Nephrol Dial Transplant (2015) 30: 441–451 doi: 10.1093/ndt/gfu294 Advance Access publication 30 September 2014
Original Articles Disease burden and risk profile in referred patients with moderate chronic kidney disease: composition of the German Chronic Kidney Disease (GCKD) cohort Florian Kronenberg8 and Kai-Uwe Eckardt1 for the GCKD study investigators 1
Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, FAU, Erlangen, Germany, 2Department of
Medical Informatics, Biometry and Epidemiology, University of Erlangen-Nürnberg, Erlangen, Germany, 3Department of Medical Biometry, Informatics, and Epidemiology, (IMBIE), University of Bonn, Bonn, Germany, 4Division of Nephrology, University of Freiburg, Freiburg, Germany, 5Department of Internal Medicine III, University Hospital Jena, Jena, Germany, 6Department of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany, 7Division of Nephrology, Department of Medicine, University Hospital of Würzburg, Würzburg, Germany and 8Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
Correspondence and offprint requests to: Kai-Uwe Eckardt; E-mail: [email protected]
A B S T R AC T Background. A main challenge for targeting chronic kidney disease (CKD) is the heterogeneity of its causes, co-morbidities and outcomes. Patients under nephrological care represent an important reference population, but knowledge about their characteristics is limited. Methods. We enrolled 5217 carefully phenotyped patients with moderate CKD [estimated glomerular filtration rate (eGFR) 30–60 mL/min per 1.73 m2 or overt proteinuria at higher eGFR] under routine care of nephrologists into the German Chronic Kidney Disease (GCKD) study, thereby establishing the currently worldwide largest CKD cohort. Results. The cohort has 60% men, a mean age (±SD) of 60 ± 12 years, a mean eGFR of 47 ± 17 mL/min per 1.73 m2 and a median (IQR) urinary albumin/creatinine ratio of 51 (9–392) mg/g. Assessment of causes of CKD revealed a high degree of uncertainty, with the leading cause unknown in 20% and frequent suspicion of multifactorial pathogenesis. Thirtyfive per cent of patients had diabetes, but only 15% were considered to have diabetic nephropathy. Cardiovascular disease prevalence was high (32%, excluding hypertension); prevalent risk factors included smoking (59% current or former
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
smokers) and obesity (43% with BMI >30). Despite widespread use of anti-hypertensive medication, only 52% of the cohort had an office blood pressure 60 mL/ min per 1.73 m2 and ‘overt’ albuminuria/proteinuria as defined by any of the four following thresholds of urinary albumin or protein excretion: urinary albumin/creatinine >300 mg/g, albuminuria >300 mg/day, urinary protein/creatinine >500 mg/g, or proteinuria >500 mg/day. Screening laboratory values were taken from local laboratories and the GFR defining eligibility was estimated using a locally implemented equation, usually the 4-variable Modification of Diet in Renal Disease (MDRD) formula [20]. Exclusion criteria were solid organ or bone marrow transplantation, active malignancy within 24 months prior to screening, heart failure New York Heart Association Stage IV, legal attendance or inability to provide consent. In addition, patients with non-Caucasian ethnicity were excluded, since they represent a relatively small, heterogeneous group in Germany. Enrolment Between March 2010 and March 2012, 5298 patients were enrolled. Eighty-one patients were excluded from final analysis because of invalid informed consent (n = 1), data loss (n = 2) or the presence of exclusion criteria at the time of enrolment (n = 78), resulting in a final cohort of 5217 patients. Of these, 4775 patients (91.5%) were enrolled on the basis of an eGFR between 30 and 60 mL/min per 1.73 m2 and 442 patients (8.5%) on the basis of an eGFR >60 mL/min per m2 and overt proteinuria. Baseline visits All patients were met by a trained and certified study team in the practice of the nephrologist or in outpatient units of the regional centres. Resting blood pressure was measured thrice in upright position after 3 min sitting time using a standardized device (Omron M5 Professional devices) and the mean is reported. Information was collected on sociodemographic factors, medical and family history, and medications ( prescribed drugs and over the counter drugs). Validated instruments were used to assess health-related quality of life [21], symptoms of heart failure [22], angina pectoris [23] and intermittent claudication [24]. Disease, co-morbidity and other parameter definitions were used according to international standards (see Supplementary Table S1). Plasma, serum, blood and spot-urine samples were collected, processed and shipped frozen to a central laboratory for routine clinical chemistry of a core set of parameters (Synlab; Heidelberg, Germany), Hb and HbA1C measurements (Central Lab, University Hospital Erlangen, Germany), DNA extraction and storage for future analyses (Central Biobank, University Hospital Erlangen). Laboratory parameters presented throughout this article were all measured using constant methodology. Serum creatinine was analysed using an IDMS traceable methodology (Creatinine plus, Roche). Cystatin C was measured using Tina-quant, Roche. GFR values were calculated using the MDRD IV formula [20] as defined in the study protocol, and creatinine
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particular, CKD has been recognized as a major cardiovascular risk factor [4]. Despite the importance of CKD, the number of randomized clinical trials in CKD patients remains small [5]. The heterogeneity of CKD is a major challenge in this respect. While CKD may be relatively stable and benign in some patients, it can be rapidly progressive and associated with many adverse consequences in others. Novel therapeutic strategies are unlikely to be successful unless sub-groups of patients can be identified that are relatively homogenous with respect to the underlying disease, the dominating pathomechanisms and the risk for disease progression and complication development. The reduction in glomerular filtration rate (GFR) and the level of albuminuria and proteinuria are associated with poor prognosis, but otherwise relatively little is yet known about determinants of the course of CKD [3, 6, 7]. Several studies have shown that CKD patients under the care of nephrologists have a better prognosis than patients not receiving specialized care [8–10]. This is despite the fact that specific therapies to target CKD are very limited, suggesting that a combination of aspects of nephrological management and complication awareness rather than single interventions are likely to impact on CKD prognosis. The better prognosis of patients cared for by nephrologists suggests that novel therapies need to be validated against the benchmark of existing nephrological care. However, while much progress has been made in characterizing individuals with CKD in general population cohorts, comparatively little remains known about characteristics of CKD patients under nephrological care. The Chronic Renal Insufficiency Cohort (CRIC) is a large US cohort of 3612 patients with CKD recruited in seven renal centres with a pre-defined composition, aiming for an equal gender distribution and certain proportions of patients with different ethnicities and in different age groups, both in the absence and presence of diabetes mellitus [11, 12]. A similar study is being conducted in Japan [13]. Several other, smaller cohorts with CKD of variable severity have been established in other countries [14–18]. We have recently enrolled >5200 patients treated by nephrologists into the German Chronic Kidney Disease (GCKD) study, a long-term observational cohort study [19]. Exclusion criteria were deliberately kept unrestrictive and we chose not to predefine cohort composition to reflect the full spectrum of patients under nephrological care. Here we report characteristics of enrolled patients to define the existing risk factors, disease burden and perspectives for improved strategies of care.
and cystatin C based Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formulas [25, 26]. Workflows to track sample processing, transportation and storage are quality assured and supported by a dedicated biobank management system [27]. Data collection procedures were monitored by an internal quality control panel that was advised by external reviewers. Patient interviews were recorded and audited for quality control.
