Predicting the FSH threshold dose in women with WHO Group II anovulatory infertility failing to ovulate or conceive on clomiphene citrate

BACKGROUND The objective of this investigation was to establish independent predictors of follicle-stimulating hormone (FSH) threshold dose in anovulatory women undergoing ovulation induction with FSH preparations.
Introduction
Approximately 20–30% of the women seeking fertility treatment present with anovulation (Healy et al., 1994). Clomiphene citrate has been used as the first line treatment for inducing ovulation in anovulatory women. In most women who failed to ovulate or conceive with clomiphene citrate, ovarian stimulation with gonadotrophins leads to ovulation (Coelingh-Benning et al., 1998; Yarali et al., 1999; Platteau et al., 2006; Balen et al., 2007). The use of low-dose step-up protocols has been shown to be successful in producing mono-follicular development in more than half of the women undergoing stimulation with gonadotrophins, and thereby minimizing the risk of multiple follicular development and the associated risks of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy (Homburg and Howles, 1999).
A typical low-dose step-up protocol starts with 50–75 IU/day of follicle-stimulating hormone (FSH) or menotrophins for ∼7 to 14 days, and the dose is then increased by 37.5–50 IU/day if adequate response is not obtained. For some patients, the dose of gonadotrophin needed to provide adequate response is relatively high and the use of low-dose regimens will in these cases lead to stimulations of long duration. A long ovarian stimulation is associated with more monitoring visits and would be expected to result in increased costs and inconvenience for the patients. Selection of the most optimal starting dose of gonadotrophin for each individual patient should minimize these disadvantages, while ensuring adequate response.
Imani et al. (1998) have identified clinical and laboratory parameters such as body mass index (BMI), menstrual cycle history, mean ovarian volume and free androgen index (FAI) which can predict ovulation in WHO type II anovulatory women undergoing clomiphene citrate treatment. A similar investigation in anovulatory women undergoing ovulation induction with gonadotrophins suggested BMI, clomiphene citrate resistance, serum insulin-like growth factor-1 (IGF-1) and serum FSH as significant predictors of FSH threshold dose (Imani et al., 2002). The clinical application of this latter result is complicated by the fact that the IGF-1 assay is not part of most clinics standard battery for laboratory screening of anovulatory patients. Therefore, further data are needed to identify simple parameters which can predict the FSH threshold dose in women who will undergo low-dose protocols with gonadotrophins.
The purpose of the present prospective investigation was to evaluate the influence on the FSH threshold dose of clinical, sonographic and endocrine parameters available at the start of ovarian stimulation as well as type of FSH preparation to be used in a low-dose step-up protocol. The data from this investigation form the basis for constructing a nomogram which provides an indication of the expected FSH threshold dose for the individual patient, facilitating the selection of the most appropriate starting FSH dose for ovarian stimulation.
Materials and Methods
Study population and design
This investigation included 151 women with anovulatory WHO Group II infertility who were included in a randomized, open label, assessor-blind, parallel group, multicentre, multinational, non-inferiority study comparing two different FSH preparations (highly purified (HP)-FSH, BRAVELLE, Ferring Pharmaceuticals A/S, Copenhagen, Denmark and recombinant FSH (rFSH), follitropin alfa, GONAL-F, Serono, Geneva, Switzerland) with respect to ovulation rate. Patients were recruited in 22 fertility centres (12 in Belgium, 7 in Denmark and 3 in the UK) that on average each included seven patients, ranging from 2 to 20. A detailed description of the study population, all inclusion and exclusion criteria, all study procedures, as well as the main outcome of the study, is described in detail in a separate publication (Balen et al., 2007).
Patients were to be 18–39 years of age with BMI 19–35 kg/m2, have been diagnosed with infertility for ≥1 year, have chronic anovulation (amenorrhea, oligomenorrhea or anovulatory cycles based on progesterone levels in patients with cycle lengths of 21–35 days) and have failed to ovulate with clomiphene citrate doses of at least 100 mg/day for at least 5 days or failed to conceive after three cycles of ovulation induction with clomiphene citrate. Women with a history of ≥12 unsuccessful ovulation induction cycles, persistent ovarian cysts (≥15 mm) for >1 cycle or ovarian endometrioma on ultrasound and any significant systemic disease, endocrine or metabolic abnormalities were excluded. The study was carried out in accordance with the declaration of Helsinki on good clinical practice and ethical committee approval was obtained in all participating centres.
All patients underwent screening assessments prior to start of ovarian stimulation. These included evaluation of demographics (age), physical characteristics (body weight, height, waist and hip circumference), obstetric history (previous pregnancies, previous live births), infertility history (duration of infertility, number of previous ovulation induction cycles with clomiphene citrate and in total, failure to ovulate with clomiphene citrate, failure to conceive with clomiphene citrate) and menstrual cycle history. Just prior to the first dose of gonadotrophin, patients underwent a transvaginal ultrasound and blood sampling for endocrine evaluation. The sonographic recordings comprised dimensions of right and left ovary, number of follicles (antral follicles >2 mm) in right and left ovary and endometrial thickness. The endocrine evaluation included the following parameters: luteinizing hormone (LH), FSH, estradiol (E2), prolactin, total testosterone, sex hormone binding globulin (SHBG), FAI, glucose and insulin. Chemiluminescent immunometric assays were used for LH, FSH, prolactin, total testosterone and SHBG, and radioimmunoassays were used for E2 and androstenedione, whereas a hexokinase assay was used for glucose and immulite technology was applied for analysis of insulin. All endocrine analyses were conducted by a central laboratory (Quest Diagnostics—Quest Diagnostics Limited, Heston, UK; Quest Diagnostics Limited, Van Nuys, CA, USA; Nichols Institute, San Juan Capistrano, CA, USA). FAI was calculated as (total testosterone/SHBG) × 100.
All patients underwent ovarian stimulation following a low-dose step-up protocol. Stimulation was started 2–5 days after a spontaneous or progesterone-induced menstrual bleed. The starting dose of gonadotrophin was 75 IU daily, which was maintained for 7 days. After the first 7 days, the gonadotrophin dose was either maintained or increased by 37.5 IU increments according to individual response. Patients were maintained on any specific dose level for at least 7 days. The maximum allowed daily dose was 225 IU and patients were treated with gonadotrophin for a maximum of 6 weeks. Gonadotrophin stimulation was maintained until at least one of the following criteria for human chorionic gonadotrophin (hCG) administration was met: one follicle with a diameter of 17 mm or greater, or 2–3 follicles with a diameter of 15 mm or greater. Patients were not given hCG in either of the following situations: no follicular response after 6 weeks of gonadotrophin treatment, ≥4 follicles with diameters of ≥15 mm or serum E2 levels >2000 pg/ml. Patients who reached the hCG criteria received a single s.c. or i.m. injection of hCG (PROFASI, Serono) at a dose of 5000 IU to trigger ovulation. At least one blood sample was taken during the midluteal phase (6–9 days after hCG administration) and analysed for progesterone by a central laboratory using competitive immunoassay using direct chemiluminometric technology with a sensitivity of 0.48 nmol/l (Quest Diagnostics Limited, UK). Ovulation was defined as a mid-luteal serum progesterone concentration of ≥25 nmol/l (≥7.9 ng/ml).
The FSH threshold dose was defined as the dose of FSH that was given when the criteria for hCG was reached. The analysis involved the influence of the type of gonadotrophin preparation (i.e. HP-FSH or rFSH) as well as of clinical, sonographic and basal endocrine parameters on the FSH threshold dose. All potential predictive variables were investigated: age, BMI, waist–hip ratio, previous pregnancy, duration of infertility, failure to ovulate on clomiphene citrate, menstrual cycle history (amenorrhea if the patient had absent menstruation, oligomenorrhea if menstruation intervals were longer than 35 days or cycle length of 21–35 days in which case anovulation had been documented by progesterone levels), total number of follicles, mean ovarian volume (based on length, width and depth of both right and left ovary), LH/FSH ratio, androstenedione, total testosterone, SHBG, FAI, prolactin, estradiol, glucose, insulin and insulin/glucose ratio.
Statistical analysis
The primary end-point of the study was ovulation rate after one cycle of gonadotrophin treatment, and these data have been reported elsewhere (Balen et al., 2007). The influence of the selected clinical, sonographic and endocrine parameters as well as type of gonadotrophin on FSH threshold dose were assessed in univariate and multivariate analyses using proportional odds polytomous logistic regression models (an extension of the model and method for binary response). Multivariate analyses were performed including characteristics that had statistically significant influence on the FSH threshold dose in the univariate analysis first by entering all selected characteristics into the polytomous logistic model in a forward selection approach and secondly by entering all selected characteristics into the polytomous logistic model using a backward elimination approach. P-values of <0.05 were regarded as statistically significant. Score tests were used to evaluate the proportional odds assumption and Wald tests were used to assess the influence of the baseline characteristics on the FSH threshold dose. For the present analysis, all parameters were analysed as continuous variables, except for type of gonadotrophin, previous pregnancy, failure to ovulate on clomiphene citrate and menstrual cycle history (glucose and insulin were categorical variables as normal/abnormal and insulin/glucose ratio was a continuous variable).
In addition to the above, the model was evaluated on the subset of patients with mono-follicular development (one follicle ≥17 mm and no follicles of 15–16 mm). In this evaluation, the same set of variables was used as selected for the main model according to the above procedure. The predictive performance of the model was assessed by using the ‘leave-one-out’ cross-validation procedure. In addition, the residual standard error after a standard multiple regression analysis was evaluated.
Finally, ROC curves were produced and AUC under the ROC curves were calculated. For the standard situation where ROC curves are used, the classification is binary, whereas the threshold dose had four possible outcomes (87.5, 112.5, 150 and 187.5) and the prediction model therefore also predicts into four classes. A consensus approach on how to handle multiclass ROC has not been reached (Landgrebe and Duin, 2007), but when the outcome classes are ranked, ROC curves can be made for each of the possible levels (Waegeman et al., 2006).
