2nd tertile (intermediate responders)
3rd tertile (good responders)
P
Number of patients
297
99
99
99
Male gender (%)
57.2
51.5
63.6
56.6
0.18
Age (years)
66.3 ± 13.7
67.4 ± 12.8
65.7 ± 13.4
65.8 ± 14.1
0.63
Body mass index (kg/m2)
23.4 ± 3.9
22.8 ± 3.4
23.4 ± 4.2
23.8 ± 4.0
0.15
Hypertension (%)
90.2
90.9
90.9
87.9
0.72
Chronic glomerulonephritis (%) Diabetes nephropathy (%)
46.1 42.1
52.5 37.4
45.5 42.4
40.4 46.5
0.23 0.43
Nephrosclerosis
6.7
7.1
6.1
7.1
0.95
Others
5.1
3.0
6.0
6.0
0.23
24.6
24.2
25.2
24.2
0.93
Cardiac events (%)
16.8
18.2
19.2
13.2
0.48
Cerebrovascular events (%)
6.1
4.0
6.1
8.1
0.50
Peripheral artery disease events (%)
2.0
2.0
2.0
2.0
1.00
Causes of chronic kidney disease
History of cardiovascular events (%)
Systolic blood pressure (mmHg)
138 ± 19
138 ± 19
140 ± 20
137 ± 18
0.36
Diastolic blood pressure (mmHg)
75 ± 13
77 ± 13
75 ± 13
75 ± 12
0.39
Antihypertensive medications ACEI and/or ARB (%)
74.4
69.7
82.8
74.8
0.07
Calcium channel blocker (%)
77.8
83.8
74.8
74.8
0.21
b-blocker (%)
21.2
24.2
16.2
23.2
0.32
Use of iron supplement (%)
23.6
20.2
25.3
25.3
0.63
Laboratory measurements Hb before ESA use (g/dL)
9.00 ± 1.02
9.20 ± 0.98
8.90 ± 1.02
8.94 ± 1.03
0.08
eGFR (ml/min/1.73 m2)
16.7 ± 9.5
16.2 ± 9.8
16.5 ± 9.7
17.3 ± 7.3
0.66
Transferrin saturation (%)
26.8 ± 12.5
25.9 ± 12.1
27.8 ± 12.8
26.7 ± 12.7
0.59
Ferritin (ng/mL)
189.4 ± 161.6
178.8 ± 155.5
189.6 ± 159.8
200.3 ± 170.5
0.66
Albumin (g/dL)
3.50 ± 0.56
3.57 ± 0.55
3.46 ± 0.48
3.45 ± 0.54
0.21
Ca (mg/dL)
8.54 ± 0.73
8.59 ± 0.69
8.47 ± 0.73
8.56 ± 0.78
P (mg/dL)
4.07 ± 0.89
4.32 ± 0.89
4.03 ± 0.93*
3.86 ± 0.78*
0.78 \0.01
iPTH (pg/mL)
218.6 ± 162.4
231.4 ± 194.1
229.9 ± 141.2
193.6 ± 126.0
CRP (mg/dL)
0.09 (0.27)
0.07 (0.25)
0.10 (0.30)
0.09 (0.26)
0.20 0.40
Urine protein (g/gCr)
3.09 ± 3.51
2.75 ± 2.64
3.333 ± 3.31
3.21 ± 3.95
0.45
Categorical and continuous values are expressed as % and mean ± SD, respectively. Because the distribution of CRP was non-parametric, data are expressed as median and interquartile range (in parenthesis) ESA erythropoiesis-stimulating agent, ACEI angiotensin-converting-enzyme inhibitor, ARB angiotensin-receptor blocker, eGFR estimated glomerular filtration rate * P \ 0.05 compared to poor responder group by analysis of variance (ANOVA)
Discussion The period from the start of ESA treatment to dialysis in the poor responder group was significantly shorter than in the other two responder groups, suggesting that Hb response after 12 weeks of ESA administration might predict the prognosis of CKD. This finding was basically consistent with the previous results [20], where poor responsiveness to ESA was shown to be associated with higher risk for RD
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using multivariable Cox proportional hazards analysis (hazard ratio 2.49, 95 % CI 1.28–4.84). The Hb level was consistently lower in the RD patients than in the non-RD patients. Anemia is known to be a factor in the progression of CKD [1, 2]. Prevalence of CVE history, onset frequency of CVE during the study period, and blood pressure level at the beginning and at 12 weeks after ESA use were not statistically different among the three responder groups. Therefore, we speculate that hyporesponsiveness to ESA
Clin Exp Nephrol Table 2 Follow-up data of patients after administration of ESA Characteristics
1st tertile (poor responders)
2nd tertile (intermediate responders)
3rd tertile (good responders)
P
9.45 ± 1.00
10.09 ± 1.00*
10.76 ± 0.89**
\0.01
2.74 ± 6.11
17.29 ± 4.66*
48.36 ± 24.9**
\0.01
After 12 weeks Hb after ESA use (g/dL) DHb/week (g/dL/week) 9104/EPO dose (U/kg/week) Administered ESA EPO (%)
57.6
55.6
43.4
DPO (%)
22.2
27.3
34.2
20.2
16.1
22.2
Systolic blood pressure (mmHg)
EPObp (%)
139 ± 18
140 ± 18
135 ± 17
0.15
Diastolic blood pressure (mmHg)
77 ± 8
75 ± 10
75 ± 10
0.18
During entire study period Final Hba
9.83 ± 1.23
10.10 ± 1.18
10.44 ± 0.95**
\0.01
Final DHb/week (g/dL/week) 9 104/EPO dose (U/kg/week)
1.42 ± 2.54
2.23 ± 3.30
4.98 ± 6.97**
\0.01
Cardiovascular events after ESA use (%)
