Serum cobalt levels after metal-on-metal total hip arthroplasty

BACKGROUND: Systemic cobalt dissemination from the Metasul Co-28Cr-6Mo-0.2C metal-on-metal total hip prosthesis has been demonstrated in the first year after implantation. The aim of this prospective study was to monitor the serum cobalt concentrations in patients during the first five years after total hip arthroplasty with a metal-on-metal articulation. METHODS: A total hip arthroplasty was performed without cement in 100 consecutive patients who had either unilateral osteoarthritis or unilateral osteonecrosis. Fifty patients were randomized to be treated with a metal-on-metal articulation, and fifty patients, with a ceramic-on-polyethylene bearing. The femoral stem was made of a Ti-6Al-7Nb alloy, and the threaded acetabular cup was made of commercially pure titanium. Blood samples were taken before the operation and at multiple time-points for five years after the operation. Serum cobalt concentrations were measured with use of atomic absorption spectrometry. RESULTS: In the metal-on-metal group, the median serum cobalt concentration was 1 micro g/L at one year after surgery and 0.7 micro g/L at five years. The median of the serum cobalt concentrations measured from three to twelve months did not differ from the median of subsequent measurements, with the numbers available. The median serum cobalt level in the control group of patients treated with the ceramic-on-polyethylene articulation was below the detection limit at all time-points. CONCLUSIONS: Systemic cobalt release from Metasul metal-on-metal articulations was demonstrated throughout the five-year study period. The median serum cobalt concentrations were found to be slightly above the detection limit and remained in a constant range. The serum cobalt concentrations did not reflect a so-called run-in wear period of the metal-on-metal articulations.     

Transplacental transfer of cobalt and chromium in patients with metal-on-metal hip arthroplasty: a controlled study

Metal-on-metal bearings are being increasingly used in young patients. The potential adverse effects of systemic metal ion elevation are the subject of ongoing investigation. The purpose of this study was to investigate whether cobalt and chromium ions cross the placenta of pregnant women with a metal-on-metal hip resurfacing and reach the developing fetus. Whole blood levels were estimated using high-resolution inductively-coupled plasma mass spectrometry. Our findings showed that cobalt and chromium are able to cross the placenta in the study patients with metal-on-metal hip resurfacings and in control subjects without any metal implants. In the study group the mean concentrations of cobalt and chromium in the maternal blood were 1.39 microg/l (0.55 to 2.55) and 1.28 microg/l (0.52 to 2.39), respectively. The mean umbilical cord blood concentrations of cobalt and chromium were comparatively lower, at 0.839 microg/l (0.42 to 1.75) and 0.378 microg/l (0.14 to 1.03), respectively, and this difference was significant with respect to chromium (p < 0.05). In the control group, the mean concentrations of cobalt and chromium in the maternal blood were 0.341 microg/l (0.18 to 0.54) and 0.199 microg/l (0.12 to 0.33), and in the umbilical cord blood they were 0.336 microg/l (0.17 to 0.5) and 0.194 microg/l (0.11 to 0.56), respectively. The differences between the maternal and umbilical cord blood levels in the controls were marginal, and not statistically significant (p > 0.05). The mean cord blood level of cobalt in the study patients was significantly greater than that in the control group (p < 0.01). Although the mean umbilical cord blood chromium level was nearly twice as high in the study patients (0.378 microg/l) as in the controls (0.1934 microg/l), this difference was not statistically significant. (p > 0.05) The transplacental transfer rate was in excess of 95% in the controls for both metals, but only 29% for chromium and 60% for cobalt in study patients, suggesting that the placenta exerts a modulatory effect on the rate of metal ion transfer.     

Four-year study of cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip replacements.

BACKGROUND: Metal-on-metal total hip prostheses will produce a certain amount of wear debris. This results in increased whole-blood metal levels, which may cause adverse effects. It is not known to what extent the problem has been overcome by advances in alloy technology. METHODS: In 259 patients who with total hip replacement, blood cobalt and chromium concentrations were measured with atomic absorption spectrophotometry over a period of four years after arthroplasty. Of the patients enrolled in the study, 131 had been managed with a METASUL cobalt-chromium alloy metal-on-metal bearing combination, while 128 had been given a SIKOMET-SM21 cobalt-chromium alloy metal-on-metal combination. The control group consisted of 31 age- and gender-matched subjects. RESULTS: Compared with the controls, all the patients had higher cobalt and chromium levels. Cobalt concentrations were up to 50 times higher, while chromium concentrations were up to 100 times higher. CONCLUSIONS: Both systems showed evidence, in the whole-blood samples, of wear debris production by the implants. Therefore, patients managed with metal-on-metal bearing combinations should be carefully monitored in order to ensure that any local or systemic complications are detected early on.     