Results
The clinical, sonographic and endocrine characteristics of the 151 patients included in the study are shown in Table I. The mean age of the study population was 28.9 years, ranging from 19 to 39 years. The BMI spanned from 18 to 39 kg/m2, with 54% of the patients having a normal BMI, 32% being overweight and 14% being obese and with the mean BMI being 24.8 kg/m2. On average, patients had been infertile for ∼3 years and had undergone four previous ovulation induction cycles with clomiphene citrate, with 34% of the patients failing to ovulate on clomiphene citrate. Regarding menstrual cycle history, 56% of the patients were oligomenorrheic and 15% amenorrheic. An LH/FSH ratio above 1 was noted for 59% of the patients. Among the 151 patients who started stimulation with FSH (HP-FSH 73, rFSH 78), 132 patients met the hCG criteria (HP-FSH 65, rFSH 67) and contributed with data to the analysis of FSH threshold dose. There were 19 patients who initiated gonadotrophin therapy but did not contribute to this analysis; 10 discontinued from the study during ovarian stimulation (five because of excessive response), 2 had spontaneous ovulation and 7 received hCG despite either not meeting or exceeding the hCG criteria.
Table I.
Clinical, sonographic and endocrine parameters just prior to starting ovarian stimulation with FSH (Day 1 of stimulation).
Total (n = 151)
Clinical parameters
Age (years)
28.9 ± 3.7
Body weight (kg)
68.6 ± 13.2
BMI (kg/m2)
24.8 ± 4.5
Primary infertility, n (%)
97 (64%)
Duration of infertility (years)
2.8 ± 1.7
Previous cycles of ovulation induction (all)
4.9 ± 2.4
Previous cycles of ovulation induction (with clomiphene citrate)
4.1 ± 2.4
Clomiphene citrate non-responders, n (%)
 Failure to ovulate on clomiphene citratea
51 (34%)
 Failure to conceive on clomiphene citrateb
100 (66%)
Menstrual cycle history, n (%)
 Amenorrhea
23 (15%)
 Oligomenorrhea
84 (56%)
 Anovulatory cycles with cycle length 21–35 days
44 (29%)
Sonographic parameters
Mean ovarian volume (cm3)
7.1 ± 3.5
Antral follicles >2 mm
14.8 ± 12.5
Endometrial thickness (mm)
4.1 ± 2.2
Endocrine parameters
LH (IU/l)
7.1 ± 4.6
FSH (IU/l)
5.5 ± 2.4
LH/FSH ratio
1.4 ± 0.8
Prolactin (μg/l)
16 ± 13
Androstenedione (nmol/l)
6.74 ± 3.08
Total testosterone (nmol/L)
1.8 ± 0.6
Sex hormone binding globulin (nmol/l)
61 ± 40
Free androgen index
4.45 ± 3.47
Estradiol (pmol/l)
172 ± 98
Glucose (mmol/l)
 Fasting
5.1 ± 0.6
 Non-fasting
5.2 ± 1.5
Insulin (pmol/l)
 Fasting
66.4 ± 43.1
 Non-fasting
143.9 ± 192.6
All data are mean ± SD or number of patients (percentage of patients).
aOn at least 5 days of 100 mg/day.
bAfter three cycles.
Table II provides the outcome of the univariate and multivariate analysis for the predictors of FSH threshold dose. Eight parameters were statistically significant predictors of FSH threshold dose (P < 0.05): age, BMI, failure to ovulate with clomiphene citrate, menstrual cycle history (amenorrhea, oligomenorrhea or anovulatory cycles with cycle length 21–35 days), mean ovarian volume, LH/FSH ratio, testosterone and FAI. The type of gonadotrophin preparation, HP-FSH or rFSH, did not predict FSH threshold dose. All eight significant parameters were included in a multivariate analysis which showed that only three of the parameters were independently statistically significant (P-values < 0.001) predictors of FSH threshold dose: BMI, mean ovarian volume and menstrual cycle history (Table III). The odds for needing >75 IU FSH were 1.18 [95% confidence interval (CI): 1.07–1.29] for BMI and 1.22 [95% CI: 1.09–1.37] for mean ovarian volume; thus the higher the BMI and ovarian volume prior to start of stimulation, the higher the FSH threshold dose. Regarding the menstrual cycle history, the odds for needing a FSH dose >75 IU were 11.9 [95% CI: 3.35–42.0] and 2.57 [95% CI: 0.97–6.79] for amenorrhea and oligomenorrhea, respectively, compared with anovulatory cycles with a length of 21–35 days. The observed data for these three independent predictors are presented in Table III.
Table II.
Statistically significant predictors of FSH threshold dose (univariate and multivariate analysis).
Univariate analysis
Multivariate analysis
OR (95% CI)
P-valuea
OR (95% CI)
P-valuea
Age (years)
0.91 (0.83–1.00)
0.040
—
—
BMI (kg/m2)
1.10 (1.02–1.19)
0.010
1.17 (1.07–1.29)
<0.001
Failure to ovulate on clomiphene citrate: yes versus no
2.27 (1.14–4.52)
0.020
—
—
Menstrual cycle history
<0.001
<0.001
 Amenorrhea versus cycle length 21–35 days
8.33 (2.81–24.7)
11.88 (3.35–42.1)
 Oligomenorrhea versus cycle length 21–35 days
3.48 (1.51–8.03)
2.57 (0.97–6.79)
Mean ovarian volume (cm3)
1.18 (1.06–1.31)
0.002
1.22 (1.08–1.37)
<0.001
Free androgen index (nmol/l)
1.25 (1.13–1.38)
<0.001
—
—
Total testosterone (nmol/l)
2.14 (1.14–4.03)
0.018
—
—
LH/FSH ratio (IU/l)
1.59 (1.03–2.45)
0.038
—
—
aWald test for effect of factor/covariate.
Table III.
BMI, mean ovarian volume and menstrual cycle history by observed FSH threshold dose.
BMI (kg/m2)
Mean ovarian volume (cm3)
Menstrual cycle history (%) Amenorrhea / oligomenorrhea / cycle length 21–35 days
75 IU (n = 67)
23.8 ± 4.2
6.3 ± 2.9
8% / 48% / 45%
112.5 IU (n = 46)
25.5 ± 4.8
7.3 ± 3.4
22% / 63% / 15%
150 IU (n = 15)
25.8 ± 4.0
9.5 ± 4.8
33% / 47% / 20%
187.5 IU (n = 4)
28.1 ± 4.6
10.2 ± 2.3
25% / 75% / 0%
All data are mean ± SD or percentage of patients.
The model predicted the FSH threshold dose to be the same as the dose observed in the study for 59% of the patients. The AUC under the ROC curve was 0.78 for 75 IU (Fig. 1a) and 0.79 for 112.5 IU (Fig. 1b). In a multiple regression analysis with the same three variables as in the logistic model, the FSH threshold dose was estimated on a continuous scale. From this estimation, the residual mean square error was 25 IU and the R2 = 25%.
Figure 1:
ROC curves for threshold dose (a) 75 IU versus <75 (AUC = 0.78) and (b) ≤112.5 IU versus >112.5 IU (AUC = 0.79).
A simple nomogram can be constructed based on the two clinical and one sonographic parameters that significantly predict the FSH threshold dose. Figure 2 displays three nomograms—one for each type of menstrual cycle history—where the shaded areas indicate the predicted FSH threshold dose, based on the BMI displayed on the x-axis and mean ovarian volume on the y-axis. For example, the expected threshold FSH dose for a patient with amenorrhea (Fig. 2a), mean ovarian volume of 10.5 cm3 and a BMI of 30 kg/m2 will be 150 IU. In the case that the patient presents with oligomenorrhea (Fig. 2b), but similar mean ovarian volume and BMI, the expected threshold FSH dose would be 112.5 IU. As another example, a threshold FSH dose of 75 IU will be expected for a patient with anovulatory cycles of 21–35 days, mean ovarian volume of 8.5 cm3 and BMI 27 kg/m2, whereas it will be 112.5 IU for a patient with oligomenorrhea and similar mean ovarian volume and BMI.
Figure 2:
Nomograms for prediction of individual FSH threshold dose in anovulatory patients undergoing ovulation induction with FSH preparations, according to menstrual cycle history, BMI and mean ovarian volume. (a) Amenorrhea, (b) oligomenorrhea and (c) anovulatory cycles with cycle length 21–35 days.
The accuracy of the model was 60% when applied to the subset of patients with mono-follicular development (80 patients), and thus similar to that achieved for the overall study population.
Discussion
The main finding in the present study was identification of the three variables: menstrual cycle history, BMI and mean ovarian volume, as independent predictors of the FSH threshold dose during FSH treatment of anovulatory infertility. For clinical use, such data could be implemented and used as screening predictors to determine the individual FSH threshold dose of any patient before start of gonadotrophin treatment, in order to select the most appropriate starting dose. For this purpose, we have used the three independent predictors to develop the FSH dose nomograms presented in Fig. 2. The proposed model had an accuracy of 59–60%, which is well above the 25% that would be expected by random allocation to one of the four dose levels evaluated in this study.
Our findings are partly in line with those obtained by Imani et al. (2002) who studied 90 anovulatory women, also treated with either urinary or rFSH, and showed that BMI, clomiphene resistance, free IGF-1 and basal FSH were independent predictors of the FSH threshold dose. Imani et al. (2002) made an equation showing that the predicted dose was: [4 BMI (in kg/m2)] + [32 clomiphene citrate resistance (yes = 1 or no = 0] + [7 initial free IGF-I (in ng/ml)] + [6 initial serum FSH level (in IU/l)] − 51. Similar to our study, it was found that menstrual bleeding interval as well as clomiphene resistance were significant predictors in the univariate analysis, but among the possible clinical predictors only clomiphene resistance and BMI remained significant in the multivariable analysis. The population studied by Imani et al. (2002) seems very similar to the present study, even though the latter included patients if they failed to conceive after three clomiphene cycles, whereas the study by Imany et al. (2002) only included women with six failed ovulatory clomiphene citrate cycles, but it seems unlikely that this would explain the difference in predictive factors. A more plausible explanation could be that the study by Imani et al. (2002) included, in the forward step-wise multivariate analysis, some endocrine factors, such as free-IGF-I and its binding proteins, that may alter the predictors that remained in the final model during the analysis.
It is worth briefly discussing a statistical methodological difference between the present model and that suggested by Imani et al. (2002). The polytomous logistic regression model used on the present data set predicts FSH threshold doses that correspond to actual dose levels applied in the clinical trial, in contrast to a multiple regression where the predicted dose is on the continuous scale, as the equation published by Imani et al. (2002). In our model, the residual mean square error was 25 IU and therefore the individual prediction is at least as good as in the model suggested by Imani et al. (2002) where the residual mean square error was 35 IU. The R2 value of 25% in the present model is explained by the relatively few patients in the two highest dose levels in our trial compared with a more even distribution of patients in the trial conducted by Imani et al. (2002) yielding an R2 of 39% in their model.