17.2
17.1
11.1
0.39
11.1 5.1
11.1 4.1
9.1 4.1
0.93 0.926
Cardiac events (%) Cerebrovascular events (%)
2.0
2.0
2.0
Number of renal death patients (n)
Peripheral artery disease events (%)
61
64
35**
Period from ESA use to renal death (days)
438 ± 328
602 ± 444*
637 ± 471*
1.00 \0.01 0.03
Categorical and continuous values are expressed as % and mean ± SD, respectively ESA erythropoiesis-stimulating agent, EPO, epoetin beta, DPO darbepoetin alfa, EPObp epoetin beta pegol * P \ 0.05 and ** P \ 0.05 compared to poor responders and both poor and intermediate responders, respectively, by analysis of variance (ANOVA) a Hb value just before starting dialysis (renal death patients) or Hb value at the end of study (non-renal death patients)
Fig. 1 Renal survival rate of patients who started dialysis after ESA use. Data are presented according to ESA response separately: in poor responders (n = 61), intermediate responders (n = 64), and good responders (n = 35)
was mainly responsible for the shorter period of renal survival in the poor responders. In baseline data, only the P level in the poor responders was significantly higher than in the other two responder groups. In spite of the lack of a relationship between hyperphosphatemia and responsiveness
to ESA in pre-dialysis patients as far as we know, hyperphosphatemia has been known as a risk factor for decline in renal function in CKD patients before dialysis [23, 24]. Thus, hyperphosphatemia might also influence shortened renal survival to some extent, which was also supported by our following analysis. We performed Cox regression to precisely determine factors associated with RD. Univariate analysis found seven significant factors associated with RD. Further multivariate analysis detected four significant risk factors: hyperphosphatemia, diabetic nephropathy, low final DHb/week/EPO dose, and low Hb after 12-week ESA use. Of these, low Hb after 12-week ESA use was a clearly significant factor related to hyporesponsiveness to ESA because Hb before ESA use did not significantly differ in RD patients and non-RD patients. Low final DHb/week// EPO dose was also related to ESA responsiveness, suggesting again a close relationship between hyporesponsiveness to ESA and decline of kidney function. Our finding that diabetic nephropathy is a risk factor is in accordance with a previous observation [17]. Hyporesponsiveness to ESA is known to be caused by numerous factors such as iron deficiency, inflammation,
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Clin Exp Nephrol Table 3 Predictors of renal survival using Cox proportional hazards model Parameters
Univariate HR (95 %CI)
Multivariate P value
Male gender
0.992 (0.697–1.434)
Age (1/year increase)
1.006 (0.999–1.013)
0.10
Body mass index (/1 kg/m2 increase)
1.036 (0.997–1.076)
0.07
HR (95 %CI)
P value
1.665 (1.189–2.331)
0.003
1.530 (1.244–1.881)
\0.001
0.804 (0.688–0.940)
0.006
0.992 (0.871–0.976)
0.005
0.97
Cause of chronic kidney disease Chronic glomerulonephritis
0.755 (0.567–1.059)
0.11
Diabetic nephropathy
1.541 (1.121–2.117)
0.01
1.006 (0.997–1.015) 1.007 (0.995–1.019)
0.21 0.27
Systolic BP (/1 mmHg increase) Diastolic BP (/1 mmHg increase) Antihypertensive medications ACEI and/or ARB (%)
1.059 (0.734–1.527)
0.76
Calcium channel blocker (%)
1.711 (1.073–2.716)
0.23
b-blocker (%)
0.646 (0.448–0.932)
0.19
1.220 (0.801–1.748)
0.28
Cardiac events
0.950 (0.662–1.541)
0.81
Cerebrovascular events
1.249 (0.705–2.211)
0.50
Peripheral artery disease events
0.678 (0.299–1.540)
0.36
0.995 (0.691–1.433)
0.98
0.898 (0.761–1.060)
0.20
eGFR (/1 mL/min/1.73 m increase)
0.988 (0.965–1.012)
0.34
Transferrin saturation (/1 % increase)
1.001 (0.988–1.014)
0.81
Ferritin (/1 ng/mL increase) Albumin (/1 g/dL increase)
1.001 (0.999–1.002) 0.747 (0.528–1.508)
0.30 0.10
Ca (/1 mg/dL increase)
0.729 (0.561–0.946)
0.02
P (/1 mg/dL increase)
1.766 (1.452–2.149)
\0.01
iPTH (/1 pg/mL increase)
1.000 (0.999–1.001)
0.72
Urine protein (/1 g/gCr increase)
1.087 (1.033–1.143)
\0.01
CRP (/1 mg/dL increase)
1.154 (0.879–1.515)
0.30
