Revista Societatii de Medicina Interna
Articolul face parte din revista :
Nr.6 din luna 2010
Autor LM de Francisco
Titlu articolESTIMATION OF RENAL FUNCTION IN HOSPITALIZED PATIENTS IN SPAIN
Cuvinte cheieGlomerular filtration rate; hospitalized patients; modification of diet in renal disease equation; serum creatinine
Articol
Angel LM de Francisc1, Eloy Fernandez2, Emilio Rodrigo, Celestino Piñera1, Rosa Palomar1, Gema Fernandez Fresnedo1, Jorge Ruizn Criado1, Manuel Arias MD PhD1
1 Servicio de Nefrología, Hospital Universitario Valdecilla, Santander, Spain
2 Servicio de Bioquímica, Hospital de Cabueñes, Asturias, Spain.
Running header: CKD prevalence among hospitalized patients–Spain
Correspondence: Angel LM de Francisco, Servicio De Nefrología, Hospital Universitario Valdecilla, Santander 39008, Cantabria, Spain
Tel: +34 942 202738; Fax: +34 942 320415; E-mail: angelmartindefrancisco@gmail.com
Introduction
More than 500 million people worldwide have some form of kidney damage (www.worldkidneyday.org). Results from studies assessing the prevalence of decreased estimated glomerular filtration rate (eGFR <60 ml/min/1.73 m2) in the general population showed 4.7% and 4.9% in the USA(1) and the UK, (2) respectively. Preliminary results from a pilot study sponsored by the Spanish Society of Nephrology showed that approximately 11% of the adult Spanish population has chronic kidney disease (CKD) of any severity(3) and another study found that CKD stages 3–5 (eGFR <60 ml/min/1.73 m2) is present in 21.3% of patients attending primary care services in Spain(4).
The incidence of CKD is expected to increase within the next 10 years due to progressive aging of the population and as chronic conditions such as diabetes mellitus, hypertension, and obesity continue to become more prevalent(4). It is apparent that the identification, early detection, and accurate assessment of CKD are of great importance, especially when comorbid disease is present.
The National Kidney Foundation Dialysis Outcome Quality Initiative (NKF/KDOQI)(5) and the European Best Practice Guidelines(6) recommend the use of prediction equations to estimate the GFR from serum creatinine (SCr). The most commonly used formulae (currently the gold-standard formulae for calculating eGFR) for assessing renal function among adults are those derived from the modification of diet in renal disease (MDRD) study population. Both MDRD equations measure GFR from renal clearance of [125I] iothalamate(7). The abbreviated (four-variable) MDRD equation, recommended in the NKF/KDOQI guidelines for estimating GFR in outpatients with CKD, includes only age, sex, race, and SCr level(8). However, the six-variable MDRD equation, in addition to the previously mentioned variables, incorporates albumin and BUN levels, and may be a more suitable method by which to estimate GFR in sick inpatients(7).
The MDRD formula has been validated extensively in Caucasian and African American populations(9) and several studies have attempted to validate the MDRD in the elderly(10–12), diabetics(9), patients with advanced heart failure(13), renal transplant patients(14–16), patients with systemic sclerosis(17), and in the obese(18). However, the applicability of the MDRD equations in ill hospitalized patients is still unclear(19).
In a study assessing the prevalence of CKD using general practice computer data, among the patients identified as having CKD stages 3–5, only 8% of these individuals had received a renal diagnosis or had been seen by a renal clinician(20). The consequences of undetected CKD could be even greater among hospitalized patients receiving potentially nephrotoxic drugs, radio contrast, or major surgery and include the development of in-hospital acute kidney failure(21). Hospitalized patients with CKD are at an increased risk for adverse safety events such as hip fracture, infection, or complications of anesthesia(22). Identifying and accurately assessing renal function in hospitalized patients remains an important and unresolved matter.
The aim of the present study was to estimate the prevalence of CKD in the stage 3–5 range (<60 ml/min/1.73 m2) in hospitalized patients in Spain.
Results
Demographics
Table 1 lists demographic characteristics of the studied population classified by departments including percentage of patients with GFR <60 ml/min/1.73 m2 (CKD stages 3–5). The mean age was 63.2 18.4 years; median 67 (range 18–103) years 46.3% were women, and 99.0% were of nonblack race. Mean SCr level was 1.11 0.79 mg/dl, whereas mean MDRD 4 eGFR (CKD stages 3–5) was 42.0 14.0 ml/min/1.73 m2; range 3–59. Mean MDRD 6-variable eGFR (stages 3–5 was 40.6 + 13.7 ml/min/1.73 m2; range 4–59.
Table 2 shows the prevalence of each CKD stage by gender classified by MDRD 4 and MDRD 6.
MDRD 4 eGFR lower than 60 ml/min/1.73 m2 (stages 3–5) was present in 28.3% of hospitalized patients (24.2% in men and 33.2% in women). It is important to consider that 14.2% had an eGFR <44 ml/min/1.73 m2 (CKD stages 3b, 4 and 5).
An examination of eGFR MDRD 4 <60 ml/min/1.73m2 by age and gender (Figure 1) showed that the percentage of patients with eGFR <60 ml/min/1.73 m2 was 23.8% in the range 60–69 years, 39.0% in the range 70–79 years and 54.6 % over 80 years. While the prevalence of eGFR <60 ml/min/1.73 m2 increased with age, the mean eGFR was similar among age groups with slightly greater values exhibited by female patients compared to the male patients.
Concordance MDRD 4 versus MDRD 6
The percentage of patients in each CKD stage was similar although significant increases for 3a (P < 0.01), 3b (P < 0.0001) and 4 stage (P < 0.001) according to the MDRD6 GFR estimation were found (Figure 2).
Figure 3 shows correlation between eGFR MDRD 4 and eGFR MDRD 6 with a correlation coefficient r of 0.9557 (P < 0.0001) (n = 8611). The strength of agreement between MDRD 4 and MDRD 6 CKD NKF/KDOQI stages 3–5 was very good, with a Kappa statistic 0.868 (95% CI: 0.857–0.879).