Our finding that the menstrual status was important is in line with expectations. Patients with amenorrhea may need more FSH to reach the threshold than a patient with oligomenorrhea, who may also need more FSH compared with patients with anovulatory cycles, indicating that the severity of the ovarian dysfunction may well be reflected in the degree of menstrual cycle disturbance. The relative resistance to FSH in amenorrheic patients is supported by the finding that these patients also have a relative resistance to endogenously released FSH during clomiphene citrate treatment (Imani et al., 1998), as patients with clomiphene resistance do release a similar amount of endogenous FSH as the clomiphene sensitive women (Polson et al., 1989). This supports the concept that it is indeed the threshold of the ovarian sensitivity that is altered.
A high BMI was associated with a higher FSH threshold dose; an observation that is supported by the findings that the total dose of gonadotrophins needed to induce ovulation is increased in parallel with body weight (Hamilton-Fairly et al., 1992; Balen et al., 2006). The cause of the association with BMI may be that the endocrine disturbance is related to the degree of body fat and hyperinsulinaemia, but it may also be due to a lower bioavailability of exogenous gonadotrophins in obese women (Chan et al., 2003; Steinkampf et al., 2003).
The type of gonadotrophin used for stimulation was not a significant predictor of FSH threshold dose, and thus of limited relevance compared with the patient's clinical characteristics.
In theory, the threshold is defined as the lowest dose that induces growth of the single most sensitive follicle. In this clinical trial, a dual criterion for hCG administration was used, covering not only the development of a single dominant follicle, defined as one follicle of 17 mm or greater, but also the presence of 2–3 follicles of 15 mm or greater. Therefore, our threshold is based on the stimulation in those 132 (87%) patients who reached either of these criteria, including those patients with up to 3 follicles ≥15 mm. The threshold dose in the study and subsequently the model could also be termed the ‘response dose’ and can be viewed as a surrogate for the real threshold. It should be considered that serum FSH may accumulate over time so the theoretically ideal threshold should be defined as the dose that caused growth of a single dominant follicle to around 9–10 mm, where dominance is normally established. The exact timing of dominance was not determined in the present study, but it is important to note that the model for threshold dose predictions also applied in the subset of patients with mono-follicular development defined as only one follicle ≥17 and no follicles of 15–16 mm. The average number of follicles ≥15 mm was 1.5 (Balen et al., 2007) indicating that some patients did indeed receive FSH doses slightly above the threshold for single dominant follicle development. However, the analysis restricted to patients with mono-follicular development showed that the accuracy of the model was the same for this subset of patients as for the overall study population. On the basis of the intention to treat population in the present study, 92% of the patients received hCG and the ongoing pregnancy rate was 19%, of which 79% accounted for singletons and 21% for multiple pregnancies (Balen et al., 2007). These figures are much in line with literature data on 7 day step-up protocols (Homburg and Howles, 1999), but it could be argued that the multiple pregnancy rate is somewhat high, compared with a number of recent studies using starting doses of FSH <75 IU/day (Balasch et al., 2000; Calaf Alsina et al., 2003). Indeed, multiple pregnancy rates as low as 6% have been reported in a large clinical trial using starting doses of 50 IU/day, even though up to 3 follicles >16 mm before hCG administration was accepted (Calaf Alsina et al., 2003). An alternative approach is to restrict hCG administration to those patients who have only one or two mature follicles, but this would increase the cancellation rates. As published (Balen et al., 2007), 3.3% (5/151) of the patients had their cycle cancelled before hCG, due to development of multiple follicles. Identification of these patients with a very low threshold would have necessitated a starting dose of <75 IU/l.
Ovarian volume was another significant parameter predicting the FSH threshold dose. The larger the ovaries, the more FSH was needed to obtain adequate ovarian response. This finding is consistent with earlier clinical studies of ovulation induction with gonadotrophins, where it has been shown that patients with larger ovaries need longer duration of stimulation and higher doses of gonadotrophins (Lass et al., 2002).
Van den Meer et al. (1994) studied three consecutive cycles in 16 patients during gradually increased doses of intravenously infused urinary FSH and elegantly documented how the inter-individual variability in FSH threshold dose was far greater than the variability from cycle to cycle. The key problem is therefore to define the appropriate dose for any individual patient and the present study provides a suggestion for nomograms that may be used clinically. A major concern, if patients were dosed according to the nomograms, would be that 13% would receive a higher starting dose that the observed threshold dose. The implications of an excessive starting dose are likely to be the same as when step-down protocols are used, i.e. risk of multiple follicular development. Indeed, van Santbrink et al. (2002) have used the prediction model developed by the same group of investigators (Imani et al., 2002), and retrospectively evaluated the doses used in a step-down regimen. In that study, even though the average excessive dose was 28.5 IU/day above the threshold, the step-down approach resulted in an overall multiple pregnancy rate of 17% and not a single case of OHSS (van Santbrink et al., 2002).
The expected main advantage of dosing according to the nomogram would be a shortening of the stimulation phase. It is important to note that the suggested dosage nomograms could be easily used clinically because they only include simple characteristics that are routinely recorded in all anovulatory patients. Before using this model in clinical practice, a randomized controlled trial should be conducted to compare the presently used low-dose step-up protocol with a flexible protocol using this model.
Funding
The study was sponsored by Ferring Pharmaceuticals A/S, Copenhagen, Denmark. Funding to pay the Open Access publication charges for this article was provided by Ferring Pharmaceuticals A/S, Copenhagen, Denmark.

threshold dose
anovulation
predictors
follicle-stimulating hormone
efficiency


Dual-source CT for chest pain assessment

Comprehensive CT angiography protocols offering a simultaneous evaluation of pulmonary embolism, coronary stenoses and aortic disease are gaining attractiveness with recent CT technology. The aim of this study was to assess the diagnostic accuracy of a specific dual-source CT protocol for chest pain assessment. One hundred nine patients suffering from acute chest pain were examined on a dual-source CT scanner with ECG gating at a temporal resolution of 83 ms using a body-weight-adapted contrast material injection regimen. The images were evaluated for the cause of chest pain, and the coronary findings were correlated to invasive coronary angiography in 29 patients (27%). The files of patients with negative CT examinations were reviewed for further diagnoses. Technical limitations were insufficient contrast opacification in six and artifacts from respiration in three patients. The most frequent diagnoses were coronary stenoses, valvular and myocardial disease, pulmonary embolism, aortic aneurysm and dissection. Overall sensitivity for the identification of the cause of chest pain was 98%. Correlation to invasive coronary angiography showed 100% sensitivity and negative predictive value for coronary stenoses. Dual-source CT offers a comprehensive, robust and fast chest pain assessment.
Introduction
Comprehensive CT angiography protocols for a complete assessment of the thoracic vessels, often referred to as “triple rule out” protocols, are used in the differential diagnosis of chest pain increasingly often [1–4]. These protocols aim to opacify pulmonary and coronary arteries as well as the aorta simultaneously to rule out pulmonary embolism, coronary artery disease and aortic aneurysm or dissection in a single exam. With ECG gating, the acquired images of the coronary arteries should have a similar diagnostic accuracy as a specific coronary CT angiography. Quite a few studies have meanwhile shown the feasibility of a simultaneous evaluation of these vascular territories in one single breathhold scan with a good sensitivity in the identification of the cause of chest pain [5]. Also, recent studies indicate that coronary CT angiography can be helpful for a fast and cost-effective triage of chest pain patients [6, 7]. So far, a major limitation of these studies especially in acutely ill patients is the restricted image quality of the coronary arteries in high heart rates [8]. The administration of beta-blockers to lower heart rates is general practice in 16- and 64-slice CT [9]. However, this approach is time consuming and limited by contraindications, and a sufficient reduction of the heart rate cannot be achieved in many acutely ill patients. Initial studies of dual-source CT (DSCT) cardiac imaging have shown a robust image quality and a very good diagnostic accuracy of coronary CT angiography even in high heart rates [10, 11]. Additionally, a more comprehensive cardiac assessment including wall motion and valve function is possible with DSCT [10]. The aim of this study was to assess the diagnostic accuracy of a specific dual-source CT protocol for chest pain assessment, regarding a 6-month follow-up for other findings and coronary angiography in patients in whom coronary artery disease could not be reliably excluded as standard of reference.
Materials and methods
Patients
One hundred nine consecutive patients [31 women, 78 men; median age 64 (59–67) years] were prospectively enrolled in the trial. The study was approved by the institutional review board, and informed written consent was obtained from every patient prior to the examination. All patients with acute chest pain were eligible for the study if referred by a colleague after initial diagnostic workup including physical examination, ECG and serum levels of creatinine and TSH. Exclusion criteria were positive ECG changes or troponine test, severe ventricular arrhythmia, a history of severe allergoid reaction to iodinated contrast material, renal insufficiency and young age below 30 years. Also, severe dyspnea with inability to hold the breath for at least 15 s was regarded as exclusion criterion. The patients were asked to hold their breath for approximately 15 s prior to the examination. If the breathhold could not be maintained, the patient was excluded from the study, and seven otherwise eligible patients had to be excluded for this reason. Heart rates were 68 ± 14, ranging from 58 to 118 bpm. Beta-blockers were not administered in preparation of the scan. Eighteen patients had known coronary artery disease and 14 were on continuous oral beta blocker medication. One patient had a known chronic aortic dissection.