Demographic and clinical characteristics The mean age at baseline was 60.1 ± 12.0 years. Sixty per cent were male and 35% had diabetes mellitus (39% of men and 29% of women). Baseline demographic and clinical characteristics for male and female patients with and without diabetes are shown in Table 1. Frequency distributions of age categories according to gender and the absence or presence of diabetes are shown in Supplementary Figure S1. The proportion of patients with a positive family history for cardiovascular disease, diabetes and renal disease was large. Among parents, grandparents or siblings, half were reported to have diabetes, three-fourths hypertension and slightly more than one-third stroke or myocardial infarction, respectively. Among this group of relatives 28% had at least one family member with CKD and 7.8% with renal failure; 5.9% requiring dialysis and 1.6% treated with a renal transplant. Almost 60% of patients in the whole cohort were either current or former smokers, this proportion being lowest in women with diabetes (42%) and highest in men with diabetes (75%). The mean body mass index (BMI) for the entire cohort was 29.8 kg/m2 ranging from a mean value of 28.1 kg/m2 in women without diabetes to 33.4 kg/m2 in women with diabetes. Overall, 43% of enrolled patients had a BMI >30 kg/m2. Mean blood pressure was 139.5/79.3 mmHg. In only slightly more than one quarter it was 25 to ≤30 (kg/m²), n; % 378 115 BMI ≤25 kg/m2, n; % Pulse and blood pressure Pulse (bpm), mean; SD 70.6 SBP (mmHg), mean; SD 143.8 DBP (mmHg), mean; SD 76.4 MAP (mmHg), mean; SD 98.9 BP < 130/80 mmHg, n; % 275 BP < 140/90 mmHg, n; % 529 Kidney function measures Serum creatinine (mg/dL), 1.7 mean; SD Serum cystatin C (mg/L), 1.6 mean; SD 45.6 eGFR (MDRD) (mL/min × 1.73 m2), mean; SD eGFR ≥ 60, n; % 155 eGFR 45–59, n; % 422 eGFR 30–44, n; % 497 eGFR < 30, n; % 136 U-albumin/creatinine ratio, 76.4 median; IQR (UACR; mg/g) UACR < 30, n; % 454 UACR 30–300, n; % 359 UACR > 300, n; % 394 Anti-hypertensives and diuretics ACE-Inhibitors, n; % 586 AII receptor blockers (ARB), n; % 395 ACE-Inhibitors + ARB 92 combined, n; % ACE-Inhibitors or ARB, n; % 1073 Diuretics, n; % 846 >thiazides, n; % 221 >aldosterone antagonists, n; % 140 >loop diuretics, n; % 715 Calcium channel blockers, n; % 556 Beta blockers, n; % 854 Renal biopsy, n; % 163
SD or %a 7.7
n or meana 58.3
SD or %a 12.5
Diabetics (n = 615)
n or meana 64.0
SD or %a 8.7
Non-diabetics (n = 1470) n or meana 56.7
SD or %a 13.6
(n = 5217)
n or meana 60.1
SD or %a 12.0
37.6 33.6 74.9 61.8 24.6 6.2 4.6 0.3
598 657 1105 652 436 136 113 26
33.8 37.1 72.7 38.5 25.8 7.2 5.9 1.4
236 244 414 381 173 52 29 5
40.8 42.8 78.9 66.3 31.5 8.5 4.7 0.8
554 586 1018 666 446 142 110 49
39.7 42.2 78.2 48.3 32.9 9.7 7.5 3.3
1816 1867 3277 2388 1312 406 308 84
37.2 38.4 75.6 50.1 28.2 7.8 5.9 1.6
14.9 60.2 24.9 79.6
329 900 667 1343
17.4 47.5 35.2 72.5
87 171 356 487
14.2 27.9 58.0 80.1
229 433 802 1017
15.6 29.6 54.8 70.6
828 2242 2131 3813
15.9 43.1 41.0 74.5
6.6 18.7 5.7 59.5 31.1 9.5
177 89.8 28.6 587 893 406
6.9 16.2 4.7 31.1 47.4 21.5
162.9 88.7 33.4 409 137 64
6.7 19.5 7.0 67.1 22.5 10.5
164.0 75.4 28.1 474 478 499
6.8 16.4 6.0 32.7 32.9 34.4
171.2 87.6 29.8 2193 1886 1084
9.2 19.2 6.0 42.5 36.5 21.0
12.4 21.3 12 13.4 22.5 43.3
69.2 140.3 81.2 100.9 443 954
12.2 19.2 11.5 12.6 23.4 50.4
72.6 138·6 75.9 96.8 191 333
13.1 21.1 11.6 12.9 31.5 55.0
71.3 135.2 80.6 98.8 466 883
11.5 19.9 11.1 12.5 31.9 60.4
70.5 139.5 79.3 99.3 1375 2699
12.2 20.4 11.7 12.8 26.5 52.1
0.5
1.7
0.5
1.3
0.4
1.3
0.4
1.5
0.5
0.5
1.5
0.5
1.6
0.5
1.4
0.5
1.5
0.5
15.8
47.3
16.0
43.9
15.8
49.3
18.4
47.1
16.7
12.8 34.9 41.1 11.2 11.1–537.9
303 668 743 175 76.9
16.0 35.4 39.3 9.3 10.9–484.0
72 177 269 87 21.1
11.9 29.3 44.5 14.4 6.6–124.9
308 484 536 129 33.9
21.1 838 33.2 1751 36.8 2045 8.9 527 7.9–300.5 50.9
16.2 33.9 39.6 10.2 8.9–391.7
37.6 29.7 32.6
698 594 585
37.2 31.7 31.2
337 157 104
56.4 26.3 17.4
702 383 362
48.5 26.5 25.0
2191 1493 1445
42.7 29.1 28.2
48.5 32.7 7.6
906 650 152
50.6 36.3 8.5
259 195 27
43.1 32.5 4.5
515 461 61
40.0 35.8 4.7
2266 1701 332
46.3 34.8 6.8
88.8 69.8 18.3 11.6 59.1 46 70.6 13.3
1708 797 213 129 591 638 956 662
95.4 44.5 11.9 7.2 33.0 35.6 53.4 34.8
481 412 96 66 341 240 407 69
80.1 68.6 16.0 11.0 56.7 39.9 67.7 11.2
1037 505 113 92 352 334 642 472
80.5 39.2 8.8 7.1 27.3 25.9 49.8 32.1
4299 2560 643 427 1999 1768 2859 1366
87.9 52.4 13.2 8.7 40.9 36.2 58.5 26.2
a All values are mean and SD with the exception of values for urinary albumin/creatinine ratio, which are presented as median and interquartile range. The number of missing values was 60 years w CVD, n; % Kidney function measures Serum creatinine (mg/dL), mean; SD Serum cystatin C (mg/L), mean; SD eGFR (MDRD) (mL/min × 1.73 m2), mean; SD U-albumin/creatinine ratio (UACR; mg/g), median; IQR Renal biopsy, n; % Glomerulopathy as dominant disease, n; % Disease cause Diabetic nephropathy, n; % Vascular nephropathy, n; % Systemic disease, n; % Primary glomerulopathy, n; % Interstitial nephropathy, n; % Acute kidney injury, n; % Single kidney, n; % Hereditary kidney disease, n; % Obstructive nephropathy, n; % Miscellaneous, n; % Undetermined, n; %