In a group of patients (n = 3032) with hypoalbuminemia (serum albumin <3.5 g/l) there was also a good MDRD 4 to MDRD 6 correlation: r = 0.9675 (95% CI: 0.9652–0.9657); P < 0.0001.
Intercenter concordance
Results obtained from each center are shown in Table 3. Significant differences in the percentage of patients with CKD stages 3 were found according to the creatinine method used, as shown in Table 4. These differences could be due to age and gender.
Occult renal failure in hospitalized patients
We defined occult renal failure as the coexistence of eGFR MDRD 4 <60 ml/min/1.73 m2 and normal creatinine, i.e. <1.1 mg/dl in women and <1.2 mg/dl in men. With this definition, we found occult renal failure in 1147 patients, which represents 7.8 % (95% CI: 7.4–8.3) of the studied population. Out of the total number of patients with eGFR MDRD 4 <60 ml/min/1.73 m2, the prevalence of occult renal failure was 27.6 % (95% CI: 26.3–29.0), i.e. renal failure was not detected in more than 27% by determination of plasma creatinine. The distribution of occult renal failure by age and gender may be seen in Figure 4, which highlights the presence of significant differences by gender (female, 14.6% vs male, 2.0%, P < 0.0001). Only gender was associated with presence of occult renal failure (expB = 8.702; 95% CI: 7.208–10.506; P < 0.0001), showing no association the following variables: age, department (medical or surgical) and creatinine method. By age, we observed higher prevalence in those older than 70 years compared with groups younger than 70 years of age (14.9% vs 2.8% respectively; P < 0.0001).
Anemia
Hemoglobin was determined in 12 545 patients (5895 female; 6650 male) yielding values 11 g/dl in 32.2% (male: 29.2%, female: 35.5%). Mean hemoglobin differences in CKD stages are shown in Table 5. There were significant differences among groups attending to eGFR (P < 0.01). In the pairwise comparison analysis only group eGFR ≥60 versus stage 3a, and stages 4 versus 5 showed no significant differences. The percentage of patients with eGFR <60 ml/min/1.73 m2 and hemoglobin 11 g/dl was 43.3% versus 27.9% in patients with eGFR 60 ml/min/1.73 m2 (P < 0.0001).
Discussion
The prevalence of CKD is increasing worldwide caused in part by older age and increasing prevalence of hypertension and type 2 diabetes. In studies conducted in different populations the median prevalence of CKD stages 1–5 was 7.2% in persons aged 30 years or older. In persons aged 64 years or older prevalence of CKD varied from 23.4 to 35.8%(23). A recent final study performed in adult 18 years or older in the general population in Spain report the prevalence of CKD stages 1–5 to be 9.16 and 6.8% with GFR <60 ml/min/1.73 m2(24). The prevalence of CKD stages 3–5 among patients attending Primary Care Services in Spain was estimated as 21.3% from the EROCAP study (an adult population sample of 7702 patients).
Despite this high prevalence, there has been relatively little attention focused on the prevalence of CKD among hospitalized patients, a population who generally is receiving potentially nephrotoxic drugs, exposed to major surgery or to radio contrast agents.
The current study aimed to define the prevalence of CKD stages 3–5 in hospitalized patients by gathering data from 14 658 patients from 10 centers located throughout Spain. The study shows that a great percentage of hospitalized patients in Spain have CKD stages 3–5.
Demographics
MDRD 4 eGFR lower than 60 ml/min/1.73 m2 (stages 3–5) was present in 28.3% of hospitalized patients (24.2% in men and 33.2% in women). It is important to consider that 14.2% had an eGFR <44 ml/min/1.73 m2 (CKD stages 3b, 4 and 5), a figure that represents a higher risk group(25).
The mean age was 63.2 years; nearly half of which were women. Mean SCr level was 1.11 0.79 mg/dl, whereas mean eGFR (CKD stages 3–5) was 42.0 14.0 ml/min/1.73 m2; range 3–59 and 40.6 13.7 ml/min/1.73 m2; range 4–59 (MDRD 4 and MDRD 6, respectively). The prevalence increased with age in both sexes. A similar trend was reported for the general population (patients attending Primary Care services) with 33.7% of patients over 70 years of age presenting with an eGFR <60 ml/min/1.73 m2 (4).
Our results also showed that women had a lower GFR than men. Similar results were reported in a study conducted by Khatami et al(26).
The number of patients classified as stage 3 (946) is more than five times greater than the number of patients identified as stage 4 and 5 (170 and 58 patients, respectively). This supports the new stratification of CKD stages presented in the consensus National Kidney Foundation Chronic Kidney Disease Staging System which was prompted by the large number of patients that fell into the stage 3 versus other stage classes.
More than a quarter (27.3%) of the hospitalized patients in this study had an eGFR <60 ml/min/1.73 m2 with 23% aged 60–69 years, 37% aged 70–79 years and 50% aged 80 years or older. This greater prevalence of CKD among those of advanced age heightens the risk for complications.
Prevalence of CKD and implications
This is a very important figure not only in terms of cardiovascular complications associated with renal disease but also because existing kidney disease appears to be among the strongest predictors of acute declines in kidney function following exposure to radio contrast(27), major surgery(28) and other medical conditions(29).
A heightened risk of acute renal failure is another adverse sequela of CKD that becomes apparent at an estimated GFR of below 60 ml/min/1.73 m2. Hsu et al.21 compared 1746 hospitalized adult members of Kaiser Permanente Northern California who developed dialysis-requiring acute renal failure to those who did not (600 820 hospitalized members). Subjects with eGFR 45–59 ml/min/1.73 m2 (CKD stage 3a) had a twofold increase in adjusted odds ratio of acute renal failure compared with subjects with eGFR 60 ml/min/1.73 m2 or above.