Examination
Examinations were acquired on a DSCT Somatom Definition (Siemens, Forchheim, Germany) in supine position. A coronal topogram was scanned to plan the spiral acquisition, which included the whole chest from the first ribs to the diaphragm. The level of the carina was defined as the trigger point where the second tube is switched on additionally. The volume and flow rate of the contrast material (Ultravist 370, Schering, Germany) were adapted to the patient’s body weight as described elsewhere [5] according to Table 1. A bolus tracking technique was used to assess the transit time of the contrast agent. For this purpose, a region of interest was defined in the ascending aorta to detect the arrival of the contrast material bolus in images scanned at 2-s intervals, and the scan was initiated with a delay of 4 s if the density increased more than 100 Hounsfield units (HU). The patient was then instructed to hold his breath at a mild inspiratory position, and the spiral scan was started. The parameters for the acquisition in craniocaudal direction were 0.33-s gantry rotation time, 120-kVp tube voltage, 560-mAs effective tube current with 0.6-mm collimation and double Z-sampling. The pitch and the tube current modulation were adapted automatically to the heart rate of the patient. Pitch values ranged between 0.2 and 0.48, whereas the full tube current was only applied at 70% of the cardiac cycle for heart rates below 70 bpm and between 30 and 70% for higher heart rates. Scan duration was 15 ± 3 s.
Table 1Body-weight-adapted contrast material injection protocolWeight (kg)Volume (ml)Flow (ml/s)501063.5551113.7601163.9651214.0701254.2751304.3801344.5851384.6901424.7951464.91001505.01051545.11101575.21151615.41201645.5
Image reconstruction
Continuous ECG-gated axial slices and coronal images of the whole chest were reconstructed with a temporal resolution of 330 ms using a soft kernel (B30f). Slice thickness of 3 mm and 2.5-mm increment were applied to avoid artificial inhomogenities in the lung parenchyma due to undersampling with gating. Additionally, axial slices of the heart were reconstructed for a limited range from the carina to the diaphragm with a 200-mm field of view, 0.75-mm slice thickness and 0.5-mm increment using a B26f convolution kernel. If stents had been implanted, an additional reconstruction was performed using a B46 kernel to reduce blooming and enhance the depiction of the lumen. For ECG gating, a single segment reconstruction algorithm utilizing quarter scan segments from both detectors was applied to achieve a temporal resolution of 83 ms, and delays were set to 300 ms and 70% of the cardiac cycle for the initial reconstructions. Also, axial slices with 1-mm thickness and increment were reconstructed with a B26f kernel for the whole cardiac cycle at 10% intervals for dynamic evaluation.
Diagnostic evaluation
The examinations were read by two radiologists in consensus immediately after the exam, including a review of axial and coronal slices for evaluation of pulmonary embolism and aortic disease (Figs. 3 and 4). Additionally, a complete cardiac workup (Figs. 1 and 2) was done using a 3D workstation (Multimodality Workplace, Siemens, Forchheim, Germany) to interactively browse multiplanar reconstructions and volume-rendered images if necessary. Multiphase reconstructions were reviewed as cine loops of the heart with interactive browsing of dynamic short- and long-axis sections. The coronary artery tree was extracted using region-growing algorithms, and curved multi-planar reformats were created for review (Fig. 1a,b). In case of motion artifacts, additional reconstructions with an optimized delay were available. If these still did not resolve motion artifacts sufficiently to make a sufficient diagnostic evaluation feasible, the depiction of the respective coronary artery segment was rated as non-diagnostic and excluded from further analysis. Additionally, the multiphase reconstructions were reviewed to assess wall motion abnormalities and valvular disease (Fig. 2a-d).
Fig. 1High grade stenosis (arrows) of the left anterior descending coronary artery. a Curved multiplanar reconstruction along the centerline of the vessel. b Orthogonal curved multiplanar reconstruction. c Left anterior oblique-cranial projection at invasive angiography. d Respective right anterior oblique projectionFig. 2Subendocardial scar (arrows) from a myocardial infarction in the territory of the left anterior descending coronary artery. a Diastolic mid-ventricular short axis view. b Systolic short axis view. c Diastolic left two-chamber view. d Systolic two-chamber view. Note the dyskinesia bulging out of the anterior wall. e Multiplanar reconstruction of the left anterior descending coronary artery. Note the stent (white arrow) in the proximal vessel, which had been implanted after interventional re-perfusion of the occluded vessel
Indication for invasive angiography was evaluated by a cardiologist based on CT and clinical findings. Invasive angiography was always initiated if significant coronary artery disease could not be reliably excluded in CT and there was no other evident pathology explaining the symptoms. Selective catheterization and coronary angiography were performed by an experienced cardiologist using a transfemoral arterial approach and standard Seldinger technique. At least three standard projections including a 45° left anterior oblique, a 30° right anterior oblique and a 45° left anterior and 30° cranial projection were acquired for both coronary arteries. For quantitative coronary assessment (QCA) analysis, a densitometrical analysis of two projection images was performed using the Quant-Cor QCA software (Siemens, Erlangen). Conventional coronary angiograms of 29 patients were available for correlation. A third reader correlated the findings in the reports to invasive coronary angiography and performed dose calculations, which were based on the dose length product given in the patient protocol of the CT scanner. Also, he reviewed the files of patients with initially negative results for further diagnoses in the subsequent 6 months. The readers of the initial CT images were unaware of any findings from conventional angiography, and most invasive angiographies were performed to further evaluate or treat lesions detected in CT. Thus, the cardiologists performing the coronary angiography were mostly aware of the CT findings.
Statistical analysis
Continuous variables are given as median and range. Ninety-five percent confidence intervals were calculated using MedCalc software (MedCalc Software, Mariakerke, Belgium). Diagnostic accuracy was calculated as sensitivity, specificity, positive and negative predictive values based on standard contingency tables.
Results
Technical success
The scans were acquired from all 109 patients without severe adverse events. Although previously tested, three patients were unable to hold their breath for the duration of the scan, which resulted in artifacts in the lower part of the chest, rendering the coverage and depiction of the coronary arteries insufficient for diagnostic evaluation. All examinations showed an adequate contrast enhancement of the pulmonary arteries, the coronary arteries and the aorta except for six examinations. In two, the bolus was too short due to hemodynamic parameters, making the assessment of pulmonary embolism only possible in the central arteries. In three examinations an erroneous administration of a smaller volume of contrast material caused a weak opacification of the pulmonary arteries, and in one examination overall opacification was too weak (220–245 HU) for coronary artery assessment.
Patient findings
The diagnoses in the patient population were spread over the different organs and vascular territories quite evenly (Table 2). Ten patients had pulmonary embolism (Fig. 3) and three had morphological signs of chronic pulmonary hypertension. Twelve patients showed other, non-vascular pulmonary findings including pneumonic consolidation in four patients and edema from left heart failure in four cases. Thirty-seven patients had coronary atherosclerosis, and in 21 of these patients, stenoses were rated as hemodynamically significant (>50%) (Fig. 1). Three coronary arteries were occluded. Fifteen patients had had bypass surgery, and five bypass graft vessels were occluded. One bypass was rated as stenotic, but invasive angiography showed a patent lumen and a very slow runoff. There were 20 non-coronary cardiac findings including valvular disease in seven patients. Among those, there were four cases of aortic stenosis, one bicuspid aortic valve and one with vegetations from endocarditis. In one patient an insufficiency of tricuspid valve leaflets was diagnosed. Three patients had had aortic valve replacement, and the valve prostheses worked normally. Seven patients showed an abnormal global or regional wall motion with pulmonary congestion in four cases. Areas of myocardial infarction were noted in three patients (Fig. 2). Other non-coronary cardiac findings were left ventricular hypertrophy, scars from myocarditis and ventricular thrombi. Among the aortic pathologies there were seven aneurysms, five dissections (Fig. 4), one case of intramural hematoma and one acute rupture with active bleeding into the mediastinum. Incidental vascular findings were a lusorian artery and a right descending aorta with Kommerell’s diverticulum (Fig. 5). Another frequent finding was neoplastic lesions, partially with unknown primary cancer. Three patients had disseminated pulmonary metastases, one patient had a previously known lymphoma and one an esophageal cancer. In 26 patients there were no findings that were regarded as the main cause of chest pain. The review of the files of those patients in a 6-month follow-up showed additional diagnoses in two patients: One had intermittent arrhythmia that was identified as the cause of chest pain. The other patient developed pleural effusion and was diagnosed to have pleuritis. In the other 24 patients there was no evidence of the cause of chest pain in follow-up. Considering those results as correct-negative, the sensitivity of the protocol in the identification of the cause of chest pain amounts to 98%. Specificity can be estimated at 92% based on these data, although the exact significance of the findings for chest pain is frequently unclear and may therefore be regarded as arbitrary.
Fig. 3Curved multiplanar reconstruction of the lower lobe pulmonary arteries showing emboli in the lobar and segmental arteriesFig. 4Dissection of the descending aorta. a Multiplanar reconstruction. Arrows indicate the depiction of the left coronary artery in the gated reconstruction (black arrow), the dissection membrane (white arrow) and the junction between the gated scan and the non-gated scan, which had been continued in this case to include the whole extent of the dissection (outlined arrow). b Angulated para-coronal reconstruction showing the topographyFig. 5Kommerell’s diverticulum (arrows). a Volume-rendered reconstruction showing the origin from the aortic arch and the course of the subclavian artery. Note the median-right course of the descending aorta ventral to the spine. b Curved multiplanar reconstruction showing the proximity to the tracheaTable 2Diagnoses found in the study populationTerritoryTypeDiagnosisnPulmonary19%Vascular62%Embolism77%10Pulmonary hypertension23%3Non-vascular38%Pneumonia50%4Edema50%4Cardiac40%Coronary84%Atherosclerosis100%37Relevant stenosis57%21Occlusion8%3Bypass grafts18%Patent75%15Occluded25%5Non-coronary13%Valvular50%7Myocardial50%7Aortic13%Aneurysm50%7Dissection43%6Rupture7%1Other7%Vascular variants25%2Neoplastic75%6Negative24%26Sum of patients100%109
Correlation to invasive angiography
The 29 conventional coronary angiograms that were available for correlation of the coronary findings were evaluated in a segment-based and a patient-based analysis. Thirty-two coronary artery segments (7%) of these patients were excluded from analysis due to small size or insufficient visualization in CT. Of the 29 patients, 25 had evidence of coronary atherosclerosis in CT. Nineteen stenoses were rated as potentially hemodynamically relevant with more than 50% stenosis in CTA, but invasive angiography confirmed only 15 of those, whereas the other 4 were overrated. There were no false-negative results, i.e., all the stenoses had been cited in CTA, although it has to be taken into account that the indication for invasive angiography was frequently derived from CTA findings. Thus, sensitivity, specificity, positive and negative predictive value amounted to 100%, 99%, 79% and 100%, respectively, in the segment-based analysis.