Overt proteinuria at eGFR >60 (n = 442)
0.3 0.3 21.4 261.6–1338.1 61.5 52.7 8.4 5.7 13.4 52.7 0.9 0.5 1.1 2.5 1.1 0.9 12.9
Overt albuminuria/proteinuria was defined by any of the four following thresholds of urinary albumin or protein excretion: urinary albumin/creatinine >300 mg/g, albuminuria >300 mg/day, urinary protein/creatinine >500 mg/g, or proteinuria >500 mg/day. The number of missing values was 60 mL/min × 1.73 m2
445
ORIGINAL ARTICLE
Patient knowledge about kidney disease and treatment by nephrologist Figure 3 illustrates how long the presence of kidney disease was known to the patient (from patient questionnaire) and how long patients were treated by a nephrologist (from treating nephrologist questionnaire). Approximately 80% of the patients were under nephrological care for >1 year and >50% for at least 3 years. The time distribution of kidney disease awareness was similar. Cardiovascular disease burden The burden of cardiovascular disease at the study onset is substantial. Apart from the presence of arterial hypertension in >95% of patients enrolled, 32% reported at least one of the events specified in Table 4, or had cardiac valve replacement or aortic aneurysm surgery. In patients with diabetes, the number of events in most event categories was at least approximately 2-fold higher. The cardiovascular disease burden was lower in those patients enrolled with overt proteinuria and eGFR >60 mL/min per 1.73 m2 when compared with patients with eGFR ≤60 mL/min per 1.73 m2 (Table 2).
DISCUSSION The analysis of patient characteristics in this large CKD cohort, where approximately 80% of patients have been under nephrological care for at least 1 year, illustrates important challenges for improving the outcome of patients with CKD.
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In particular, we observed a remarkable uncertainty about the underlying causes of CKD, a high prevalence of comorbidities and insufficient blood pressure control in many patients. In many patients enrolled, the treating nephrologist assumed a multifactorial aetiology of kidney disease; in almost 20% the leading cause was unknown. Twenty-six per cent of the entire GCKD cohort had undergone a renal biopsy. Renal biopsies were largely confined to patients in whom either primary glomerulopathy or renal involvement in systemic diseases was considered as the most probable cause of CKD. Only 17% in all other disease categories had been biopsied, indicating that diagnostic assessment was mostly made on clinical, biochemical and imaging grounds. Apart from primary glomerulopathy, the two other most frequent categories of leading causes of CKD were diabetic and vascular nephropathy, which are considered as leading causes of CKD worldwide [1, 2]. However, in the absence of specific diagnostic tests and given the low biopsy rate, the diagnostic certainty for both entities may be low. Interestingly, in less than half of the patients with diabetes, diabetic nephropathy was considered to be the leading cause of CKD. Patients who were categorized as having diabetic nephropathy had higher levels of albuminuria than those with diabetes that were not considered to have diabetic nephropathy, presumably reflecting the traditional view that proteinuria is a hallmark of diabetic nephropathy. On the other hand, more than one-third had an UACR below 30 mg/g, which is consistent with studies showing that a relevant proportion of patients with diabetic nephropathy has low levels of albuminuria [29, 30]. Obviously, diabetes is an important
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F I G U R E 2 : Presumed causes of CKD and the percentage of patients with diabetes and hypertension in whom a specific diagnostic entity was considered as the leading cause. Bars show number of patients in whom a disease entity is considered as the leading cause (light grey) or as either leading or additional cause (dark grey).
Treating nephrologists were requested to identify the presumed leading cause and additional contributing causes of kidney disease on a CRF form with tic boxes with pre-defined disease categories. Numbers of patients with specific causes of kidney diseases and their proportion are given in the first two columns. Numbers of patients in whom additional contributing causes were specified are presented for each category of leading cause in columns 3–14. Column 15 gives the total number of patients in whom a specific disease entity was considered as either the leading or a contributing cause. Renal biopsy rates are presented in column 16.