Drug administration
CKD affects renal drug elimination and other pharmacokinetic processes involved in drug disposition (e.g. absorption, drug distribution, nonrenal clearance). Dosages of drugs cleared by the kidney should be adjusted according to creatinine clearance or GFR. Drug dosing errors are common in patients with renal impairment and can cause adverse effects and affect clinical outcomes. Several studies have reported the development of nephrogenic systemic fibrosis (NSF), a disorder with potentially fatal consequences, in patients with advanced kidney disease after exposure to gadolinium, a widely used as a magnetic resonance imaging contrast agent. Development of NSF may possibly be due to impaired renal elimination resulting in prolonged tissue exposure(30).
Cardiological complications
Many hospitalized patients have congestive heart failure and the presence of CKD may further complicate treatment. In our study, more than one-third (36.7%) of hospitalized cardiological patients presented with an eGFR lower than 60 ml/min/1.73 m2. Those especially at risk are women of advanced age who, due to a significant reduction in muscle mass, present with low levels of serum creatinine despite the presence of reduced GFR.
The reporting of eGFR whenever the measurement of SCr is ordered, facilitate detection, evaluation, and management of the hospitalized patients with congestive heart failure, and they should result in improved patient care and better clinical outcomes.
Anemia
Among the 12 545 patients in which hemoglobin was determined, nearly one-third (32.2%) of had hemoglobin values 11 g/dl, (male: 29.2%, female: 35.5%). There were significant differences in mean hemoglobin among CKD groups (P < 0.01). In the pairwise comparison only group eGFR 60 ml/min/1.73 m2 versus stage 3a, and stages 4 versus 5 showed no significant differences. The percentage of patients with eGFR <60 ml/min/1.73 m2 and hemoglobin 11 g/dl was 43.3% versus 27.9 in patients with CKD stages 3–5 (eGFR 60 ml/min/1.73 m2) (P < 0.0001).
It has been recognized that many patients with congestive heart failure are also anemic and this anemia is very often associated with CKD. In this study, 1089 of the 1249 cardiology patients had hemoglobin determined. Among these patients, 447 presented with a hemoglobin lower than 12 (10 12; median 10; range 6.8–11.9). In a recent study among anemic CKD-congestive heart failure patients a significant improvement of cardiac, renal, and functional status occurred after correction of anemia(31). Adequate treatment of all three conditions is essential to prevent the progression of both congestive heart failure and CKD(32).
Concordance MDRD 4 versus MDRD 6
The MDRD study equation has been evaluated in several populations, kidney-transplant recipients, and potential kidney donors including blacks, whites, and Asians with nondiabetic kidney disease, diabetic patients with and without kidney disease(33).
Although reasonably accurate in nonhospitalized patients, the MDRD equations have not been thoroughly validated in a large number of ill hospitalized patients, for whom the laboratory variables may be distorted(34,35).
In this study the there was very good strength of agreement between MDRD 4 and MDRD 6 for the distribution of CKD NKF/KDOQI stages 3–5. In a study conducted in 107 sick inpatients with renal dysfunction, it was found that although use of the six-variable MDRD equation provides a better estimation of GFR compared to the MDRD-4 equation suggesting that improved estimation of GFR may be possible in sick hospitalized patients by incorporating albumin and BUN levels.
The same study states that MDRD equations are not reliable measures of actual level of renal function and may be unsuitable for clinical application in this population(9). However, the Poggio et al. (9) study was limited due to the fact that inpatient selection was based on the individual nephrologist’s perception of laboratory values which is not reflective of actual GFR and nearly half (43%) of the patients included in the investigation were at intensive care units. In our study only 4.6% of the study population were in the intensive care unit.
However, limitations of this study include the fact that the MDRD equations have not been thoroughly validated in a large number of ill hospitalized patients.
Occult renal failure
In order to treat CKD you must first be able to detect it. We have shown that a high percentage of the hospitalized patients in this study have reduced renal function and many of them with a serum creatinine within the normal range. Studies performed at Primary Care units reported similar results with 37.3% of patients with eGFR <60 ml/min/1.73 m2 having normal SCr levels.(4) Annear et al.(36) showed that by using the MDRD-4 formula, 31% more patients were identified as having CKD stages 3–5 than identified with creatinine measurements. Consequently many of these patients are considered to have normal renal function and receive medications that are potentially dangerous.
In summary reduced renal function lower than 60 ml/min/1.73 m2 is common in hospitalized patients and in many of them, due to low muscular mass, SCr is within the normal range concealing the real renal function. When SCr is required eGFR estimates facilitate detection, and management of hospitalized patients with congestive heart failure or receiving potentially nephrotoxic drugs, radio contrast, or major surgery.
Consequently physicians should be familiar with commonly used eGFR equations and with medications that require dosage adjustments. We would like to highlight the importance of introducing eGFR estimation by means of the MDRD equation(s) in laboratory reports and particularly in hospitalized patients in which the report of the estimated GFR lower than 60 ml/min/1.73 m2 may improve physicians’ recognition of CKD better than serum creatinine alone. A more precise classification of CKD stage 3 with two subgroups 3a (GFR 45–59 ml/min/1.73 m2) and 3b (GFR 30–44 ml/min/1.73 m2) is also recommended.
Subjects and methods
Patients
Patients were recruited into this study from a population (n = 14 658) of adults (>18 years) hospitalized at 10 centers in Spain in May to June 2007 (Table 6). Patients belonging to Obstetrical and Nephrology Departments were excluded from this study serum samples were taken for the analysis of hemoglobin, creatinine, albumin and urea nitrogen upon at the time of hospital admittance.
Assays
Creatinine was measured using different methods. SCr levels were determined by alkaline picrate reaction methods: Roche assay, calibrated to be traceable to isotope-dilution mass spectrometry (IDMS) in centers 6, 9 and 10, and nontraceable method for SCr in the remaining centers: Bayer assay in centers 1, 2, 3, 7, 8; Abbott assay in center 4 and Dade Behring assay in center 5.