In the patient-based analysis, all 13 patients with significant stenoses were identified. There were two patients with completely negative CTA and symptoms very suggestive of coronary ischemia who had additional invasive angiography, and both of them remained negative. The overrated stenoses occurred in patients with other, significant stenoses. Thus, CTA achieved full diagnostic accuracy in correlation to invasive angiography for this patient-based analysis. The database of the coronary angiography laboratory was screened for those patients who had not initially been examined invasively, and there were no readmissions for angiography within 6 months after inclusion of the last patient.
Radiation exposure
As the patient protocols had not been archived in all patients, there were only 51 dose-length products available for calculation. Based on a conversion factor of 0.012 for chest exams, the estimated equivalent dose ranged between 9.2 mSv in low heart rates with strict dose modulation to 19.5 mSv in tall patients with heart rates around 70–80 bpm, which resulted in a wide pulsing interval of 30–70% with a still quite low pitch below 0.3. Overall, the median radiation exposure was 15.1 mSv (95% CI 9.9–18.8).
Discussion
CT angiography can be regarded as the modality of choice for the assessment of pulmonary embolism and aortic disease in acute care [12]. The fast volume coverage that has become available with recent CT technology has triggered efforts for a combined assessment of these pathologies, and the additional evaluation of the coronary arteries would make the protocol a universal diagnostic tool for chest pain assessment [2, 4, 12]. Quite a few studies showed the feasibility of this approach based on 64-slice CT technology with temporal resolution in the area of 165–200 ms, but also indicated that coronary CTA still represented the limitation of the method due to the high incidence of high heart rates that made coronary assessment unreliable [1, 3]. Recent studies have shown that diagnostic images of the coronary arteries can be obtained reliably with dual-source CT even in very high heart rates [10, 11]. Thus, dual-source CT was expected to greatly improve the diagnostic accuracy of the combined CT protocol, and our results indicate that this assumption was correct: There were no examinations rated as non-diagnostic because of blurring of the coronary arteries due to high heart rates. There were six exams with partially insufficient contrast opacification, which mainly affected pulmonary artery evaluation and three examinations with breathing artifacts that impeded coronary assessment, but otherwise the main coronary artery segments were reliably assessable. This is reflected in the detailed analysis of the coronary CT angiography in relation to invasive angiography, in which only 7% of coronary artery segments were excluded, mainly due to very small size in distal vessel segments and side branches. Regarding the diagnostic accuracy, the excellent performance in the patient-based analysis confirms that the method can be very helpful for fast patient triage. However, it has to be acknowledged that stenoses were quite frequently rated as ‘potentially relevant’ in CTA so that invasive angiography was not only necessary for intervention, but also for definite diagnosis. Also, some false-positive results would have to be expected in larger patient groups.
Still, it has to be emphasized that a valid, relevant diagnosis could be made in 62% of the patients, and in 25% relevant diseases were ruled out. Regarding sensitivity for the cause of chest pain, the value of 98% in the present study is somewhat higher than the 93% observed in a study on ECG-gated 64-slice thoracic CTA [1] and compares well with an initial DSCT study that reported a sensitivity of 96% [13]. In 13% of patients there were findings such as coronary atherosclerosis or vascular variants that were not immediately relevant as a reason for chest pain, but that are still valuable information for further patient management.
Comparing the results of coronary CTA correlation in this study, sensitivity, specificity, positive and negative predictive values of 100%, 99%, 79% and 100% are comparable to an initial study by Scheffel et al. [11]. They observed respective values of 96%, 98%, 86% and 99% for dual-source CT coronary CTA without heart rate control in a high pretest-probability group, although the rate of 1.4% non-assessable segments was remarkably low compared to 7% in our study. The somewhat higher negative and lower positive prediction may be attributed to a more sensitive diagnostic reading in our group of acutely ill patients. In a similar 64-slice CT study by Nikolaou et al. [9], respective values of 97%, 79%, 86% and 96% with 10% non-assessable segments were recorded for an intermediate likelihood population with strict heart rate control. These values suggest that a similar accuracy can be achieved with DSCT without beta blockers.
Due to the variability in body size and habitus, the equivalent doses calculated from dose length products are only correct for less than half of the population and therefore can only serve as rough estimations. The median value of 15.1 mSv is about twice that of coronary artery CTA with dual-source CT, but only moderaltely higher than that for coronary CTA alone with single-source 64-slice CT [14, 15]. The increase is mainly related to the high heart rates in this acute patient group that require a wider pulsing interval for the reconstruction of systolic images. The longer coverage including the upper chest contributes rather little to the dose because it is acquired normally with only one tube switched on. Therefore, performing coronary CTA alone without coverage of the upper chest would save only little of the dose in this patient group. Thus, the additional dose from the longer coverage is well invested considering the diagnostic value. Also, comparing DSCT to single source CTA, the high diagnostic accuracy of DSCT can be regarded as well invested dose compared to single source scanners in which the dose can be estimated to be higher for this patient group because the pitch would have to be reduced to apply multi-segment reconstruction algorithms [16, 17], and pulsing would mostly have to be switched off to yield diagnostic examinations with optimized reconstructions [8]. Also, considering alternative diagnostic approaches for the evaluation of chest pain, for example, including pulmonary CTA, aortic CTA and invasive coronary angiography, this combination would result in a higher total patient dose [1]. Magnetic resonance imaging would be an alternative modality for the assessment of pulmonary embolism and aortic pathology, and an MR exam of myocardial wall motion and perfusion could serve as a method to rule out hemodynamically relevant coronary pathology without radiation exposure [18, 19]. However, the limited availability and the long examination times currently let such an approach seem less applicable in a clinical setting [20].
Several limitations of this study have to be acknowledged. One limitation is the exclusion of patients with the evidence of an acute coronary syndrome based on ECG or serum markers, which causes a bias in the assessment of the diagnostic accuracy of coronary CTA. Another limitation is the lacking correlation to other diagnostic approaches in the evaluation of pulmonary embolism and aortic disease. Of course, additional ventilation/perfusion scintigraphy and aortic MRI would be desirable for study purposes, but cannot be justified considering the necessary time and the encroachment of acutely ill patients and the involved radiation exposure. Also, additional invasive coronary angiography of the patients without coronary findings would be helpful to assess the actual negative predictive value, but the application of this invasive procedure involving radiation exposure to patients with other pathologies would of course not be acceptable. The follow-up of the coronary angiography database that showed no readmissions at least confirms the unlikelihood of relevant coronary artery stenoses in these patients.
The fact that immediately therapy-relevant findings in all vascular districts were represented and quite evenly distributed in our patient population emphasizes that a combined protocol can be a valuable tool for diagnostic workup of acute, unclear chest pain. In conclusion, the specific dual-source CT protocol for chest pain assessment proved to be a very helpful tool offering a fast diagnostic workup and patient triage.

chest pain
ct angiography
pulmonary
embolism
coronary artery disease
aortic dissection


Cardiovascular complications of pediatric chronic kidney disease

Cardiovascular disease (CVD) mortality is a leading cause of death in adult chronic kidney disease (CKD), with exceptionally high rates in young adults, according to the Task Force on Cardiovascular Disease. Recent data indicate that cardiovascular complications are already present in children with CKD. This review summarizes the current literature on cardiac risk factors, mortality and morbidity in children with CKD.
Learning objectives:
To review recent data on the epidemiology of CVD in children with CKD
To understand the mechanisms of cardiovascular abnormalities in pediatric CKD
To review recent advances in the diagnosis and clinical presentation of cardiovascular complications in children with CKD
To outline current understanding in the strategies to prevent progression of CVD in children with CKD.
Cardiovascular mortality and morbidity
The survival of children with CKD in the U.S. remains low: for children on dialysis the lifespan is 40–60 years less and for transplant patients, about 20–25 years less than that of an age- and- race-matched US population [1, 2]. The most likely cause of this is increased cardiovascular mortality due to the development of accelerated ischemic heart disease and premature dilated cardiomyopathy. The evidence comes from studies of young adults who developed renal failure during childhood. Oh et al. [3] analyzed the outcome of 283 young adults with childhood onset CKD between 1970 and 1997. Fifty percent of the deceased patients had died of cardiovascular or cerebrovascular events. Groothoff et al. [4] conducted a national retrospective and prospective cross-sectional study to evaluate the late physical, social and psychological effects of renal insufficiency (LERIC) in all Dutch children who started renal replacement therapy between 1972 and 1992. Of 381 patients, 85 had died. Cardiovascular disease was the most common cause of death and accounted for 41% of all deaths. Cerebrovascular accident, congestive heart failure, myocardial infarction and cardiac arrest (respectively) were the most common causes of cardiac death. Similar analysis of long-term survival from the Australia and New Zealand Dialysis and Transplant Registry [5] of all children and adolescents who were under 20 years of age when renal replacement therapy commenced (study period was 40 years) showed mortality rates 30 times higher than in the age-matched general population; CVD was the most common cause of death (45%).
Cardiovascular death happens not only in later life, but also in childhood CKD. In the general pediatric population, the incidence of annual death due to cardiac disease is less than 3%. Yet annual reports from the United States Renal Data System (USRDS) indicate that over the last decade CVD has remained the second most common cause of death in children on chronic dialysis or after transplantation, accounting for approximately 20–25% of all deaths. Parekh et al. [6], using the USRDS database, performed a detailed cross-sectional analysis to evaluate the risk of a cardiac death in children and young adults (age 0–30 years) and to identify factors potentially associated with CVD mortality. A total of 1,380 deaths between 1990 and 1996 were analyzed. There were 311 cardiac deaths (22.5% of the total). Cardiac deaths in children and young adults in whom ESRD developed during childhood were approximately 1,000 times more frequent than in the general pediatric population. Of the specific categories of cardiovascular deaths, cardiac arrest was the most common cause in each of the age groups, followed by arrhythmia and cardiomyopathy. These causes of cardiac death are different from those of adults. In adults, coronary artery disease and chronic congestive heart failure are the leading causes of CVD mortality and, as shown by Parekh et al. [6], these causes are extremely rare in children and adults younger than 30 years of age. The incidence of cardiac arrest in the youngest age group (0–4 years) was five to ten times higher than in other age groups, perhaps, as noted by the authors, a reflection of the difficulty of ascertaining the true cause of death in young children. Some of these young children might have died from other co-morbid conditions such as congenital disorders that are not included in the USRDS database.