3.9 7.8 74.6 80.7 16.0 10.8 5.8 8.4 4.7 2.2 6.4 1408 2157 612 1185 450 244 328 233 381 239 1054 274 480 398 801 108 310 191 787 95 130 32 33 37 100 34 181 48 79 10 35 736 318 1963 3254 17 53 3 11 15 5 4 3 9 0 74 194 24 41 7 23 20 7 9 6 0 1 116 254 1 2 0 1 1 0 0 0 0 0 13 18 17 37 0 7 13 1 0 5 12 1 98 191 22 35 15 14 13 0 4 0 4 0 72 179 12 50 11 12 0 4 0 1 8 0 127 225 10 24 53 0 1 2 3 3 1 0 110 207 18 52 0 28 15 2 4 5 2 1 67 194 201 0 32 82 36 14 16 8 23 5 541 958 754 14.5 0 1199 23.0 171 418 8.0 14 978 18.7 40 225 4.3 20 65 1.2 9 137 2.6 5 215 4.1 8 127 2.4 4 45 0.9 5 1054 20.2 378 5217 100.0 654 Leading cause of CKD Diabetic nephropathy Vascular nephropathy Systemic disease Primary glomerulopathy Interstitial nephropathy Acute kidney injury Single kidney Hereditary kidney disease Obstructive nephropathy Miscellaneous Undetermined Total additional cause (n)
n
%
Diabetic nephropathy
Vascular nephropathy
Systemic disease
Primary glomerulopathy
Interstitial Acute Single nephropathy kidney injury kidney
Hereditary kidney disease
Obstructive Miscellaneous Any nephropathy
Biopsy Total leading or rate (%) None additional cause (n) Additional causes of CKD
Table 3. Distribution of diagnoses for underlying cause of CKD
ORIGINAL ARTICLE
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Characteristics of referred CKD patients
contributor to the disease burden in CKD patients far beyond those with presumed diabetic nephropathy. The diabetes prevalence of 35% in GCKD is more than twice as high as in Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten THerapie chronischer ERkrankungen in der älteren Bevölkerung (ESTHER) [31], a general population-based health examination in Germany with similar age distribution (50–74 years; mean age 62.1 years) and almost 4-fold higher than in Study of Health in Pomerania, a general population-based study in northern Germany [32]. It is only slightly higher, however, than the 32% prevalence in individuals with CKD in the US National Health and Nutritional Examination Survey (NHANES) [33], suggesting that the proportion of diabetics in CKD populations with and without nephrological care in Europe and the USA is similar. Analogous considerations as for patients with diabetes hold true for the large group of patients considered to have vascular nephropathy. The high frequency of arterial hypertension in all diagnostic categories illustrates a lack of discriminative potency. Together with the low biopsy rate in patients with the presumed diagnosis of vascular nephropathy (8%), this suggests a diagnosis on the basis of clinical exclusion of other causes in most cases. The apparent uncertainty in diagnosis and the multifactorial nature of CKD likely reflect important hurdles for testing and implementing novel treatment strategies that target specific pathomechanisms. Although the GCKD study was not designed to identify risk factors for CKD, several characteristics of the patients enrolled provide indirect evidence for predisposing factors in addition to diabetes and arterial hypertension. First, we observed a gender imbalance, with 60% male study participants. This is consistent with male predominance in patients on dialysis [34] but stands in contrast with studies assessing CKD prevalence in the general population, where the proportion of females is usually larger [31, 33, 35–38]. The reasons for this difference could include a lower detection rate, as well as gender inequity in referral practice or recruitment bias. Male gender is associated with a higher prevalence of cardiovascular disease (CVD), which might indirectly cause an increased association with CKD. However, the proportion of male patients among those enrolled with overt proteinuria and no significant reduction in GFR, in whom primary renal disease was frequent, was also ∼60%. Secondly, we observed a significant degree of obesity in both men and women. Even in patients without diabetes, approximately one-third had a BMI above 30 kg/m2. Although the study recruited across different regions within Germany, there was no centre effect on BMI. Moreover, BMI values observed in the GCKD study are consistent with those in recently reported CKD registry data [39], but higher than in the general population [32, 37, 38, 40]. This corroborates evidence that obesity may affect kidney function beyond its effect on glucose metabolism and systemic atherosclerosis [41, 42]. Third, almost 60% of the GCKD study participants are current or former smokers, compared with 60 mL/min per m2, which had a much smaller proportion of patients with diabetes and cardiovascular disease manifestation.
F I G U R E 3 : Patient awareness about kidney disease and treatment period by nephrologist. Bars indicate number of patients in each time
Table 4. Cardiovascular disease burden in patients enrolled into the GCKD study, stratified by gender and presence and absence of diabetes mellitus
ORIGINAL ARTICLE
Male
Female
Total
Diabetics (n = 1229)
Non-diabetics (n = 1903)
Diabetics (n = 615)
Non-diabetics (n = 1470)
(n = 5217)
n or mean
SD or %
n or mean
SD or %
n or mean
SD or %
n or mean
SD or %
n or mean
SD or %
116 526 642 1214 30 432 259 175 312 175 148 37 17 204 94 19 44 106
39.7 56.1 52.2 98.8 2.4 35.2 21.1 14.2 25.4 14.2 12.0 3.0 1.4 16.6 7.6 10.5 3.6 8.6
152 419 571 1837 36 345 197 118 238 178 146 51 31 146 44 16 48 66
16.7 42.1 30.0 96.5 1.9 18.1 10.4 6.2 12.5 9.4 7.7 2.7 1.6 7.7 2.3 0.8 2.5 3.5
51 173 224 590 18 134 69 37 94 64 56 13 2 62 14 2 18 38
30.4 38.8 36.4 95.9 2.9 21.8 11.2 6.0 15.3 10.4 9.1 2.1 0.3 10.1 2.3 0.3 2.9 6.2
68 175 243 1319 18 128 58 17 99 93 80 17 10 81 25 7 32 30
8.9 24.8 16.5 89.7 1.2 8.7 3.9 1.2 6.7 6.3 5.4 1.2 0.7 5.5 1.7 0.5 2.2 2.0
387 1293 1680 4960 102 1039 583 347 743 510 430 118 60 493 177 44 142 240
18.2 41.9 32.2 95.1 2.0 19.9 11.2 6.7 14.2 9.8 8.2 2.3 1.2 9.4 3.4 0.8 2.7 4.6
a
Cardiovascular disease Patients ≤60 years w CVD, n; % Patients > 60 years w CVD, n; % All, n; % Arterial hypertension, n; % Cardiac valve replacement, n; % Coronary artery disease, n; % MI, n; % Bypass surgery, n; % PTCA, n; % Cerebrovascular disease, n; % Stroke, n; % Carotic surgery, n; % Carotic intervention, n; % Peripheral vascular disease, n; % Amputations, n; % Y-graft, n; % Other types of surgery, n; % PTA, n; % a
The composite of cardiovascular disease includes all patients with one or more of the following: cardiac valve replacement, aortic aneurysm, coronary artery disease, cerebrovascular disease or peripheral artery disease.
These observations are consistent with other data suggesting adverse effects of smoking on kidney function independent of atherosclerosis [43]. Fourth, family history provided evidence for familial aggregation of CKD. Approximately 30% of patients reported that at least one of their parents, grandparents or siblings had CKD and 7.5% were either on dialysis or had a renal transplant. Studies in dialysis patients also found evidence for familial aggregation of renal failure [44, 45]. Apart from adult polycystic kidney disease, monogenic kidney diseases are so far considered to be rare, but evidence for polygenic predisposition for CKD is emerging [46, 47]. Blood pressure control is considered a mainstay of CKD management. Although optimal blood pressure targets in CKD patients remain controversial [48, 49], the most recent
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guidelines propose maintaining blood pressure ≤140/90 mmHg in CKD patients with UACR below 30 mg/g and ≤130/80 mmHg in patients with UACR above 30 mg/g [3, 48]. Given that only slightly more than 50% of patients in GCKD had an office blood pressure below 140/90 mmHg and only slightly more than a quarter below 130/80 mmHg, it is obvious that there is a large gap between targets and clinical reality. This is consistent with other CKD cohort studies [12, 13, 15–18] and suggests a potential for improvement, but also illustrates the difficulties of blood pressure control in CKD. On the other hand, in ESTHER systolic blood pressure was similar and the percentage of individuals with blood pressure below 130/80 mmHg was much smaller, i.e.