Formula calculations
eGFR was estimated using the formulae identified in Table 7. The full MDRD equation containing six variables (equation 7) was described by Levey et al.7 The MDRD equations containing four and five variables were described in an abstract by Levey et al.8 Laboratories using a creatinine method calibrated to be traceable to IDMS used the IDMS-Traceable MDRD Study equation(37). Therefore the IDMS-Traceable MDRD Study equation was only used with those creatinine methods that were recalibrated to be traceable to IDMS. The MDRD 4 study equation was used with all other methods.
Results are expressed as MDRD for both MDRD 4 and MDRD IDMS (n = 14 658) and as MDRD 6 when serum albumin and BUN were included (n = 8611).
Statistical analysis
On the basis of the MDRD eGFR, individuals were classified as having either GFR >60 ml/min/1.73 m2, stage 3 CKD (GFR 30–59 ml/min/1.73 m2) stage 4 CKD (GFR 15–29 ml/min/1.73 m2), and stage 5 (<15 ml/min/1.73 m2) according to the internationally accepted staging system and the prevalence of CKD in the hospitalized population was estimated accordingly.(38) Additionally, the population was studied in relation to a recently proposed stratification of CKD in which stage 3 is broken down into two sub-stages: 3A (GFR 45–59 ml/min/1.73 m2) and 3B (GFR 30–44 ml/min/1.73 m2 (25). For simplicity, those with GFR >60 ml/min/1.73 m2 are referred to as “CKD stages 3–5”.
Continuous variables with nonparametric distribution are expressed as median (interquartile range) and categorical variables as percentages. Fisher’s exact test was used to compare categorical variables, and continuous variables were evaluated using Mann-Whitney test. One-way analysis of variance was used for multiple comparisons of more than three groups followed by Student-Newman-Keuls test for all pairwise comparisons. Agreement between MDRD 4 and MDRD 6 classification in the present study was evaluated utilizing a Kappa statistic. Logistic multiple regression was performed to identify associations between occult renal disease and participants’ characteristics. The significance of the association was based on the Wald statistic. We performed all statistical analyses using SPSS version 12 (SPSS, Inc., Chicago, Illinois, USA). All tests were two-tailed and a probability value < 0.05 was considered significant.
Disclosures
All the authors declared no competing interests.
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Acknowledgements
This study was carried out under the auspices of the Spanish Society of Nephrology.
Authors contributions: E Fernandez and JJ Cruz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis
Concept and design: ALM de Francisco; E Fernandez; M Arias
Data provision: E Fernandez; MT Casas; J Gómez-Gerique;, A León; F Cava; JL Bedini; A Enguix; E Ripoll; LA Borque; A Fernandez
Analysis and interpretation of data: ALM de Francisco; E Fernandez; M Arias
Drafting of the paper: ALM de Francisco
Statistical analysis: E Fernandez; JJ Cruz
Critical revision of the paper for important intellectual content: ALM de Francisco; E Fernandez; M Arias
Supervision: ALM de Francisco; E Fernandez; M Arias
We are indebted to Roche Anemia Spain for an unrestricted grant and Angel Hernandez, Raquel Gomez and Liliana Ercole from Roche for technical assistance. We would also like to thank Emily H Seidman for editorial assistance.
CKD, chronic kidney disease; SD, standard deviation
MDRD, modification of diet in renal disease
Table 3. Results obtained from each hospital
*data from patients with eGFR <60 ml/min/1.73 m2. eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease; SD, standard deviation
Table 4. Percentage chronic kidney disease stages 3–5 according to the creatinine method
*Hospital number. eGFR, estimated glomerular filtration rate
Mean (SD) ages for each creatinine method: Roche (59.8 18.3); Bayer (65.7 18.4); Abbott (63.1 16.9); Dade-Behring (62.2 16.8).
Table 5. Mean hemoglobin difference in chronic kidney disease stages
eGFR, estimated glomerular filtration rate
Table 6. Hospitals included in the study and creatinine assays
*total n patients, 14 658
Table 7. Formulae to predict GFR derived from the MDRD study. GFR is expressed in ml/min/1.73 m2
• The 6-variable (or original or equation 7) MDRD formula
GFR (ml/min/1.73 m2) = 170 x (Scr)-0.999 x (Age)-0.176 x BUN-0.170 x SAlb0.318 x (0.762 if female) x 1.180 (if African American) (conventional units)
• The 4-variable ( or abbreviated or modified ) MDRD formula
GFR (ml/min/1.73 m2) = 186.3 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American) (conventional units)
• The IDMS traceable MDRD formula :
GFR (ml/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American) (conventional units)
GFR, glomerular filtration rate; MDRD, modification of diet in renal disease; SCr, serum creatinine in mg/dl (multiply by 88.4 to convert to mmo/l); BUN serum urea nitrogen in mg/dl (multiply by 0.357 to convert to mmol/l); SAlb, serum albumin in gr/dl ; IDMS, isotope dilution mass spectrometry.