The high rate of sudden death in children, especially in infants with ESRD, is poorly understood and warrants further investigation. In adults, sudden death is often a result of fatal arrhythmias due to acute ischemia of preexisting atherosclerotic disease. It is believed that arrhythmias are also the likely cause of most cases of sudden cardiac death (SCD) in children. However, the origin of acquired malignant arrhythmias in children is unlikely to be an atherosclerotic lesion. Dilated, especially hypertrophic, cardiomyopathies are a leading cause of SCD in children [7]. The macroscopic and microscopic structural abnormalities in cardiomyopathies involve fibrosis and cellular hypertrophy prone to produce an electrical instability with resultant arrhythmias. Ischemia of small coronary vessel disease secondary to medial hypertrophy might result in dispersion of repolarization properties and arrhythmia from re-entrant or autonomic mechanisms. As we discuss in more detail below in this review, children with CKD develop left ventricular hypertrophy (LVH), which is frequently severe, especially in children on prolonged dialysis therapy [8, 9]. It is currently unknown if LVH in young patients with CKD is characterized by structural abnormalities similar to familial or idiopathic hypertrophic cardiomyopathies associated with SCD. Whether LVH of children with ESRD can contribute to increased SCD is also not known. Another possibility for deadly arrhythmias in children with ESRD is acute changes in the cardiac extra- or intracellular ionic milieu, especially involving abnormalities of sodium- and potassium-based repolarization currents.
Because the causes of cardiac death in children and adults are different, it is not surprising that none of the traditional or uremia-related risk factors for adult atherosclerotic CVD predicted cardiac death in the study by Parekh [6]. One of the examples presented in this paper is the effect of race on CVD death. In adults with ESRD, white males are at higher risk for CVD mortality. In contrast, black children as shown by Parekh et al. [6] appear to have an increased risk for cardiac death. Another important observation of this study is that transplant recipients had 78% lower risk of cardiac death than dialysis patients. However, the authors pointed out that the CVD mortality rate in transplanted patients was still significantly higher (approximately ten times) than in the general pediatric population.
The analysis of cardiac morbidity in children on chronic dialysis performed by Chavers et al. [10] has confirmed that cardiac disease in children is different from adults. A total of 1,454 Medicare incident pediatric (0–19 years) dialysis patients were identified from 1991 to 1996. Among them, 452 (31.2%) developed a cardiac-related event. Arrhythmia was most common (19.6%), followed by valvular disease (11.7%), cardiomyopathy (9.6%) and cardiac arrest (3%). Ischemic heart disease was extremely rare in these children.
Risk factors for cardiovascular disease
The risk factors and pathogenic mechanisms of development of CVD in young adults who had onset of CKD in childhood are better understood than are those producing cardiac morbidity and mortality in children. The conventional thinking is that two groups of risk factors are responsible for accelerated CVD in adults with CKD (Table 1).
Table 1Cardiovascular risk factors in chronic kidney disease in adultsTraditionalCKD-relatedOlder ageDecreased GFRWhite raceProteinuriaMale genderPeripheral renin-angiotensin-aldosterone activityHypertensionAbnormal calcium and phosphorus↑ LDL CholesterolDyslipidemia↓ HDL CholesterolHypoalbuminemiaDiabetes mellitusHemodynamic overloadTobacco useAnemiaPhysical inactivityThrombogenic factorsPsychosocial stressHyperhomocysteinemiaFamily history of CVDOxidative stressLVHInfection (Chlamydia pneumoniae)ObesityChronic inflammation
First, as compared to the non-uremic population, there is an over-representation in uremic patients of classical risk factors, e.g., diabetes, hypertension and hyperlipidemia. A majority of the adults who develop ESRD do so as a complication of diabetes or generalized atherosclerosis. Often cardiac disease antedates the onset of CKD in these patients. Unfortunately, children with CKD share with adults a similar high prevalence of risk factors for adult-type atherosclerotic CVD. It is also troubling that the frequencies of these traditional risk factors have not changed over last decade. The North American Pediatric Renal Trials Collaborative Studies (NAPRTCS) data demonstrate that hypertension develops at early stages of CKD (48%) and persists (50–75%) in uremic children [11–14]. Dyslipidemia is found in 70 to 90% during chronic dialysis [15–18]. Successful renal transplantation leads to a dramatic improvement in renal function and elimination of many risk factors for atherosclerotic CVD that were present while on dialysis. However, transplant recipients are not free from multiple complications, and transplantation may amplify some of the traditional risk factors. Indeed, the prevalence of hypertension in pediatric renal allograft recipients is between 50–80% [19–21]. Also, hyperlipidemia may not disappear after renal transplantation; the reported prevalence is above 50% [22–24]. The NAPRTCS data also show that the rate of obesity, another CV risk, is increasing in children with ESRD at the time of transplantation (12.4% after 1995 vs. 8% prior to 1995) [25]. Single-center study data indicate that the number of obese patients can double at 1 year after transplantation [26].
Second, there is a multitude of uremia-related risk factors for atherosclerotic CVD. In adults with CKD, an increased homocysteine level appeared to be an independent risk factor for CVD morbidity and mortality [27–29]. Anemia has been linked to negative CVD outcome [30]. Hyperphosphatemia with increased calcium-phosphorus product constitutes a risk for cardiovascular calcification, cardiac ischemia and adverse cardiovascular outcomes [31, 32]. Elevated serum C-reactive protein (CRP), a marker of systemic inflammation, has been found to be a strong predictor of cardiac morbidity and cardiac death in CKD patients [33]. Another marker of inflammation, IL-6, has been associated with increased cardiac morbidity in adults with CKD [34, 35]. The role of systemic inflammation in CKD has been reviewed recently elsewhere [36]. Inflammation is directly linked to oxidative stress, which is now considered as a hallmark of uremia [37]. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase and a marker of oxidative stress, has been extensively evaluated in patients with CKD by Zoccali et al. [38]. The authors demonstrated that elevated ADMA per se was responsible for a 52% higher risk of death and for a 34% higher risk of cardiovascular events in dialysis patients [39]. Another subset of novel CVD risk factors is adipokines. Adipokines, leptin and adiponectin, are the products of adipose tissue involving in regulation of lipid and glucose metabolism. Abnormal adipokines are strongly linked to insulin resistance, a known CV risk in CKD [40]. It has been determined that lower plasma adiponectin concentration independently predicts increased CVD morbidity and mortality in adults with ESRD [41]. Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients extensively reviewed the current literature on CVD biomarkers, and the reader is referred to this publication for more information [42]. As in adults, in children with CKD many of these risk factors are very prevalent (Table 2).
Table 2Prevalence of risk factors for CVD in children with CKDRisk factorsCRIa (%)Dialysisb (%)Transplantc (%)ReferencesHypertension4852–7563–8111a, 12–14b, 19–21cDyslipidemia25–5333–8755–8415a, 15–18a, b, 22–24cAnemia4840–6732–6443a, 44–47b, 48–51c,Hyperparathyroidism32.6–43.758–43Hyperhomocysteinemia87–9225–10052c, 53b, c, 54c, 55b↑ CRP761656b,57cHypoalbuminemia–40–60–43b, 44b, 58–59b
Recent studies in adults on chronic hemodialysis place a malnutrition-inflammation complex at the center of a debate about the role of traditional and non-traditional risk factors for poor cardiovascular outcome. This issue emerged after publication of a series of articles, summarized in the review by Nurmohamed and Nube [60], describing the phenomenon of “reverse epidemiology.” The studies have shown that in adults on chronic hemodialysis low blood pressure, low body mass index (BMI), low serum cholesterol and low serum homocysteine are often correlated with an unfavorable clinical outcome. Thus, whereas traditional risk factors of CVD are correlated with an unfavorable outcome in the general population and patients with CKD not yet on dialysis, in hemodialyzed patients, mild hypertension, hypercholesterolemia and being overweight appear to be protective and associated with an improved survival. It has been speculated that a malnutrition-inflammation-atherosclerosis complex underlies, at least partly, the phenomenon of reverse epidemiology, since malnutrition causes a low BMI, hypocholesterolemia and low serum homocysteine levels.
Mechanisms of cardiovascular disease in chronic kidney disease
There are two parallel processes involved in the development of CVD in CKD patients (Fig. 1).
Fig. 1Cardiovascular disease in chronic kidney disease
The first is cardiac remodeling leading to hypertrophy of the left ventricle (LV) as a response to mechanical or hemodynamic overload. Two different patterns of LV remodeling can produce increase in LV mass (LVM) [61]. The concentric LV remodeling and hypertrophy may be the results of pressure overload as occurs with hypertension, whereas eccentric LVH may be related to volume and sodium retention, anemia and arteriovenous shunt. The patterns of sarcomere formation induced by pressure or volume overload are distinct. Pressure-induced concentric LVH is characterized by a parallel addition of sarcomeres resulting in the increase of cross-sectional area and diameter of the myocytes. Increase in LVM in this case is obtained by a marked increase in wall thickness with a less evident increase in the LV cavity that yields an elevated relative wall thickness and concentric LVH. From the physiological view, increased systolic blood pressure (BP) and pulse pressure, due to increased peripheral resistance and arterial stiffness, are the principal factors opposing LV ejection and leading to an increased LV workload and concentric LVH. An increase in LVM can also be obtained by an increase in the LV cavity with a symmetric increase in wall thickness to maintain the ratio between the wall thickness and LV transversal radius (relative wall thickness) normal, producing eccentric LVH. In this case, the addition of sarcomeres occurs mainly in series resulting in longitudinal cell growth. In the transition to maladaptive LVH, LV dilatation becomes disproportional to wall thickness, with myocytes elongated without an increase in diameter.
Experimental models of cardiac hypertrophy support the theory that mechanical stress due to either pressure or volume overload is a trigger for activation of other multiple mechanisms leading to myocardial remodeling [62]. These factors include a local overexpression of the renin-angiotensin-aldosterone system (RAAS), adrenergic system, inflammatory cytokines and other autocrine and paracrine mechanisms. In patients with CKD, these mechanisms might be activated independently of hemodynamic overload since uremia per se is associated with an alteration in multiple humoral factors [63, 64]. With time, a maladaptive phase of LVH develops, characterized by decreased capillary density, decreased coronary reserve and subendocardial perfusion, a tendency to arrhythmia, and the development of myocardial fibrosis. All this leads to myocyte death and, finally, to diastolic and systolic dysfunction.