Original Articles Disease burden and risk profile in referred patients with moderate chronic kidney disease: composition of the German Chronic Kidney Disease (GCKD) cohort Florian Kronenberg8 and Kai-Uwe Eckardt1 for the GCKD study investigators 1
Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, FAU, Erlangen, Germany, 2Department of
Medical Informatics, Biometry and Epidemiology, University of Erlangen-Nürnberg, Erlangen, Germany, 3Department of Medical Biometry, Informatics, and Epidemiology, (IMBIE), University of Bonn, Bonn, Germany, 4Division of Nephrology, University of Freiburg, Freiburg, Germany, 5Department of Internal Medicine III, University Hospital Jena, Jena, Germany, 6Department of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany, 7Division of Nephrology, Department of Medicine, University Hospital of Würzburg, Würzburg, Germany and 8Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
Correspondence and offprint requests to: Kai-Uwe Eckardt; E-mail: [email protected]
A B S T R AC T Background. A main challenge for targeting chronic kidney disease (CKD) is the heterogeneity of its causes, co-morbidities and outcomes. Patients under nephrological care represent an important reference population, but knowledge about their characteristics is limited. Methods. We enrolled 5217 carefully phenotyped patients with moderate CKD [estimated glomerular filtration rate (eGFR) 30–60 mL/min per 1.73 m2 or overt proteinuria at higher eGFR] under routine care of nephrologists into the German Chronic Kidney Disease (GCKD) study, thereby establishing the currently worldwide largest CKD cohort. Results. The cohort has 60% men, a mean age (±SD) of 60 ± 12 years, a mean eGFR of 47 ± 17 mL/min per 1.73 m2 and a median (IQR) urinary albumin/creatinine ratio of 51 (9–392) mg/g. Assessment of causes of CKD revealed a high degree of uncertainty, with the leading cause unknown in 20% and frequent suspicion of multifactorial pathogenesis. Thirtyfive per cent of patients had diabetes, but only 15% were considered to have diabetic nephropathy. Cardiovascular disease prevalence was high (32%, excluding hypertension); prevalent risk factors included smoking (59% current or former
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
smokers) and obesity (43% with BMI >30). Despite widespread use of anti-hypertensive medication, only 52% of the cohort had an office blood pressure 60 mL/ min per 1.73 m2 and ‘overt’ albuminuria/proteinuria as defined by any of the four following thresholds of urinary albumin or protein excretion: urinary albumin/creatinine >300 mg/g, albuminuria >300 mg/day, urinary protein/creatinine >500 mg/g, or proteinuria >500 mg/day. Screening laboratory values were taken from local laboratories and the GFR defining eligibility was estimated using a locally implemented equation, usually the 4-variable Modification of Diet in Renal Disease (MDRD) formula [20]. Exclusion criteria were solid organ or bone marrow transplantation, active malignancy within 24 months prior to screening, heart failure New York Heart Association Stage IV, legal attendance or inability to provide consent. In addition, patients with non-Caucasian ethnicity were excluded, since they represent a relatively small, heterogeneous group in Germany. Enrolment Between March 2010 and March 2012, 5298 patients were enrolled. Eighty-one patients were excluded from final analysis because of invalid informed consent (n = 1), data loss (n = 2) or the presence of exclusion criteria at the time of enrolment (n = 78), resulting in a final cohort of 5217 patients. Of these, 4775 patients (91.5%) were enrolled on the basis of an eGFR between 30 and 60 mL/min per 1.73 m2 and 442 patients (8.5%) on the basis of an eGFR >60 mL/min per m2 and overt proteinuria. Baseline visits All patients were met by a trained and certified study team in the practice of the nephrologist or in outpatient units of the regional centres. Resting blood pressure was measured thrice in upright position after 3 min sitting time using a standardized device (Omron M5 Professional devices) and the mean is reported. Information was collected on sociodemographic factors, medical and family history, and medications ( prescribed drugs and over the counter drugs). Validated instruments were used to assess health-related quality of life [21], symptoms of heart failure [22], angina pectoris [23] and intermittent claudication [24]. Disease, co-morbidity and other parameter definitions were used according to international standards (see Supplementary Table S1). Plasma, serum, blood and spot-urine samples were collected, processed and shipped frozen to a central laboratory for routine clinical chemistry of a core set of parameters (Synlab; Heidelberg, Germany), Hb and HbA1C measurements (Central Lab, University Hospital Erlangen, Germany), DNA extraction and storage for future analyses (Central Biobank, University Hospital Erlangen). Laboratory parameters presented throughout this article were all measured using constant methodology. Serum creatinine was analysed using an IDMS traceable methodology (Creatinine plus, Roche). Cystatin C was measured using Tina-quant, Roche. GFR values were calculated using the MDRD IV formula [20] as defined in the study protocol, and creatinine
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particular, CKD has been recognized as a major cardiovascular risk factor [4]. Despite the importance of CKD, the number of randomized clinical trials in CKD patients remains small [5]. The heterogeneity of CKD is a major challenge in this respect. While CKD may be relatively stable and benign in some patients, it can be rapidly progressive and associated with many adverse consequences in others. Novel therapeutic strategies are unlikely to be successful unless sub-groups of patients can be identified that are relatively homogenous with respect to the underlying disease, the dominating pathomechanisms and the risk for disease progression and complication development. The reduction in glomerular filtration rate (GFR) and the level of albuminuria and proteinuria are associated with poor prognosis, but otherwise relatively little is yet known about determinants of the course of CKD [3, 6, 7]. Several studies have shown that CKD patients under the care of nephrologists have a better prognosis than patients not receiving specialized care [8–10]. This is despite the fact that specific therapies to target CKD are very limited, suggesting that a combination of aspects of nephrological management and complication awareness rather than single interventions are likely to impact on CKD prognosis. The better prognosis of patients cared for by nephrologists suggests that novel therapies need to be validated against the benchmark of existing nephrological care. However, while much progress has been made in characterizing individuals with CKD in general population cohorts, comparatively little remains known about characteristics of CKD patients under nephrological care. The Chronic Renal Insufficiency Cohort (CRIC) is a large US cohort of 3612 patients with CKD recruited in seven renal centres with a pre-defined composition, aiming for an equal gender distribution and certain proportions of patients with different ethnicities and in different age groups, both in the absence and presence of diabetes mellitus [11, 12]. A similar study is being conducted in Japan [13]. Several other, smaller cohorts with CKD of variable severity have been established in other countries [14–18]. We have recently enrolled >5200 patients treated by nephrologists into the German Chronic Kidney Disease (GCKD) study, a long-term observational cohort study [19]. Exclusion criteria were deliberately kept unrestrictive and we chose not to predefine cohort composition to reflect the full spectrum of patients under nephrological care. Here we report characteristics of enrolled patients to define the existing risk factors, disease burden and perspectives for improved strategies of care.
and cystatin C based Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formulas [25, 26]. Workflows to track sample processing, transportation and storage are quality assured and supported by a dedicated biobank management system [27]. Data collection procedures were monitored by an internal quality control panel that was advised by external reviewers. Patient interviews were recorded and audited for quality control.