Titles and Legends
Figure 1. Percentage of hospitalized patients with eGFR MDRD 4 <60 ml/min/1.73 m2 by age and gender
eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease
Figure 2. Distribution of CKD stages using MDRD 4 and MDRD 6
GFR, glomerular filtration rate; MDRD, modification of diet in renal disease
Figure 3. Correlation between eGFR MDRD 4 and eGFR MDRD 6 (n = 8611); Correlation coefficient r = 0.9557 (CI 95% 0.9559–0.9594) P < 0.0001
eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease
Figure 4. Percentage of patients with ORF (occult renal failure: eGFR MDRD 4 <60 ml/min/1.73 m2 and normal creatinine, i.e. <1.1 mg/dl in women. and <1.2 mg/dl in men) by age and gender
eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease
Nr.6 din luna 2010
Angel LM de Francisc1, Eloy Fernandez2, Emilio Rodrigo, Celestino Piñera1, Rosa Palomar1, Gema Fernandez Fresnedo1, Jorge Ruizn Criado1, Manuel Arias MD PhD1
1 Servicio de Nefrología, Hospital Universitario Valdecilla, Santander, Spain
2 Servicio de Bioquímica, Hospital de Cabueñes, Asturias, Spain.
Running header: CKD prevalence among hospitalized patients–Spain
Correspondence: Angel LM de Francisco, Servicio De Nefrología, Hospital Universitario Valdecilla, Santander 39008, Cantabria, Spain
Tel: +34 942 202738; Fax: +34 942 320415; E-mail: angelmartindefrancisco@gmail.com
Introduction
More than 500 million people worldwide have some form of kidney damage (www.worldkidneyday.org). Results from studies assessing the prevalence of decreased estimated glomerular filtration rate (eGFR <60 ml/min/1.73 m2) in the general population showed 4.7% and 4.9% in the USA(1) and the UK, (2) respectively. Preliminary results from a pilot study sponsored by the Spanish Society of Nephrology showed that approximately 11% of the adult Spanish population has chronic kidney disease (CKD) of any severity(3) and another study found that CKD stages 3–5 (eGFR <60 ml/min/1.73 m2) is present in 21.3% of patients attending primary care services in Spain(4).
The incidence of CKD is expected to increase within the next 10 years due to progressive aging of the population and as chronic conditions such as diabetes mellitus, hypertension, and obesity continue to become more prevalent(4). It is apparent that the identification, early detection, and accurate assessment of CKD are of great importance, especially when comorbid disease is present.
The National Kidney Foundation Dialysis Outcome Quality Initiative (NKF/KDOQI)(5) and the European Best Practice Guidelines(6) recommend the use of prediction equations to estimate the GFR from serum creatinine (SCr). The most commonly used formulae (currently the gold-standard formulae for calculating eGFR) for assessing renal function among adults are those derived from the modification of diet in renal disease (MDRD) study population. Both MDRD equations measure GFR from renal clearance of [125I] iothalamate(7). The abbreviated (four-variable) MDRD equation, recommended in the NKF/KDOQI guidelines for estimating GFR in outpatients with CKD, includes only age, sex, race, and SCr level(8). However, the six-variable MDRD equation, in addition to the previously mentioned variables, incorporates albumin and BUN levels, and may be a more suitable method by which to estimate GFR in sick inpatients(7).
The MDRD formula has been validated extensively in Caucasian and African American populations(9) and several studies have attempted to validate the MDRD in the elderly(10–12), diabetics(9), patients with advanced heart failure(13), renal transplant patients(14–16), patients with systemic sclerosis(17), and in the obese(18). However, the applicability of the MDRD equations in ill hospitalized patients is still unclear(19).
In a study assessing the prevalence of CKD using general practice computer data, among the patients identified as having CKD stages 3–5, only 8% of these individuals had received a renal diagnosis or had been seen by a renal clinician(20). The consequences of undetected CKD could be even greater among hospitalized patients receiving potentially nephrotoxic drugs, radio contrast, or major surgery and include the development of in-hospital acute kidney failure(21). Hospitalized patients with CKD are at an increased risk for adverse safety events such as hip fracture, infection, or complications of anesthesia(22). Identifying and accurately assessing renal function in hospitalized patients remains an important and unresolved matter.
The aim of the present study was to estimate the prevalence of CKD in the stage 3–5 range (<60 ml/min/1.73 m2) in hospitalized patients in Spain.
Results
Demographics
Table 1 lists demographic characteristics of the studied population classified by departments including percentage of patients with GFR <60 ml/min/1.73 m2 (CKD stages 3–5). The mean age was 63.2 18.4 years; median 67 (range 18–103) years 46.3% were women, and 99.0% were of nonblack race. Mean SCr level was 1.11 0.79 mg/dl, whereas mean MDRD 4 eGFR (CKD stages 3–5) was 42.0 14.0 ml/min/1.73 m2; range 3–59. Mean MDRD 6-variable eGFR (stages 3–5 was 40.6 + 13.7 ml/min/1.73 m2; range 4–59.
Table 2 shows the prevalence of each CKD stage by gender classified by MDRD 4 and MDRD 6.
MDRD 4 eGFR lower than 60 ml/min/1.73 m2 (stages 3–5) was present in 28.3% of hospitalized patients (24.2% in men and 33.2% in women). It is important to consider that 14.2% had an eGFR <44 ml/min/1.73 m2 (CKD stages 3b, 4 and 5).
An examination of eGFR MDRD 4 <60 ml/min/1.73m2 by age and gender (Figure 1) showed that the percentage of patients with eGFR <60 ml/min/1.73 m2 was 23.8% in the range 60–69 years, 39.0% in the range 70–79 years and 54.6 % over 80 years. While the prevalence of eGFR <60 ml/min/1.73 m2 increased with age, the mean eGFR was similar among age groups with slightly greater values exhibited by female patients compared to the male patients.
Concordance MDRD 4 versus MDRD 6
The percentage of patients in each CKD stage was similar although significant increases for 3a (P < 0.01), 3b (P < 0.0001) and 4 stage (P < 0.001) according to the MDRD6 GFR estimation were found (Figure 2).
Figure 3 shows correlation between eGFR MDRD 4 and eGFR MDRD 6 with a correlation coefficient r of 0.9557 (P < 0.0001) (n = 8611). The strength of agreement between MDRD 4 and MDRD 6 CKD NKF/KDOQI stages 3–5 was very good, with a Kappa statistic 0.868 (95% CI: 0.857–0.879).
In a group of patients (n = 3032) with hypoalbuminemia (serum albumin <3.5 g/l) there was also a good MDRD 4 to MDRD 6 correlation: r = 0.9675 (95% CI: 0.9652–0.9657); P < 0.0001.