Hemoglobin after 12-week ESA use (/1 g/dL increase)
0.788 (0.674–0.820)
\0.01
DHb/week (g/dL/week) 9104/EPO dose (U/kg/week)
0.988 (0.977–1.000)
0.05
0.929 (0.809–1.066)
0.29
0.903 (0.856–0.953)
\0.01
History of cardiovascular events
Use of iron supplement Laboratory measurements Initial hemoglobin (/1 g/dL increase) 2
Follow-up data After 12 weeks
During entire study period Final Hb (/1 g/dL increase)a 4
Final DHb/week (g/dL/week) 9 10 /EPO dose (U/kg/week)
ESA erythropoiesis-stimulating agent, ACEI angiotensin-converting-enzyme inhibitor, ARB angiotensin-receptor blocker, eGFR estimated glomerular filtration rate a
Hb value just before starting dialysis
chronic blood loss, malignancies, severe hyperparathyroidism, malnutrition, use of ACEI/ARB, vitamin deficiencies, and carnitine deficiency [10–12]. During the initial 12-week treatment with ESA, possible iron deficiency hardly existed, and patients with sustained positive CRP constituted only 7.4 % in our study. Patients with potential chronic blood loss and malignancies were excluded from the study in advance. Severe
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hyperparathyroidism, if defined as iPTH [500 pg/mL, was observed in 5.1 % of the study patients. The patients with \2.5 g/dL albumin constituted 4.7 % of the total number of study patients. Thus, the numbers of patients complicated with potential iron deficiency, chronic inflammation, severe hyperparathyroidism, and malnutrition were low, and laboratory data accounting for these factors were similar in the three responder groups. The frequency of use
Clin Exp Nephrol
of ACEI/ARB was also similar in the three responder groups. Vitamins and carnitine were unmeasured in the present study. However, we speculate that the effect on anemia of these deficiencies appeared small because almost all patients were able to eat well nutritiously. A previous study indicated that older age, BMI, pretreatment Hb, use of ACEI/ARB, and diabetic nephropathy were associated with increased EPO requirement to normalize (Hb 13–15 g/dL) in anemic CKD patients not on dialysis [17]. Another study found that female gender, history of cardiovascular disease, and inflammation are factors associated with a higher ESA/Hb index in patients before dialysis [19]. These findings were partially inconsistent with our results. The exact reasons for discrepancies between their and our results were undetected. It might be possible that differences in target Hb level, index of responsiveness to ESA, methods of data analysis, and races account for the discrepancies. In CKD patients with type II diabetes, a low initial response to DPO was shown to cause an increased risk of death or cardiovascular events [18]. Because our diabetic patients’ group treated with DPO was too small to obtain a meaningful analysis, we failed to validate the above finding. The present study had several limitations. First, the number of study patients was small. Second, three different types of ESA were used and ESA dose was converted based on a dose conversion ratio. However, we were unable to verify whether the ratio was reasonable. Third, the follow-up period was not enough long. Therefore, the findings of the present study might not be definitive. A larger sample group and a longer follow-up period are necessary to confirm our findings. In conclusion, we observed that response to the initial 12-week treatment with ESAs is associated with a risk for RD in pre-dialysis CKD patients. Our analysis also suggests hyporesponsiveness to ESA a risk factor for RD even after 12 weeks. In addition, we found that hyperphosphatemia and diabetic nephropathy are potent risks for RD in CKD patients before dialysis. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Roth D, Smith RD, Schulman G, Steinman TI, Hatch FE, Rudnick MR, et al. Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients. Am J Kidney Dis. 1994;24:777–84. 2. Kuriyama S, Tomonari H, Yoshida H, Hashimoto T, Kawaguchi Y, Sakai O. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron. 1997;77:176–85.