No association between serum metal ions and implant fixation in large-head metal-on-metal total hip arthroplasty

Background — The mechanism of failure of metal-on-metal (MoM) total hip arthroplasty (THA) has been related to a high rate of metal wear debris, which is partly generated from the head-trunnion interface. However, it is not known whether implant fixation is affected by metal wear debris.

Patients and methods — 49 cases of MoM THA in 41 patients (10 women) with a mean age of 52 (28–68) years were followed with stereoradiographs after surgery and at 1, 2, and 5 years to analyze implant migration by radiostereometric analysis (RSA). Patients also participated in a 5- to 7-year follow-up with measurement of serum metal ions, questionnaires (Oxford hip score (OHS) and Harris hip score (HHS)), and measurement of cup and stem positions and systemic bone mineral density.

Results — At 1–2 years, mean total translation (TT) was 0.04 mm (95% CI: –0.07 to 0.14; p = 0.5) for the stems; at 2–5 years, mean TT was 0.13 mm (95% CI: –0.25 to –0.01; p = 0.03), but within the precision limit of the method. For the cups, there was no statistically significant TT or total rotation (TR) at 1–2 and 2–5 years. At 2–5 years, we found 4 cups and 5 stems with TT migrations exceeding the precision limit of the method. There was an association between cup migration and total OHS < 40 (4 patients, 4 hips; p = 0.04), but there were no statistically significant associations between cup or stem migration and T-scores < –1 (n = 10), cup and stem positions, or elevated serum metal ion levels (> 7µg/L (4 patients, 6 hips)).

Interpretation — Most cups and stems were well-fixed at 1–5 years. However, at 2–5 years, 4 cups and 5 stems had TT migrations above the precision limits, but these patients had serum metal ion levels similar to those of patients without measurable migrations, and they were pain-free. Patients with serum metal ion levels > 7 µg/L had migrations similar to those in patients with serum metal ion levels < 7 µg/L. Metal wear debris does not appear to influence the fixation of hip components in large-head MoM articulations at medium-term follow-up.     

Exposure to chromium,cobalt and molybdenum from metal-on-metal total hip replacement and hip resurfacing arthroplasty

Background?All metal implants—and metal-on-metal bearings in particular—corrode and cause a release of metal ions. Because cobalt and chromium have been shown to be carcinogenic and mutagenic in human and animal models, systemic toxicity and cancer risk are considered to be possible disadvantages of the metal-on-metal articulation.

This study was designed to investigate the serum concentration profiles of chromium, cobalt and molybdenum after implantation of a Birmingham hip resurfacing arthroplasty (BHR) and a cementless total hip replacement with a 28-mm Metasul articulation (MTHR), over the first 2 years after implantation.

Methods?We analyzed profiles of metal ion serum levels in 111 patients implanted with a BHR, in 74 patients implanted with an MTHR, and in 130 implant-free probands control subjects using atomic absorption spectrophotometry.

Results?Chromium and cobalt concentrations (in μg/L) of all BHR and MTHR patients differed significantly from those of control subjects (chromium: < 0.25; cobalt: 0.25). The median chromium and cobalt concentrations in BHR patients had increased to 5.1 and 4.3 μg/ L 2 years after surgery. Concentrations in BHR patient exceeded those in the unilateral MTHR patients. Molybdenum serum concentrations hardly changed over time in either group and were not significantly different from the concentrations seen in the control subjects.

Interpretation?During the first 2 years after surgery, the Birmingham hip resurfacing arthroplasty leads to a significantly greater increase in serum chromium and cobalt levels than the 28-mm metal-on-metal MTHR. Observation of patients over a longer period will be necessary in order to evaluate any chronic adverse effects to the system due to elevated chromium and cobalt serum concentrations.     