Intercenter concordance
Results obtained from each center are shown in Table 3. Significant differences in the percentage of patients with CKD stages 3 were found according to the creatinine method used, as shown in Table 4. These differences could be due to age and gender.
Occult renal failure in hospitalized patients
We defined occult renal failure as the coexistence of eGFR MDRD 4 <60 ml/min/1.73 m2 and normal creatinine, i.e. <1.1 mg/dl in women and <1.2 mg/dl in men. With this definition, we found occult renal failure in 1147 patients, which represents 7.8 % (95% CI: 7.4–8.3) of the studied population. Out of the total number of patients with eGFR MDRD 4 <60 ml/min/1.73 m2, the prevalence of occult renal failure was 27.6 % (95% CI: 26.3–29.0), i.e. renal failure was not detected in more than 27% by determination of plasma creatinine. The distribution of occult renal failure by age and gender may be seen in Figure 4, which highlights the presence of significant differences by gender (female, 14.6% vs male, 2.0%, P < 0.0001). Only gender was associated with presence of occult renal failure (expB = 8.702; 95% CI: 7.208–10.506; P < 0.0001), showing no association the following variables: age, department (medical or surgical) and creatinine method. By age, we observed higher prevalence in those older than 70 years compared with groups younger than 70 years of age (14.9% vs 2.8% respectively; P < 0.0001).
Anemia
Hemoglobin was determined in 12 545 patients (5895 female; 6650 male) yielding values 11 g/dl in 32.2% (male: 29.2%, female: 35.5%). Mean hemoglobin differences in CKD stages are shown in Table 5. There were significant differences among groups attending to eGFR (P < 0.01). In the pairwise comparison analysis only group eGFR ≥60 versus stage 3a, and stages 4 versus 5 showed no significant differences. The percentage of patients with eGFR <60 ml/min/1.73 m2 and hemoglobin 11 g/dl was 43.3% versus 27.9% in patients with eGFR 60 ml/min/1.73 m2 (P < 0.0001).
Discussion
The prevalence of CKD is increasing worldwide caused in part by older age and increasing prevalence of hypertension and type 2 diabetes. In studies conducted in different populations the median prevalence of CKD stages 1–5 was 7.2% in persons aged 30 years or older. In persons aged 64 years or older prevalence of CKD varied from 23.4 to 35.8%(23). A recent final study performed in adult 18 years or older in the general population in Spain report the prevalence of CKD stages 1–5 to be 9.16 and 6.8% with GFR <60 ml/min/1.73 m2(24). The prevalence of CKD stages 3–5 among patients attending Primary Care Services in Spain was estimated as 21.3% from the EROCAP study (an adult population sample of 7702 patients).
Despite this high prevalence, there has been relatively little attention focused on the prevalence of CKD among hospitalized patients, a population who generally is receiving potentially nephrotoxic drugs, exposed to major surgery or to radio contrast agents.
The current study aimed to define the prevalence of CKD stages 3–5 in hospitalized patients by gathering data from 14 658 patients from 10 centers located throughout Spain. The study shows that a great percentage of hospitalized patients in Spain have CKD stages 3–5.
Demographics
MDRD 4 eGFR lower than 60 ml/min/1.73 m2 (stages 3–5) was present in 28.3% of hospitalized patients (24.2% in men and 33.2% in women). It is important to consider that 14.2% had an eGFR <44 ml/min/1.73 m2 (CKD stages 3b, 4 and 5), a figure that represents a higher risk group(25).
The mean age was 63.2 years; nearly half of which were women. Mean SCr level was 1.11 0.79 mg/dl, whereas mean eGFR (CKD stages 3–5) was 42.0 14.0 ml/min/1.73 m2; range 3–59 and 40.6 13.7 ml/min/1.73 m2; range 4–59 (MDRD 4 and MDRD 6, respectively). The prevalence increased with age in both sexes. A similar trend was reported for the general population (patients attending Primary Care services) with 33.7% of patients over 70 years of age presenting with an eGFR <60 ml/min/1.73 m2 (4).
Our results also showed that women had a lower GFR than men. Similar results were reported in a study conducted by Khatami et al(26).
The number of patients classified as stage 3 (946) is more than five times greater than the number of patients identified as stage 4 and 5 (170 and 58 patients, respectively). This supports the new stratification of CKD stages presented in the consensus National Kidney Foundation Chronic Kidney Disease Staging System which was prompted by the large number of patients that fell into the stage 3 versus other stage classes.
More than a quarter (27.3%) of the hospitalized patients in this study had an eGFR <60 ml/min/1.73 m2 with 23% aged 60–69 years, 37% aged 70–79 years and 50% aged 80 years or older. This greater prevalence of CKD among those of advanced age heightens the risk for complications.
Prevalence of CKD and implications
This is a very important figure not only in terms of cardiovascular complications associated with renal disease but also because existing kidney disease appears to be among the strongest predictors of acute declines in kidney function following exposure to radio contrast(27), major surgery(28) and other medical conditions(29).
A heightened risk of acute renal failure is another adverse sequela of CKD that becomes apparent at an estimated GFR of below 60 ml/min/1.73 m2. Hsu et al.21 compared 1746 hospitalized adult members of Kaiser Permanente Northern California who developed dialysis-requiring acute renal failure to those who did not (600 820 hospitalized members). Subjects with eGFR 45–59 ml/min/1.73 m2 (CKD stage 3a) had a twofold increase in adjusted odds ratio of acute renal failure compared with subjects with eGFR 60 ml/min/1.73 m2 or above.
Drug administration
CKD affects renal drug elimination and other pharmacokinetic processes involved in drug disposition (e.g. absorption, drug distribution, nonrenal clearance). Dosages of drugs cleared by the kidney should be adjusted according to creatinine clearance or GFR. Drug dosing errors are common in patients with renal impairment and can cause adverse effects and affect clinical outcomes. Several studies have reported the development of nephrogenic systemic fibrosis (NSF), a disorder with potentially fatal consequences, in patients with advanced kidney disease after exposure to gadolinium, a widely used as a magnetic resonance imaging contrast agent. Development of NSF may possibly be due to impaired renal elimination resulting in prolonged tissue exposure(30).