Demographic and clinical characteristics The mean age at baseline was 60.1 ± 12.0 years. Sixty per cent were male and 35% had diabetes mellitus (39% of men and 29% of women). Baseline demographic and clinical characteristics for male and female patients with and without diabetes are shown in Table 1. Frequency distributions of age categories according to gender and the absence or presence of diabetes are shown in Supplementary Figure S1. The proportion of patients with a positive family history for cardiovascular disease, diabetes and renal disease was large. Among parents, grandparents or siblings, half were reported to have diabetes, three-fourths hypertension and slightly more than one-third stroke or myocardial infarction, respectively. Among this group of relatives 28% had at least one family member with CKD and 7.8% with renal failure; 5.9% requiring dialysis and 1.6% treated with a renal transplant. Almost 60% of patients in the whole cohort were either current or former smokers, this proportion being lowest in women with diabetes (42%) and highest in men with diabetes (75%). The mean body mass index (BMI) for the entire cohort was 29.8 kg/m2 ranging from a mean value of 28.1 kg/m2 in women without diabetes to 33.4 kg/m2 in women with diabetes. Overall, 43% of enrolled patients had a BMI >30 kg/m2. Mean blood pressure was 139.5/79.3 mmHg. In only slightly more than one quarter it was 25 to ≤30 (kg/m²), n; % 378 115 BMI ≤25 kg/m2, n; % Pulse and blood pressure Pulse (bpm), mean; SD 70.6 SBP (mmHg), mean; SD 143.8 DBP (mmHg), mean; SD 76.4 MAP (mmHg), mean; SD 98.9 BP < 130/80 mmHg, n; % 275 BP < 140/90 mmHg, n; % 529 Kidney function measures Serum creatinine (mg/dL), 1.7 mean; SD Serum cystatin C (mg/L), 1.6 mean; SD 45.6 eGFR (MDRD) (mL/min × 1.73 m2), mean; SD eGFR ≥ 60, n; % 155 eGFR 45–59, n; % 422 eGFR 30–44, n; % 497 eGFR < 30, n; % 136 U-albumin/creatinine ratio, 76.4 median; IQR (UACR; mg/g) UACR < 30, n; % 454 UACR 30–300, n; % 359 UACR > 300, n; % 394 Anti-hypertensives and diuretics ACE-Inhibitors, n; % 586 AII receptor blockers (ARB), n; % 395 ACE-Inhibitors + ARB 92 combined, n; % ACE-Inhibitors or ARB, n; % 1073 Diuretics, n; % 846 >thiazides, n; % 221 >aldosterone antagonists, n; % 140 >loop diuretics, n; % 715 Calcium channel blockers, n; % 556 Beta blockers, n; % 854 Renal biopsy, n; % 163
SD or %a 7.7
n or meana 58.3
SD or %a 12.5
Diabetics (n = 615)
n or meana 64.0
SD or %a 8.7
Non-diabetics (n = 1470) n or meana 56.7
SD or %a 13.6
(n = 5217)
n or meana 60.1
SD or %a 12.0
37.6 33.6 74.9 61.8 24.6 6.2 4.6 0.3
598 657 1105 652 436 136 113 26
33.8 37.1 72.7 38.5 25.8 7.2 5.9 1.4
236 244 414 381 173 52 29 5
40.8 42.8 78.9 66.3 31.5 8.5 4.7 0.8
554 586 1018 666 446 142 110 49
39.7 42.2 78.2 48.3 32.9 9.7 7.5 3.3
1816 1867 3277 2388 1312 406 308 84
37.2 38.4 75.6 50.1 28.2 7.8 5.9 1.6
14.9 60.2 24.9 79.6
329 900 667 1343
17.4 47.5 35.2 72.5
87 171 356 487
14.2 27.9 58.0 80.1
229 433 802 1017
15.6 29.6 54.8 70.6
828 2242 2131 3813
15.9 43.1 41.0 74.5
6.6 18.7 5.7 59.5 31.1 9.5
177 89.8 28.6 587 893 406
6.9 16.2 4.7 31.1 47.4 21.5
162.9 88.7 33.4 409 137 64
6.7 19.5 7.0 67.1 22.5 10.5
164.0 75.4 28.1 474 478 499
6.8 16.4 6.0 32.7 32.9 34.4
171.2 87.6 29.8 2193 1886 1084
9.2 19.2 6.0 42.5 36.5 21.0
12.4 21.3 12 13.4 22.5 43.3
69.2 140.3 81.2 100.9 443 954
12.2 19.2 11.5 12.6 23.4 50.4
72.6 138·6 75.9 96.8 191 333
13.1 21.1 11.6 12.9 31.5 55.0
71.3 135.2 80.6 98.8 466 883
11.5 19.9 11.1 12.5 31.9 60.4
70.5 139.5 79.3 99.3 1375 2699
12.2 20.4 11.7 12.8 26.5 52.1
0.5
1.7
0.5
1.3
0.4
1.3
0.4
1.5
0.5
0.5
1.5
0.5
1.6
0.5
1.4
0.5
1.5
0.5
15.8
47.3
16.0
43.9
15.8
49.3
18.4
47.1
16.7
12.8 34.9 41.1 11.2 11.1–537.9
303 668 743 175 76.9
16.0 35.4 39.3 9.3 10.9–484.0
72 177 269 87 21.1
11.9 29.3 44.5 14.4 6.6–124.9
308 484 536 129 33.9
21.1 838 33.2 1751 36.8 2045 8.9 527 7.9–300.5 50.9
16.2 33.9 39.6 10.2 8.9–391.7
37.6 29.7 32.6
698 594 585
37.2 31.7 31.2
337 157 104
56.4 26.3 17.4
702 383 362
48.5 26.5 25.0
2191 1493 1445
42.7 29.1 28.2
48.5 32.7 7.6
906 650 152
50.6 36.3 8.5
259 195 27
43.1 32.5 4.5
515 461 61
40.0 35.8 4.7
2266 1701 332
46.3 34.8 6.8
88.8 69.8 18.3 11.6 59.1 46 70.6 13.3
1708 797 213 129 591 638 956 662
95.4 44.5 11.9 7.2 33.0 35.6 53.4 34.8
481 412 96 66 341 240 407 69
80.1 68.6 16.0 11.0 56.7 39.9 67.7 11.2
1037 505 113 92 352 334 642 472
80.5 39.2 8.8 7.1 27.3 25.9 49.8 32.1
4299 2560 643 427 1999 1768 2859 1366
87.9 52.4 13.2 8.7 40.9 36.2 58.5 26.2
a All values are mean and SD with the exception of values for urinary albumin/creatinine ratio, which are presented as median and interquartile range. The number of missing values was 60 years w CVD, n; % Kidney function measures Serum creatinine (mg/dL), mean; SD Serum cystatin C (mg/L), mean; SD eGFR (MDRD) (mL/min × 1.73 m2), mean; SD U-albumin/creatinine ratio (UACR; mg/g), median; IQR Renal biopsy, n; % Glomerulopathy as dominant disease, n; % Disease cause Diabetic nephropathy, n; % Vascular nephropathy, n; % Systemic disease, n; % Primary glomerulopathy, n; % Interstitial nephropathy, n; % Acute kidney injury, n; % Single kidney, n; % Hereditary kidney disease, n; % Obstructive nephropathy, n; % Miscellaneous, n; % Undetermined, n; %