Exposure to chromium, cobalt and molybdenum from metal-on-metal total hip replacement and hip resurfacing arthroplasty

BACKGROUND: All metal implants--and metal-on-metal bearings in particular--corrode and cause a release of metal ions. Because cobalt and chromium have been shown to be carcinogenic and mutagenic in human and animal models, systemic toxicity and cancer risk are considered to be possible disadvantages of the metal-on-metal articulation. This study was designed to investigate the serum concentration profiles of chromium, cobalt and molybdenum after implantation of a Birmingham hip resurfacing arthroplasty (BHR) and a cementless total hip replacement with a 28-mm Metasul articulation (MTHR), over the first 2 years after implantation. METHODS: We analyzed profiles of metal ion serum levels in 111 patients implanted with a BHR, in 74 patients implanted with an MTHR, and in 130 implant-free probands control subjects using atomic absorption spectrophotometry. RESULTS: Chromium and cobalt concentrations (in microg/L) of all BHR and MTHR patients differed significantly from those of control subjects (chromium: < 0.25; cobalt: 0.25). The median chromium and cobalt concentrations in BHR patients had increased to 5.1 and 4.3 microg/L 2 years after surgery. Concentrations in BHR patient exceeded those in the unilateral MTHR patients. Molybdenum serum concentrations hardly changed over time in either group and were not significantly different from the concentrations seen in the control subjects. INTERPRETATION: During the first 2 years after surgery, the Birmingham hip resurfacing arthroplasty leads to a significantly greater increase in serum chromium and cobalt levels than the 28-mm metal-on-metal MTHR. Observation of patients over a longer period will be necessary in order to evaluate any chronic adverse effects to the system due to elevated chromium and cobalt serum concentrations.     

The exercise-related rise in plasma cobalt levels after metal-on-metal hip resurfacing arthroplasty

Wear of metal-on-metal bearings causes elevated levels of cobalt and chromium in blood and body fluids. Metal-on-metal bearings have two distinct wear phases. In the early phase, the wear rate is high. Later, it decreases and the bearing enters a steady-state phase. It is expected that as the wear rates decline, the level of cobalt detected in plasma will also decrease. We studied the baseline and exercise-related cobalt rise in 21 patients (13 men and eight women) with a mean age of 54 years (38 to 80) who had undergone successful hip resurfacing at a mean of 44 months (10 to 96) earlier. Our results showed that circulating baseline cobalt levels were not significantly correlated with the time since implantation (r = 0.08, p = 0.650). By contrast, the exercise-related cobalt rise was directly correlated with the inclination angle of the acetabular component (r = 0.47, p = 0.032) and inversely correlated with the time since implantation (r = -0.5, p = 0.020). Inclination of the acetabular component should be kept less than 40 degrees to decrease the production of wear debris.     

Cobalt and chromium concentrations in patients with metal-on-metal and other cementless total hip arthroplasty

We measured the cobalt and chromium concentrations in the serum and urine of 32 patients with current designed metal-on-metal total hip arthroplasty and 43 patients with conventional metal on ultrahigh molecular weight polyethylene (UHMWPE) cementless total hip arthroplasty. The results of our study showed that the serum and urine chromium concentrations increased in 37.5% and 90.6%, respectively, of 32 patients with well-fixed metal articulation (the mean values were 0.09 microg/dl and 2.2 microg/l, respectively) and also increased in 28.6% and 85.7%, respectively, of 7 patients who received metal-on-UHMWPE articulation with loosened acetabular component or stem made of Co/Cr alloy (the mean values were 0.06 microg/dl and 1.6 microg/l, respectively). On the other hand, the serum and urine cobalt concentrations were below the detection limit in all patients.     

Chronological changes of serum chromium levels after modern metal-on-metal total hip arthroplasty

We determined changes in serum chromium concentration every 6 months up to 3 years after implantation in 44 patients (mean age 63 (49-79) years, 35 women) who underwent modern metal-on-metal total hip arthroplasty (Metasul). The serum chromium levels increased between the first and second year after implantation (1 year: 1.05 (SD 0.76) microg/L, 2 years: 1.46 (SD 0.91) microg/L). A small increase was observed during the third year (1.61 (SD 1.31) microg/L). The clinical relevance of this finding is uncertain and should be determined in long-term studies on a large scale.     