The second process involves vascular injury. Exposure to CV risk factors results in vascular changes, including atherosclerotic and arteriosclerotic processes and vascular calcification.
Atherosclerosis refers to the process of plaque formation or atheroma development. The process of atheroma formation begins with an accumulation of lipid-containing foam cells (macrophages) in the vascular intima and evolves into successive structures that penetrate the vascular wall and include lipids, smooth muscle cells and collagen fibers [65]. Calcification is an intrinsic part of the process and generally involves the intima. Atherosclerotic lesions have a patchy distribution along the length of the artery and cause local stenoses and occlusions. Recently, endothelial progenitor cells (EPCs) have been identified as contributing to angiogenesis [66]. The EPC number has been shown to be reduced in patients with CVD, leading to speculation that atherosclerosis may be caused by a consumptive loss of the endothelial repair capacity. Animal experiments have shown that EPCs reendothelialise injured vessels and that this reduces neointimal formation, confirming that EPCs have an atheroprotective effect.
Arteriosclerosis is arterial stiffening involving the entire arterial tree, although it principally affects the elastic arteries. Unlike atherosclerosis, arteriosclerosis involves both intimal and medial thickening. In CKD, arteriosclerosis can occur in the absence of significant atherosclerotic disease [67–69]. Arteriosclerosis is associated with vascular remodeling characterized by increased wall thickness, lumen enlargement and increased length of arteries. This leads to an increase of systolic BP and pulse pressure and arterial stiffening.
The triggers for vascular calcification are complex and include metabolic, mechanical, infectious and inflammatory injuries. Increased calcium x phosphate ion product or hyperphosphatemia may be the key promoter of vascular calcification [70]. The mechanisms include either stimulation of the uptake and precipitation of calcium and phosphate into the vessel or a decrease of the inhibitory process that prevents these ions from precipitation. Fetuin-A, the anti-inflammatory protein, is a highly potent inhibitor of serum calcium-phosphate complex formation [71, 72]. The serum concentrations of Fetuin-A are decreased in ESRD patients [73]. Another promoter of vascular calcification is 1,25(OH)2D3, which may have a direct effect on the calcium deposition in vascular smooth muscle cells [74]. In a comprehensive review, Vattikuti and Towler [75] defined four major histo-anatomic variants of vascular calcification, including classic atherosclerotic (fibrotic) calcification related to disorders of lipid metabolism, medial arterial calcification, vascular calcifilaxis and cardiac valve calcification.
Spectrum of cardiovascular abnormalities in children with CKD
Over the last decade, abnormalities of the LV such as LVH and LV dysfunction, abnormalities of the large arteries such as stiffness and increased intima-medial thickness (IMT) of the carotids, and calcification of the coronaries have been accepted as early markers of cardiomyopathy and atherosclerosis. They constitute strong independent predictors of cardiac morbidity and mortality both in the general population and in adults with CKD. In children and young adults with CKD, recent studies have proven that these abnormalities are also present and that risk factors for cardiac and vascular injury in children with CKD are similar to those for adults.
Left ventricular hypertrophy
LVH develops when renal insufficiency, is mild or moderate in children and progresses as renal function deteriorates. About one third of children with mild to moderate renal insufficiency have an increased left ventricular mass (LVM) index [76–78]. In a 2-year prospective longitudinal study of 31 pediatric subjects with CKD stage 2–4, Mitsnefes et al. [79] showed that a substantial proportion of children had a significant increase in the LVM index, with many of the children developing LVH. Indeed, 32% of the patients who initially had a normal LVM index have developed incident LVH. At initiation of maintenance dialysis, 69–82% of pediatric patients have evidence of LVH [80, 81]. LVH persists (40–75%) during long-term dialysis [8, 76, 82–85], with both concentric and eccentric geometric patterns of LVH present in these patients. Post-mortem studies confirmed high rate (more than 50%) of LVH in children with ESRD [86]. Small retrospective studies also suggest that with a better BP and volume control, LVH regression might be achieved in young patients on dialysis [80, 81]. On the other hand, a recent retrospective study demonstrated that LVH remains very prevalent and severe in a selected group of children who remained on maintenance dialysis for at least 2 years [9].
As in children prior to transplantation, most pediatric studies indicate that LVH remains common post transplant (48–82%) [87–91]. In contrast, a significantly lower frequency of LVH was found in a study by Englund et al. [92], who reported the results of a longitudinal analysis of children receiving renal transplants 10–20 years ago. Of 53 children who received a renal transplant between 1981 and 1991, 47 survived and were observed for 10 to 20 years. At the 10-year follow-up, echocardiography showed minor LVH in only two children with hypertension. No child without hypertension at 10 years post transplant had LVH.
The factors associated with cardiac hypertrophy in children are similar to those in adults with CKD. As in adults, most pediatric studies of patients with pre-terminal, terminal renal failure and post transplant found significant relationships between low hemoglobin and an increased LVM index [8, 78, 79, 90]. However, recent adult studies in mild to moderate CKD or in chronic dialysis determined that correction of anemia was not associated with regression of LVH [93–96]. Authors suggested that relationships between anemia and LVH might not be causal. Of note, the above studies enrolled subjects with relatively mild degrees of baseline anemia and could not answer the question whether treatment of patients with initially significantly decreased hemoglobin levels might lead to a reduction of LVM. In contrast, Morris et al. [97] observed a significant reduction in the LVM index with the correction of severe anemia in seven children on chronic dialysis.
There are several studies on the association between parathyroid hormone (PTH) levels and LVH in adults with CKD [98, 99]. In children, elevated PTH is associated with progression of LVH in stages 2–4 CKD [79]. The possible mechanisms of parathyroid-induced cardiac hypertrophy in CKD include a direct effect of PTH on cardiomyocytes and an indirect effect via elevated BP [99]. A support for a causal relationship comes from in vitro studies showing that PTH appears to have chronotropic, inotropic as well as hypertrophic effects on cardiomyocytes [100, 101].
In adults with CKD, hypertension is directly linked to the development of LVH [39]. The relationships between BP and LVH in pediatric CKD are unclear. Consistent correlations of LVM and BP are limited to children with ESRD [8, 85]. However, a detailed cross-sectional analysis of BP characteristics by ambulatory blood pressure monitoring (ABPM) in children from the ESCAPE trial did not demonstrate any relationship between office BP or ABPM parameters and LVM, suggesting only a minor role of hypertension in the pathogenesis of LVH in early CRI [78]. In contrast, analysis of longitudinal data suggests that ABPM might be an important tool to assess the risk of development of LVH in children with CKD [79]. In this study, authors determined that an increase in the nighttime systolic BP load (number of BP measurements above the 95th percentile BP value) were independently associated with the increase in the LVM index over time, arguing that persistent and chronic elevation of BP might be more important in the development of LVH [79].
Left ventricular function
In contrast to adults, in whom systolic dysfunction is frequently associated with early cardiac failure and decreased survival, in children with CKD systolic LV function is usually preserved [76, 102–104]. On the other hand, diastolic dysfunction, often the initial abnormality of cardiac function, is already present in children with CKD. Doppler measurement of mitral inflow velocity has been the most widely used method to assess LV diastolic function. Using this method, Goren et al. [103] showed that LV relaxation (E/A ratio) was impaired in dialyzed children as compared to controls. Johnstone et al. [76] also found a reduction in the E/A ratio in children on chronic peritoneal dialysis and with pre-terminal renal failure, although none of these patients had an E/A ratio <1.0, which is considered to be abnormal. Unfortunately, the transmitral Doppler velocities and, therefore, the E/A ratio, are affected by several factors, including left atrial pressure and preload. This is particularly important for patients with advanced chronic renal failure, since many of them are hypervolemic. Recently, new indices were introduced to evaluate diastolic function using tissue Doppler imaging (TDI). In contrast to E/A, the TDI indices may be less load dependent and provide a more accurate measure of diastolic function. Recent studies employing TDI determined that children with CKD might have abnormal diastolic function [105, 106]. In these studies, children on chronic dialysis had significantly worse diastolic dysfunction than children with mild-to-moderate CRI or post transplant. Poor diastolic function in patients on dialysis was associated with anemia, hyperphosphatemia, increased calcium-phosphorus ion product and LVH. The clinical significance of diastolic dysfunction in pediatric patients with CKD is not known. Longitudinal studies are necessary to determine if abnormal diastolic function predicts the development of systolic dysfunction and congestive heart failure in these patients.
Arterial structure and compliance
Studies of young adults who developed ESRD during childhood found a high prevalence of abnormal carotid IMT, diminished arterial wall compliance and coronary artery calcification (CAC). These vascular abnormalities are accepted as markers of asymptomatic atherosclerosis and predictors of future symptomatic CVD in the general population and in adults with CKD [107, 108]. Groothoff et al. [109] found increased arterial stiffness and showed that systolic hypertension was the main determinant of abnormal arterial wall compliance. Goodman et al. [110] showed that among 23 patients on chronic dialysis who were younger than 20 years of age, none had evidence of CAC; in contrast, 14 of the 16 patients who were 20 to 30 years of age had evidence of CAC on CT scanning. Oh et al. [3] screened for coronary and carotid artery disease in 39 patients, aged 19 to 39 years, with childhood onset ESRD. Coronary artery calcification was present in 92% and carotid IMT was significantly increased compared to matched controls. Carotid IMT was correlated with cumulative dialysis and serum Ca x P product in their study. Milliner et al. [111], in an autopsy study of pediatric patients with ESRD who died in 1960–1983, showed a high prevalence of soft tissue and vascular calcinosis. In their study, CAC was present in 28%. Peak Ca x P product, peak serum P and cumulative dose of calcitriol were significantly associated with the severity of the calcinosis. Civilibal et al. [112] screened 53 children with ESRD for the presence and predisposing factors of CAC. Coronary artery calcification was present in 15% of patients (three hemodialysis patients, three peritoneal dialysis patients and two renal transplant recipients). The patients with CAC had a longer duration of total dialysis, had higher time-integrated serum phosphorus, calcium-phosphate product, intact parathyroid hormone, vitamin B12 levels and the amount of cumulative calcium-containing oral phosphate binders. In a study by Briese et al. [113] of 40 young adults (mean age 23.6 years) who developed ESRD at a mean age of 11.5 years, carotid artery IMT was similar to healthy controls and only 4 (10%) patients had evidence of coronary calcification. Authors noticed that a relatively low rate of cardiac calcification compared to other studies might be explained by a significantly lower amount of prescribed calcium-containing phosphate binders and vitamin D preparations in their patients. Of note, these patients had decreased vascular reactivity and a high rate of LVH (68.2%). As in adults, cardiac valve calcification was also described in children on maintenance dialysis [114].