Overt proteinuria at eGFR >60 (n = 442)
0.3 0.3 21.4 261.6–1338.1 61.5 52.7 8.4 5.7 13.4 52.7 0.9 0.5 1.1 2.5 1.1 0.9 12.9
Overt albuminuria/proteinuria was defined by any of the four following thresholds of urinary albumin or protein excretion: urinary albumin/creatinine >300 mg/g, albuminuria >300 mg/day, urinary protein/creatinine >500 mg/g, or proteinuria >500 mg/day. The number of missing values was 60 mL/min × 1.73 m2
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ORIGINAL ARTICLE
Patient knowledge about kidney disease and treatment by nephrologist Figure 3 illustrates how long the presence of kidney disease was known to the patient (from patient questionnaire) and how long patients were treated by a nephrologist (from treating nephrologist questionnaire). Approximately 80% of the patients were under nephrological care for >1 year and >50% for at least 3 years. The time distribution of kidney disease awareness was similar. Cardiovascular disease burden The burden of cardiovascular disease at the study onset is substantial. Apart from the presence of arterial hypertension in >95% of patients enrolled, 32% reported at least one of the events specified in Table 4, or had cardiac valve replacement or aortic aneurysm surgery. In patients with diabetes, the number of events in most event categories was at least approximately 2-fold higher. The cardiovascular disease burden was lower in those patients enrolled with overt proteinuria and eGFR >60 mL/min per 1.73 m2 when compared with patients with eGFR ≤60 mL/min per 1.73 m2 (Table 2).
DISCUSSION The analysis of patient characteristics in this large CKD cohort, where approximately 80% of patients have been under nephrological care for at least 1 year, illustrates important challenges for improving the outcome of patients with CKD.
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In particular, we observed a remarkable uncertainty about the underlying causes of CKD, a high prevalence of comorbidities and insufficient blood pressure control in many patients. In many patients enrolled, the treating nephrologist assumed a multifactorial aetiology of kidney disease; in almost 20% the leading cause was unknown. Twenty-six per cent of the entire GCKD cohort had undergone a renal biopsy. Renal biopsies were largely confined to patients in whom either primary glomerulopathy or renal involvement in systemic diseases was considered as the most probable cause of CKD. Only 17% in all other disease categories had been biopsied, indicating that diagnostic assessment was mostly made on clinical, biochemical and imaging grounds. Apart from primary glomerulopathy, the two other most frequent categories of leading causes of CKD were diabetic and vascular nephropathy, which are considered as leading causes of CKD worldwide [1, 2]. However, in the absence of specific diagnostic tests and given the low biopsy rate, the diagnostic certainty for both entities may be low. Interestingly, in less than half of the patients with diabetes, diabetic nephropathy was considered to be the leading cause of CKD. Patients who were categorized as having diabetic nephropathy had higher levels of albuminuria than those with diabetes that were not considered to have diabetic nephropathy, presumably reflecting the traditional view that proteinuria is a hallmark of diabetic nephropathy. On the other hand, more than one-third had an UACR below 30 mg/g, which is consistent with studies showing that a relevant proportion of patients with diabetic nephropathy has low levels of albuminuria [29, 30]. Obviously, diabetes is an important
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F I G U R E 2 : Presumed causes of CKD and the percentage of patients with diabetes and hypertension in whom a specific diagnostic entity was considered as the leading cause. Bars show number of patients in whom a disease entity is considered as the leading cause (light grey) or as either leading or additional cause (dark grey).
Treating nephrologists were requested to identify the presumed leading cause and additional contributing causes of kidney disease on a CRF form with tic boxes with pre-defined disease categories. Numbers of patients with specific causes of kidney diseases and their proportion are given in the first two columns. Numbers of patients in whom additional contributing causes were specified are presented for each category of leading cause in columns 3–14. Column 15 gives the total number of patients in whom a specific disease entity was considered as either the leading or a contributing cause. Renal biopsy rates are presented in column 16.