Cardiological complications
Many hospitalized patients have congestive heart failure and the presence of CKD may further complicate treatment. In our study, more than one-third (36.7%) of hospitalized cardiological patients presented with an eGFR lower than 60 ml/min/1.73 m2. Those especially at risk are women of advanced age who, due to a significant reduction in muscle mass, present with low levels of serum creatinine despite the presence of reduced GFR.
The reporting of eGFR whenever the measurement of SCr is ordered, facilitate detection, evaluation, and management of the hospitalized patients with congestive heart failure, and they should result in improved patient care and better clinical outcomes.
Anemia
Among the 12 545 patients in which hemoglobin was determined, nearly one-third (32.2%) of had hemoglobin values 11 g/dl, (male: 29.2%, female: 35.5%). There were significant differences in mean hemoglobin among CKD groups (P < 0.01). In the pairwise comparison only group eGFR 60 ml/min/1.73 m2 versus stage 3a, and stages 4 versus 5 showed no significant differences. The percentage of patients with eGFR <60 ml/min/1.73 m2 and hemoglobin 11 g/dl was 43.3% versus 27.9 in patients with CKD stages 3–5 (eGFR 60 ml/min/1.73 m2) (P < 0.0001).
It has been recognized that many patients with congestive heart failure are also anemic and this anemia is very often associated with CKD. In this study, 1089 of the 1249 cardiology patients had hemoglobin determined. Among these patients, 447 presented with a hemoglobin lower than 12 (10 12; median 10; range 6.8–11.9). In a recent study among anemic CKD-congestive heart failure patients a significant improvement of cardiac, renal, and functional status occurred after correction of anemia(31). Adequate treatment of all three conditions is essential to prevent the progression of both congestive heart failure and CKD(32).
Concordance MDRD 4 versus MDRD 6
The MDRD study equation has been evaluated in several populations, kidney-transplant recipients, and potential kidney donors including blacks, whites, and Asians with nondiabetic kidney disease, diabetic patients with and without kidney disease(33).
Although reasonably accurate in nonhospitalized patients, the MDRD equations have not been thoroughly validated in a large number of ill hospitalized patients, for whom the laboratory variables may be distorted(34,35).
In this study the there was very good strength of agreement between MDRD 4 and MDRD 6 for the distribution of CKD NKF/KDOQI stages 3–5. In a study conducted in 107 sick inpatients with renal dysfunction, it was found that although use of the six-variable MDRD equation provides a better estimation of GFR compared to the MDRD-4 equation suggesting that improved estimation of GFR may be possible in sick hospitalized patients by incorporating albumin and BUN levels.
The same study states that MDRD equations are not reliable measures of actual level of renal function and may be unsuitable for clinical application in this population(9). However, the Poggio et al. (9) study was limited due to the fact that inpatient selection was based on the individual nephrologist’s perception of laboratory values which is not reflective of actual GFR and nearly half (43%) of the patients included in the investigation were at intensive care units. In our study only 4.6% of the study population were in the intensive care unit.
However, limitations of this study include the fact that the MDRD equations have not been thoroughly validated in a large number of ill hospitalized patients.
Occult renal failure
In order to treat CKD you must first be able to detect it. We have shown that a high percentage of the hospitalized patients in this study have reduced renal function and many of them with a serum creatinine within the normal range. Studies performed at Primary Care units reported similar results with 37.3% of patients with eGFR <60 ml/min/1.73 m2 having normal SCr levels.(4) Annear et al.(36) showed that by using the MDRD-4 formula, 31% more patients were identified as having CKD stages 3–5 than identified with creatinine measurements. Consequently many of these patients are considered to have normal renal function and receive medications that are potentially dangerous.
In summary reduced renal function lower than 60 ml/min/1.73 m2 is common in hospitalized patients and in many of them, due to low muscular mass, SCr is within the normal range concealing the real renal function. When SCr is required eGFR estimates facilitate detection, and management of hospitalized patients with congestive heart failure or receiving potentially nephrotoxic drugs, radio contrast, or major surgery.
Consequently physicians should be familiar with commonly used eGFR equations and with medications that require dosage adjustments. We would like to highlight the importance of introducing eGFR estimation by means of the MDRD equation(s) in laboratory reports and particularly in hospitalized patients in which the report of the estimated GFR lower than 60 ml/min/1.73 m2 may improve physicians’ recognition of CKD better than serum creatinine alone. A more precise classification of CKD stage 3 with two subgroups 3a (GFR 45–59 ml/min/1.73 m2) and 3b (GFR 30–44 ml/min/1.73 m2) is also recommended.
Subjects and methods
Patients
Patients were recruited into this study from a population (n = 14 658) of adults (>18 years) hospitalized at 10 centers in Spain in May to June 2007 (Table 6). Patients belonging to Obstetrical and Nephrology Departments were excluded from this study serum samples were taken for the analysis of hemoglobin, creatinine, albumin and urea nitrogen upon at the time of hospital admittance.
Assays
Creatinine was measured using different methods. SCr levels were determined by alkaline picrate reaction methods: Roche assay, calibrated to be traceable to isotope-dilution mass spectrometry (IDMS) in centers 6, 9 and 10, and nontraceable method for SCr in the remaining centers: Bayer assay in centers 1, 2, 3, 7, 8; Abbott assay in center 4 and Dade Behring assay in center 5.