Case report: High chromium and cobalt levels in a pregnant patient with bilateral metal-on-metal hip arthroplasties

Background  

Metal-on-metal bearings frequently are used in young patients leading to the concern that disseminated metals such as chromium (Cr) and cobalt (Co) as the main constituents could affect pregnancies.     

Serum chromium levels before and after revision surgery for loosened metal-on-metal total hip arthroplasty

We investigated the changes of serum chromium levels before and after revision surgery in 10 patients (1 male and 9 females) who underwent exchange of a metal-on-metal articulation for a metal-on-polyethylene component because of aseptic loosening of a metal-on-metal total hip prosthesis. Of the 10 patients, 2 had bilateral metal-on-metal total hip arthroplasty. In the 8 patients who had no residual metal articulation, the mean serum chromium levels before and after revision surgery were 2.53 microg/L and 0.46 microg/L, respectively. In the 2 patients who still had a metal articulation on the contralateral side, the mean serum chromium levels before and after revision surgery were 2.85 microg/L and 1.90 microg/L, respectively. Moderate serum chromium levels in patients with metal-on-metal total hip arthroplasty show a decrease after removal of the metal-on-metal articulation.     

Osteolysis in patients with a metal-on-metal hip arthroplasty

Background: Despite design and manufacturing improvements in contemporary metal‐on‐metal hip replacements, the problem of wear particles persists. The local and systemic biological consequences of this ionic debris have been the subject of much investigation and it has become clear that cell‐mediated delayed‐type hypersensitivity reactions are a discrete mode of osteolysis in susceptible patients. Methods: We have carried out a consecutive series of 125 primary hip replacements using the Metasul (Zimmer, Warsaw, IN, USA) bearing couple. The radiographs, periprosthetic tissue and retrieved implants of patients undergoing revision for osteolysis were analysed. Results: Three patients underwent revision procedures during a follow‐up period of 3–9 years. Histological analysis showed a perivascular lymphocytic infiltrate of the pseudocapsule. Infection was excluded in each patient, there was no implant loosening and no evidence of impingement between trunion and acetabular component. Conclusion: We report a prevalence of 2.6% of patients displaying femoral osteolysis associated with characteristic clinical and histological findings.     

Cobalt and chromium ion release after large-diameter metal-on-metal total hip arthroplasty

Seventy-five patients underwent unilateral metal-on-metal total hip arthroplasty using a large-diameter head. Serum levels of cobalt and chromium were determined. Significant increases in both cobalt and chromium were observed at 3 months (cobalt, 1.4 μg/L; chromium, 1.4 μg/L) compared with preoperative values (P < .001). At 1 year, the median cobalt and chromium levels were 2.3 and 2.1 μg/L, respectively, and the levels had increased significantly compared with 3 months (P < .001). There were no significant differences between levels of either metal at 1 or 2 years (cobalt, 2.3 μg/L; chromium, 1.6 μg/L). Pseudotumor occurred in 2 hips. Patients with large-diameter metal-on-metal total hip arthroplasty had higher circulating metal ion levels at 3 months and 1 year, with no additional significant increases at 2 years.     

Serum levels of cobalt and chromium in a complex modular total hip arthroplasty system

There is concern that modularity in a total hip arthroplasty system increases serum cobalt and chromium ion levels. This study measures the serum cobalt and chromium levels in patients with an Oxford Universal Hip (Corin, Cirencester, United Kingdom), which has a modular sliding mechanism; patients with a similarly manufactured hip with no sliding mechanism; and a control group. Loosening was excluded clinically and radiologically. Arthroplasty patients had statistically higher levels of serum cobalt and chromium than controls, but there was no significant difference in levels between the implanted groups.     