Evidence of early atherosclerotic changes was found in the study by Nayir et al. [115], who reported on the histopathology of internal iliac artery samples obtained at the time of kidney transplantation in 12 children. Five arteries had fibrous or fibroelastic intimal thickening, medial mucoid ground substance and disruption of the internal elastic lamella. Two of these had microcalcification in the intimal layer; another two demonstrated atheromatous plaques. These abnormalities were associated with longer duration of renal failure.
Vascular abnormalities in children develop in parallel with cardiac abnormalities early in the course of CKD and become more severe as end-stage disease is reached [116]. Mitsnefes et al. [54] showed that carotid arteriopathy is present in children after successful renal transplantation and is associated with hypertension. Litwin et al. [117], as a part of the ESCAPE trial, investigated vascular structure and function in children with chronic renal failure and after renal transplantation. The authors demonstrated vascular abnormalities in all patient groups with the most marked changes in the dialysis patients. The degree of arteriopathy in their study was correlated with conventional CVD risk factors such as hypertension and dyslipidemia in pre-dialytic CKD, while in children on dialysis and after transplantation, hyperphosphatemia, hyperparathyroidism and treatment with calcium-containing phosphate binders were determinants of arterial abnormalities. Another important observation in this study was a significantly lower carotid IMT in children post transplant, suggesting that the vascular abnormalities partially regress. Epidemiological studies should determine if vascular abnormalities detected during childhood CKD are associated with future accelerated coronary artery disease.
Endothelial dysfunction as a marker of early atherosclerosis in children with CKD
Endothelial function can be evaluated by the assessing of endothelial vasodilatation. Healthy vascular endothelium will respond to the release of nitric oxide by vasodilatation. With endothelial injury, the response to nitric oxide is diminished [118], and endothelial-mediated vasodilatation is impaired. Flow-mediated dilation (FMD) of the brachial artery is currently used to measure endothelial function. This test consists of applying obstruction to the flow of the brachial artery by placing the tourniquet or inflated BP cuff for few minutes. The artery dilates due to post-obstruction reactive hyperemia. FMD is calculated based on the difference in the diameter of the brachial artery before obstruction and after it released. Impaired (decreased) FMD predicts CVD morbidity and mortality in adults with ESRD [119]. It has been shown that endothelial dysfunction as determined by impaired FMD is also present in children with advanced renal failure, on chronic dialysis and after renal transplantation [120–122].
Evaluation and treatment recommendations
The overall strategy in the prevention of cardiovascular complications in children with CKD is avoidance of long-term dialysis. The goal is to prevent the development and delay the progression of cardiomyopathy and atherosclerosis. The identification of modifiable risk factors and markers of CVD and early intervention should be initiated at the time of mild-to-moderate renal insufficiency, prior to the need for dialysis. Even though kidney transplantation poses a continuous CV risk (hypertension, hyperlipidemia and allograft dysfunction), it eliminates many uremia-related risks, reduces the risk of cardiac death by approximately 80 percent and prolongs the life span by 20–30 years. Thus, kidney transplantation should be the ultimate goal to minimize cardiovascular morbidity and mortality in patients with advanced CKD. For those patients who must have long-term dialysis, the strategy is directly linked to achievement of optimal dialysis outcomes, which include aggressive monitoring and management of hypertension, dyslipidemia, calcium-phosphorus metabolism, anemia, nutrition, systemic inflammation and other dialysis complications.
Current recommendations on evaluation of CV abnormalities and treatment of modifiable risk factors in children are based mostly on clinical experience and adult data. Recent K/DOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients [42] recommend echocardiographic evaluation for the presence of cardiac disease in children (cardiomyopathy and valvular disease) at the time of initiation of dialysis therapy along with the screening for dyslipidemia, hypertension, anemia and increased Ca×P product. Management of modifiable risks in children with CKD should follow recommendations from the K/DOQI guidelines for treatment of anemia [123] and dyslipidemia [15] and from the Fourth Report on Blood Pressure in Children for Management of Hypertension [124]. Current K/DOQI guidelines for treatment of anemia recommend keeping the hemoglobin level above 11 g/dl by using an appropriate iron therapy and recombinant erythropoietin. In the opinion of the Working Group, there is insufficient evidence to recommend routinely maintaining hemoglobin levels above 13 g/dl or more.
K/DOQI recommends evaluation of dyslipidemia in adolescents upon presentation with CKD stage 5 (GFR <15 ml/min/1.73 m2 or on dialysis), at 2–3 months after a change in treatment or other conditions known to cause dyslipidemia and at least annually thereafter. Reasons to repeat lipid measurements after 2–3 months include changes in the kidney replacement therapy modality, treatment with diet or lipid-lowering agents, immunosuppressive agents that affect lipids (e.g., prednisone, cyclosporine or sirolimus) or other changes that may affect plasma lipids. The assessment of dyslipidemia should include a complete fasting lipid profile with total cholesterol, LDL, HDL and triglycerides. The definition of dyslipidemia differs in children and adults. Hyperlipidemia in children is defined as lipid levels greater than the 95th percentile for age and gender. The normative data for lipids in children and adolescents currently used are from the Lipid Research Clinics Program from the NIH published in 1980 and can be found in the 2003 K/DOQI guidelines for management of dyslipidemia in chronic kidney disease [15].
For adolescents with stage 5 CKD and a level of LDL ≥130 mg/dl, K/DOQI recommends treatment to reduce LDL to <130 mg/dl. If LDL is <130 mg/dl, fasting triglycerides ≥200 mg/dl and non-HDL cholesterol (total cholesterol minus HDL) ≥160 mg/dl, treatment should be considered to reduce non-HDL cholesterol to <160 mg/dl. All children with dyslipidemia should follow the recommendations for therapeutic lifestyle changes (TLC), which include diet modification with a reduction in saturated fat intake and increase in fiber intake, and moderate physical activity. Adolescents should be counseled about avoiding smoking. Unfortunately, non-compliance with TLC is one of the major problems in the management of dyslipidemia in adolescents. Pediatric nephrologists must also recognize that appropriate caloric intake, including calories from fat, should be emphasized to avoid malnutrition and ensure normal growth and development, especially in young children. If LDL cholesterol is ≥160 mg/dl and non-HDL cholesterol ≥190 mg/dl, statin therapy is recommended in children older than 10 years.
Target blood pressure in children should be lower than the 90th percentile for normal values adjusted for age, gender and height or less than 120/80 mm Hg, whichever is lower. Ambulatory blood pressure monitoring is recommended to assess the circadian rhythm. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be the preferred antihypertensive agents to slow the progression of CKD in children and possibly for regression of LVH. The Working Group on Cardiovascular Disease in Dialysis Patients recommends maintaining calcium and phosphorus levels within the normal range and the Ca×P product <55 mg2/dl2 in children on chronic dialysis [42].
There are no data available to make evidence-based recommendations on management of hyperhomocysteinemia, chronic inflammation or other potential CVD risk factors.
Questions(Answers appear following the references)
A 14-year-old African-American boy with ESRD secondary to FSGS has been treated with thrice-weekly hemodialysis for 1 year. His pre-dialysis BP is 132/85, hemoglobin is 9.8 g/dl, serum calcium is 10.6 g/dl, serum phosphorus is 8.2 g/dl and iPTH is 412 pg/ml. He is taking a calcium channel blocker to control his hypertension, erythropoietin and iron to control his anemia and calcium carbonate and a vitamin D IV preparation to control his renal bone disease.Which ONE of the following statements would be the BEST therapeutic intervention in this child to minimize the risk of future CV complications?Aggressive treatment of hypertensionMaximize dialysis treatment to achieve dry weightCorrection of anemiaKidney transplantationReduction of Ca-P productThe patient from the previous question was diagnosed with eccentric LVH.With regard to treatment of his LVH, which ONE of the following actions is MOST LIKELY to lead to reduction of LVH?Adding ACE inhibitor as a second antihypertensive agentIncrease the dose of erythropoietin and assure appropriate iron status to treat anemiaAchievement of dry weightSwitch from hemodialysis to peritoneal dialysisMaximize treatment of secondary hyperparathyroidismThe annual evaluation showed that this patient has LDL cholesterol of 170 mg/dl. You would like to start this patient on atorvastatin.With regard to the use of “statin” in this patient, which ONE of the following statements is correct?Statins are not approved by the United States Food and Drug Administration (USFDA) for use in children and adolescentsGrapefruit is contraindicatedThe dose of atorvastatin should be reduced by 50% compared to dosage in adult patients on dialysis to prevent adverse effects on growth and developmentThe target level for LDL cholesterol in children with CKD should be below 100 mg/dlAtorvastatin therapy will reduce mortality risk in this patientWhich ONE of the following statements concerning development of cardiovascular complications in a child with CKD is NOT correct?Cardiovascular disease is the cause of mortality in approximately 25% of chronically dialyzed childrenCardiac arrest is the most common cardiac cause of death in children with ESRDCardiac and vascular remodeling might develop in children during early stages of CKDCorrection of anemia reduces concentric LVHLVH is the most common cardiac abnormality in children on maintenance dialysisThe patient described in the previous questions is at risk for development of vascular calcification.Which ONE of the following choices does NOT correctly describe the mechanisms of vascular calcification in dialyzed patients?Histo-anatomic variants of calcification include classic atherosclerotic (fibrotic) calcification related to disorders of lipid metabolism, medial arterial calcification, vascular calcifilaxis and cardiac valve calcificationIncreased Ca-P product and hyperphosphatemia are the key drivers of vascular calcification in young patients with CKDInflammatory mechanisms are involved in mediating all stages of atherosclerosis including calcificationIncreased serum level of Fetuin-A promotes Ca-P ion product precipitation1, 25 (OH)2D3 increases calcium deposition in the vascular wall
Answers
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chronic kidney disease
cardiovascular disease
children
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