3.9 7.8 74.6 80.7 16.0 10.8 5.8 8.4 4.7 2.2 6.4 1408 2157 612 1185 450 244 328 233 381 239 1054 274 480 398 801 108 310 191 787 95 130 32 33 37 100 34 181 48 79 10 35 736 318 1963 3254 17 53 3 11 15 5 4 3 9 0 74 194 24 41 7 23 20 7 9 6 0 1 116 254 1 2 0 1 1 0 0 0 0 0 13 18 17 37 0 7 13 1 0 5 12 1 98 191 22 35 15 14 13 0 4 0 4 0 72 179 12 50 11 12 0 4 0 1 8 0 127 225 10 24 53 0 1 2 3 3 1 0 110 207 18 52 0 28 15 2 4 5 2 1 67 194 201 0 32 82 36 14 16 8 23 5 541 958 754 14.5 0 1199 23.0 171 418 8.0 14 978 18.7 40 225 4.3 20 65 1.2 9 137 2.6 5 215 4.1 8 127 2.4 4 45 0.9 5 1054 20.2 378 5217 100.0 654 Leading cause of CKD Diabetic nephropathy Vascular nephropathy Systemic disease Primary glomerulopathy Interstitial nephropathy Acute kidney injury Single kidney Hereditary kidney disease Obstructive nephropathy Miscellaneous Undetermined Total additional cause (n)
n
%
Diabetic nephropathy
Vascular nephropathy
Systemic disease
Primary glomerulopathy
Interstitial Acute Single nephropathy kidney injury kidney
Hereditary kidney disease
Obstructive Miscellaneous Any nephropathy
Biopsy Total leading or rate (%) None additional cause (n) Additional causes of CKD
Table 3. Distribution of diagnoses for underlying cause of CKD
ORIGINAL ARTICLE
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Characteristics of referred CKD patients
contributor to the disease burden in CKD patients far beyond those with presumed diabetic nephropathy. The diabetes prevalence of 35% in GCKD is more than twice as high as in Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten THerapie chronischer ERkrankungen in der älteren Bevölkerung (ESTHER) [31], a general population-based health examination in Germany with similar age distribution (50–74 years; mean age 62.1 years) and almost 4-fold higher than in Study of Health in Pomerania, a general population-based study in northern Germany [32]. It is only slightly higher, however, than the 32% prevalence in individuals with CKD in the US National Health and Nutritional Examination Survey (NHANES) [33], suggesting that the proportion of diabetics in CKD populations with and without nephrological care in Europe and the USA is similar. Analogous considerations as for patients with diabetes hold true for the large group of patients considered to have vascular nephropathy. The high frequency of arterial hypertension in all diagnostic categories illustrates a lack of discriminative potency. Together with the low biopsy rate in patients with the presumed diagnosis of vascular nephropathy (8%), this suggests a diagnosis on the basis of clinical exclusion of other causes in most cases. The apparent uncertainty in diagnosis and the multifactorial nature of CKD likely reflect important hurdles for testing and implementing novel treatment strategies that target specific pathomechanisms. Although the GCKD study was not designed to identify risk factors for CKD, several characteristics of the patients enrolled provide indirect evidence for predisposing factors in addition to diabetes and arterial hypertension. First, we observed a gender imbalance, with 60% male study participants. This is consistent with male predominance in patients on dialysis [34] but stands in contrast with studies assessing CKD prevalence in the general population, where the proportion of females is usually larger [31, 33, 35–38]. The reasons for this difference could include a lower detection rate, as well as gender inequity in referral practice or recruitment bias. Male gender is associated with a higher prevalence of cardiovascular disease (CVD), which might indirectly cause an increased association with CKD. However, the proportion of male patients among those enrolled with overt proteinuria and no significant reduction in GFR, in whom primary renal disease was frequent, was also ∼60%. Secondly, we observed a significant degree of obesity in both men and women. Even in patients without diabetes, approximately one-third had a BMI above 30 kg/m2. Although the study recruited across different regions within Germany, there was no centre effect on BMI. Moreover, BMI values observed in the GCKD study are consistent with those in recently reported CKD registry data [39], but higher than in the general population [32, 37, 38, 40]. This corroborates evidence that obesity may affect kidney function beyond its effect on glucose metabolism and systemic atherosclerosis [41, 42]. Third, almost 60% of the GCKD study participants are current or former smokers, compared with 60 mL/min per m2, which had a much smaller proportion of patients with diabetes and cardiovascular disease manifestation.
F I G U R E 3 : Patient awareness about kidney disease and treatment period by nephrologist. Bars indicate number of patients in each time
Table 4. Cardiovascular disease burden in patients enrolled into the GCKD study, stratified by gender and presence and absence of diabetes mellitus
ORIGINAL ARTICLE
Male
Female
Total
Diabetics (n = 1229)
Non-diabetics (n = 1903)
Diabetics (n = 615)
Non-diabetics (n = 1470)
(n = 5217)
n or mean
SD or %
n or mean
SD or %
n or mean
SD or %
n or mean
SD or %
n or mean
SD or %
116 526 642 1214 30 432 259 175 312 175 148 37 17 204 94 19 44 106
39.7 56.1 52.2 98.8 2.4 35.2 21.1 14.2 25.4 14.2 12.0 3.0 1.4 16.6 7.6 10.5 3.6 8.6
152 419 571 1837 36 345 197 118 238 178 146 51 31 146 44 16 48 66
16.7 42.1 30.0 96.5 1.9 18.1 10.4 6.2 12.5 9.4 7.7 2.7 1.6 7.7 2.3 0.8 2.5 3.5
51 173 224 590 18 134 69 37 94 64 56 13 2 62 14 2 18 38
30.4 38.8 36.4 95.9 2.9 21.8 11.2 6.0 15.3 10.4 9.1 2.1 0.3 10.1 2.3 0.3 2.9 6.2
68 175 243 1319 18 128 58 17 99 93 80 17 10 81 25 7 32 30
8.9 24.8 16.5 89.7 1.2 8.7 3.9 1.2 6.7 6.3 5.4 1.2 0.7 5.5 1.7 0.5 2.2 2.0
387 1293 1680 4960 102 1039 583 347 743 510 430 118 60 493 177 44 142 240
18.2 41.9 32.2 95.1 2.0 19.9 11.2 6.7 14.2 9.8 8.2 2.3 1.2 9.4 3.4 0.8 2.7 4.6
a
Cardiovascular disease Patients ≤60 years w CVD, n; % Patients > 60 years w CVD, n; % All, n; % Arterial hypertension, n; % Cardiac valve replacement, n; % Coronary artery disease, n; % MI, n; % Bypass surgery, n; % PTCA, n; % Cerebrovascular disease, n; % Stroke, n; % Carotic surgery, n; % Carotic intervention, n; % Peripheral vascular disease, n; % Amputations, n; % Y-graft, n; % Other types of surgery, n; % PTA, n; % a
The composite of cardiovascular disease includes all patients with one or more of the following: cardiac valve replacement, aortic aneurysm, coronary artery disease, cerebrovascular disease or peripheral artery disease.
These observations are consistent with other data suggesting adverse effects of smoking on kidney function independent of atherosclerosis [43]. Fourth, family history provided evidence for familial aggregation of CKD. Approximately 30% of patients reported that at least one of their parents, grandparents or siblings had CKD and 7.5% were either on dialysis or had a renal transplant. Studies in dialysis patients also found evidence for familial aggregation of renal failure [44, 45]. Apart from adult polycystic kidney disease, monogenic kidney diseases are so far considered to be rare, but evidence for polygenic predisposition for CKD is emerging [46, 47]. Blood pressure control is considered a mainstay of CKD management. Although optimal blood pressure targets in CKD patients remain controversial [48, 49], the most recent
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guidelines propose maintaining blood pressure ≤140/90 mmHg in CKD patients with UACR below 30 mg/g and ≤130/80 mmHg in patients with UACR above 30 mg/g [3, 48]. Given that only slightly more than 50% of patients in GCKD had an office blood pressure below 140/90 mmHg and only slightly more than a quarter below 130/80 mmHg, it is obvious that there is a large gap between targets and clinical reality. This is consistent with other CKD cohort studies [12, 13, 15–18] and suggests a potential for improvement, but also illustrates the difficulties of blood pressure control in CKD. On the other hand, in ESTHER systolic blood pressure was similar and the percentage of individuals with blood pressure below 130/80 mmHg was much smaller, i.e.