全髋表面置换与金属对金属大直径股骨头全髋置换术后的步态分析比较

目的 比较全髋关节表面置换术与金属对金属大直径股骨头全髋关节置换术患者术后1年的步态有无差异.方法 选择2006年6月至2009年3月期间行全髋关节表面置换术与金属对金属大直径股骨头全髋关节置换术的连续病例各30例,利用Vicon步态分析仪测得两组患者术后平均1年左右的步态参数和步态周期中的髋、膝关节活动度,计算自身患侧/健侧比值进行比较分析.结果 两组患者术后平均1年左右步频、单腿支撑时间等比值和美国特种外科医院评分及加州大学洛杉矶分校评分比较差异无统计学意义,但全髋关节表面置换组患者步态周期中的髋屈伸度、收展度、旋转度及膝关节屈伸度患/健比分别为1.0323、0.9747、1.0558、1.0027,明显高于大直径股骨头全髋关节置换组(患/健比分别为0.8615、0.7824、0.8162、0.9472),P值分别为0.007、0.005、0.006、0.037.结论 (1)全髋关节表面置换术与金属对金属大直径股骨头全髋关节置换术患者术后1年的步态参数接近正常;(2)全髋关节表面置换术后患者行走时的关节活动度优于金属对金属大直径股骨头全髋关节置换术患者;(3)采用全髋关节表面置换除了能够保留骨量,还能最大程度恢复患者的关节功能.     

Distribution of chromium and cobalt ions in various blood fractions after resurfacing hip arthroplasty

The most appropriate blood fraction for the measurement of metal ions in patients with metal-on-metal implants is controversial. We compared chromium (Cr) and cobalt (Co) ion levels in 29 patients after unilateral hip resurfacing with a size 54-mm femoral Birmingham Hip Resurfacing Prosthesis (Smith and Nephew, London, UK). All had well-functioning arthroplasties between 5 and 59 months after implantation. Ion levels were measured in serum, plasma, red cells, and whole blood in each patient. Our results indicate that only very minor amounts of Cr and Co are associated with red blood cells, with most being associated with serum/plasma. Previous studies using corrosion to produce the ion load have showed a predominance of Cr in the red blood cells. They have also shown that the cellular uptake of Cr is an indicator of its valence. This difference in distribution with our results is indirect evidence that the Cr released from wear of this implant is probably in the more benign trivalent form. It also suggests that most of the metal loss from a normally wearing bearing may be from wear rather than corrosion. If blood is to be used to assess rates of wear and systemic ion levels, then serum gives a better reflection of the true levels than red blood cells.     

Repeated cobalt and chromium ion measurements in patients with large-diameter head metal-on-metal ReCap-M2A-Magnum total hip replacement

Background and purpose — Whole blood (WB) cobalt (Co) and chromium (Cr) ion levels have a major role in the follow-up of metal-on-metal total hip replacement (MoM THR). We investigated, first, if there was a change in WB Co or Cr levels over repeated measurements in patients with ReCap-M2A-Magnum THR, and, second, determined how many patients had WB Co or Cr levels that exceeded the safe upper limits (SUL) in the repeated whole blood metal ion assessment.

Patients and methods — A Recap-M2A-Magnum THR was used in 1,329 operations (1,188 patients) at our institution between 2005 and 2012. We identified all patients (n = 319) with unilateral ReCap-M2A-Magnum implants who had undergone at least 2 repeated metal ion measurements with the first blood sample taken mean 5.5 years (1.8–9.3) after surgery and the second taken mean 2 years (0.5–3) after the first.

Results — The median WB Co and Cr ion levels decreased in repeated measurements from 1.40 (0.40–63) ppb to 1.10 (0.20–68) ppb and from 1.60 (0.60–13.0) ppb to 1.10 (0.30–19.0) ppb, respectively. 7% of the Co ion values exceeded SUL at the initial measurement, and 7% at the control measurement. The proportion of Cr ion values exceeding the safe upper limit (SUL) decreased during the measurement interval from 5% to 4%.

Interpretation — Repeated metal ion measurements in unilateral ReCap-M2A-Magnum patients in a mean 2-year time interval did not show any increase. Long-term ion levels are, however, not yet known.     

Sensitivity and specificity of blood cobalt and chromium metal ions for predicting failure of metal-on-metal hip replacement

Blood metal ions have been widely used to investigate metal-on-metal hip replacements, but their ability to discriminate between well-functioning and failed hips is not known. The Medicines and Healthcare products Regulatory Agency (MHRA) has suggested a cut-off level of 7 parts per billion (ppb). We performed a pair-matched, case-control study to investigate the sensitivity and specificity of blood metal ion levels for diagnosing failure in 176 patients with a unilateral metal-on-metal hip replacement. We recruited 88 cases with a pre-revision, unexplained failed hip and an equal number of matching controls with a well-functioning hip. We investigated the 7 ppb cut-off level for the maximum of cobalt or chromium and determined optimal mathematical cut-off levels from receiver-operating characteristic curves. The 7 ppb cut-off level for the maximum of cobalt or chromium had a specificity of 89% and sensitivity 52% for detecting a pre-operative unexplained failed metal on metal hip replacement. The optimal cut-off level for the maximum of cobalt or chromium was 4.97?ppb and had sensitivity 63% and specificity 86%. Blood metal ions had good discriminant ability to separate failed from well-functioning hip replacements. The MHRA cut-off level of 7 ppb provides a specific test but has poor sensitivity.     