3. Roger SD, McMahon LP, Clarkson A, Disney A, Harris D, Hawley C, et al. Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. J Am Soc Nephrol. 2004;15:148–56. 4. Silverberg DS, Wexler D, Blum M, Tchebiner JZ, Sheps D, Keren G, et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant. 2003;18:141–6. 5. Go AS, Yang J, Ackerson LM, Lepper K, Robbins S, Massie BM, et al. Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the anemia in chronic heart failure: outcomes and resource utilization (ANCHOR) study. Circulation. 2006;113:2713–23. 6. Walker AM, Schneider G, Yeaw J, Nordstrom B, Robbins S, Pettitt D. Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. J Am Soc Nephrol. 2006;17:2293–8. 7. Kuwahara M, Iimori S, Kuyama T, Akita W, Mori Y, Asai T, et al. Effect of anemia on cardiac disorders in pre-dialysis immediately before starting hemodialysis. Clin Exp Nephrol. 2011;15:121–5. 8. Dru¨eke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355: 2071–84. 9. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98. 10. Locatelli F, Aljama P, Ba´ra´ny P, Canaud B, Carrera F, Eckardt KU, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19(Suppl 2):21–47. 11. KDOQI. KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease update of hemoglobin target. Am J Kidney Dis. 2007;2007(50):471–530. 12. Tsubakihara Y, Nishi S, Akiba T, Hirakata H, Iseki K, Kubota M, et al. 2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial. 2010;14:240–75. 13. Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ. Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis. 2004;44:866–76. 14. Locatelli F, Pisoni RL, Combe C, Bommer J, Andreucci VE, Piera L, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19:121–32. 15. Robinson BM, Joffe MM, Berns JS, Pisoni RL, Port FK, Feldman HI. Anemia and mortality in hemodialysis patients: accounting for morbidity and treatment variables updated over time. Kidney Int. 2005;68:2323–30. 16. Panichi V, Rosati A, Bigazzi R, Paoletti S, Mantuano E, Beati S, et al. Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant. 2011;26: 2641–8. 17. Rossert J, Gassmann-Mayer C, Frei D, McClellan W. Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients. Nephrol Dial Transplant. 2007;22: 794–800. 18. Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363:1146–55.
123
Clin Exp Nephrol 19. de Lurdes Agostinho Cabrita A, Pinho A, Malho A, Morgado E, Faı´sca M, Carrasqueira H, et al. Risk factors for high erythropoiesis stimulating agent resistance index in pre-dialysis chronic kidney disease patients, stages 4 and 5. Int Urol Nephrol. 2011;43:835–40. 20. Minutolo R, Conte G, Cianciaruso B, Bellizzi V, Camocardi A, De Paola L, et al. Hyporesponsiveness to erythropoiesis-stimulating agents and renal survival in non-dialysis CKD patients. Nephrol Dial Transplant. 2012;27:2880–6. 21. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.
123
22. Kuwahara M, Hasumi S, Mandai S, Tanaka T, Shikuma S, Akita W, et al. Effects of three kinds of erythropoiesis-stimulating agents on renal anemia in Japanese non-dialysis chronic kidney disease patients. Clin Exp Nephrol. 2013 [Epub ahead of print]. 23. Voormolen N, Noordzij M, Grootendorst DC, Beetz I, Sijpkens YW, van Manen JG, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant. 2007;22:2909–16. 24. Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:825–31.