Formula calculations
eGFR was estimated using the formulae identified in Table 7. The full MDRD equation containing six variables (equation 7) was described by Levey et al.7 The MDRD equations containing four and five variables were described in an abstract by Levey et al.8 Laboratories using a creatinine method calibrated to be traceable to IDMS used the IDMS-Traceable MDRD Study equation(37). Therefore the IDMS-Traceable MDRD Study equation was only used with those creatinine methods that were recalibrated to be traceable to IDMS. The MDRD 4 study equation was used with all other methods.
Results are expressed as MDRD for both MDRD 4 and MDRD IDMS (n = 14 658) and as MDRD 6 when serum albumin and BUN were included (n = 8611).
Statistical analysis
On the basis of the MDRD eGFR, individuals were classified as having either GFR >60 ml/min/1.73 m2, stage 3 CKD (GFR 30–59 ml/min/1.73 m2) stage 4 CKD (GFR 15–29 ml/min/1.73 m2), and stage 5 (<15 ml/min/1.73 m2) according to the internationally accepted staging system and the prevalence of CKD in the hospitalized population was estimated accordingly.(38) Additionally, the population was studied in relation to a recently proposed stratification of CKD in which stage 3 is broken down into two sub-stages: 3A (GFR 45–59 ml/min/1.73 m2) and 3B (GFR 30–44 ml/min/1.73 m2 (25). For simplicity, those with GFR >60 ml/min/1.73 m2 are referred to as “CKD stages 3–5”.
Continuous variables with nonparametric distribution are expressed as median (interquartile range) and categorical variables as percentages. Fisher’s exact test was used to compare categorical variables, and continuous variables were evaluated using Mann-Whitney test. One-way analysis of variance was used for multiple comparisons of more than three groups followed by Student-Newman-Keuls test for all pairwise comparisons. Agreement between MDRD 4 and MDRD 6 classification in the present study was evaluated utilizing a Kappa statistic. Logistic multiple regression was performed to identify associations between occult renal disease and participants’ characteristics. The significance of the association was based on the Wald statistic. We performed all statistical analyses using SPSS version 12 (SPSS, Inc., Chicago, Illinois, USA). All tests were two-tailed and a probability value < 0.05 was considered significant.
Disclosures
All the authors declared no competing interests.
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Acknowledgements
This study was carried out under the auspices of the Spanish Society of Nephrology.
Authors contributions: E Fernandez and JJ Cruz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis
Concept and design: ALM de Francisco; E Fernandez; M Arias
Data provision: E Fernandez; MT Casas; J Gómez-Gerique;, A León; F Cava; JL Bedini; A Enguix; E Ripoll; LA Borque; A Fernandez
Analysis and interpretation of data: ALM de Francisco; E Fernandez; M Arias
Drafting of the paper: ALM de Francisco
Statistical analysis: E Fernandez; JJ Cruz
Critical revision of the paper for important intellectual content: ALM de Francisco; E Fernandez; M Arias
Supervision: ALM de Francisco; E Fernandez; M Arias
We are indebted to Roche Anemia Spain for an unrestricted grant and Angel Hernandez, Raquel Gomez and Liliana Ercole from Roche for technical assistance. We would also like to thank Emily H Seidman for editorial assistance.
CKD, chronic kidney disease; SD, standard deviation
MDRD, modification of diet in renal disease
Table 3. Results obtained from each hospital
*data from patients with eGFR <60 ml/min/1.73 m2. eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease; SD, standard deviation
Table 4. Percentage chronic kidney disease stages 3–5 according to the creatinine method
*Hospital number. eGFR, estimated glomerular filtration rate
Mean (SD) ages for each creatinine method: Roche (59.8 18.3); Bayer (65.7 18.4); Abbott (63.1 16.9); Dade-Behring (62.2 16.8).
Table 5. Mean hemoglobin difference in chronic kidney disease stages
eGFR, estimated glomerular filtration rate
Table 6. Hospitals included in the study and creatinine assays
*total n patients, 14 658
Table 7. Formulae to predict GFR derived from the MDRD study. GFR is expressed in ml/min/1.73 m2
• The 6-variable (or original or equation 7) MDRD formula
GFR (ml/min/1.73 m2) = 170 x (Scr)-0.999 x (Age)-0.176 x BUN-0.170 x SAlb0.318 x (0.762 if female) x 1.180 (if African American) (conventional units)
• The 4-variable ( or abbreviated or modified ) MDRD formula
GFR (ml/min/1.73 m2) = 186.3 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American) (conventional units)
• The IDMS traceable MDRD formula :
GFR (ml/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American) (conventional units)
GFR, glomerular filtration rate; MDRD, modification of diet in renal disease; SCr, serum creatinine in mg/dl (multiply by 88.4 to convert to mmo/l); BUN serum urea nitrogen in mg/dl (multiply by 0.357 to convert to mmol/l); SAlb, serum albumin in gr/dl ; IDMS, isotope dilution mass spectrometry.
Titles and Legends
Figure 1. Percentage of hospitalized patients with eGFR MDRD 4 <60 ml/min/1.73 m2 by age and gender
eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease
Figure 2. Distribution of CKD stages using MDRD 4 and MDRD 6
GFR, glomerular filtration rate; MDRD, modification of diet in renal disease
Figure 3. Correlation between eGFR MDRD 4 and eGFR MDRD 6 (n = 8611); Correlation coefficient r = 0.9557 (CI 95% 0.9559–0.9594) P < 0.0001
eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease
Figure 4. Percentage of patients with ORF (occult renal failure: eGFR MDRD 4 <60 ml/min/1.73 m2 and normal creatinine, i.e. <1.1 mg/dl in women. and <1.2 mg/dl in men) by age and gender
eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease
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Secretariat organizatoric
Email: office@srmi.ro
Str. C-tin Noica, nr.134, Interfon 1, sector 6, Bucuresti
Tel : 021-3156511
Fax :021-3156537
Departament Comercial
Mihaela Dragomir
Email: mihaela.dragomir@ella.ro
Str. C-tin Noica, nr.134, Interfon 1, sector 6, Bucuresti
Tel : +40 753 359 693