Repeated cobalt and chromium ion measurements in patients with bilateral large-diameter head metal-on-metal ReCap-M2A-Magnum total hip replacement

Background and purpose — Whole-blood (WB) chromium (Cr) and cobalt (Co) measurements are vital in the follow-up of metal-on-metal total hip replacement (MoM THR) patients. We examined whether there is a substantial change in repeated WB, Co, and Cr levels in patients with bilateral ReCap-M2A-Magnum THR. We also specified the number of patients exceeding the safe upper limit (SUL) of WB Co and Cr in the repeated measurement.Patients and methods — We identified 141 patients with bilateral ReCap-M2A-Magnum THR operated in our institution. 61 patients had repeated WB metal ion measurements with bilateral MoM implants still in situ in the second measurement. The mean time elapsing from the first measurement (initial measurement) to the second (control measurement) was 1.9 years (SD = 0.6, range 0.2–3.5). We used earlier established SUL levels for bilateral implants by Van Der Straeten et al. (2013).Results — The median (range) Co and Cr values decreased in the repeated measurement from 2.7 (0.6–25) to 2.1 (0.5–21) and 2.6 (0.8–14) to 2.1 (0.5–18) respectively. In 13% of the patients Co levels exceeded the SUL in the initial measurement and the proportion remained constant, at 13%, in the repeated measurement. In 5% of the patients, Cr levels were above SUL in the initial measurement and an equal 5% in the control measurement.Interpretation — Repeated WB metal ion levels did not increase in patients with bilateral ReCap-M2A-Magnum THR with a mean 1.9-year measurement interval. Long-term development of WB metal ion levels is still unclear in these patients.

More than 20,000 metal-on-metal (MoM) hip replacements were performed in Finland during 2000–2015 (Finnish Arthroplasty Register). Currently, there are still thousands of patients with a MoM THR in situ. Whole-blood (WB) metal ion measurements are an essential part of the follow-up of MoM patients, even though they do not solely identify failing implants alone (De Smet et al. 2008, Hart et al. 2014, Reito et al. 2016).While there is no agreed universal WB metal ion level that indicates revision surgery or predicts the outcome, different health authorities have suggested diverse follow-up protocols for the monitoring of MoM patients (Hannemann et al. 2013, MHRA 2017, US Food and Drug Administration (FDA) 2019). Furthermore, some MoM implants have better survival rates than others, which makes risk evaluation even more difficult (Matharu et al. 2016, MHRA 2017, Kasparek et al. 2018, Donahue et al. 2019).The evaluation of patients with bilateral MoM THR is even more challenging. Patients with bilateral MoM implants often present higher levels of Co and Cr than patients with a unilateral device (Van Der Straeten et al. 2013, Reito et al. 2014, 2016). Only a few studies have assessed blood metal ion levels in patients with bilateral MoM THR. Reito et al. (2016) evaluated ion level changes in bilateral ASR THR, and ASR (DePuy, Warsaw, IN, USA) hip resurfacing arthroplasty (HRA) patients. Both WB Co and Cr were substantially higher in the ASR THR cohort in the repeated measurement (Reito et al. 2016). However, metal ion levels were not able to distinguish failing MoM components from well-functioning hips in patients with bilateral ASR THR (Reito et al. 2016, Donahue et al. 2019).ReCap-M2A-Magnum was the most common MoM THR in Finland (Finnish Arthroplasty Register). We have previously reported that repeated metal ion measurements in unilateral ReCap-M2A-Magnum patients at a mean 2-year time interval did not show any increase (Mäntymäki et al. 2019).We performed a retrospective comparative study to further investigate the role of repeated WB metal ion measurements in patients with bilateral M2A-ReCap-Magnum THR. Our main objectives were to investigate:

1. Is there a substantial change in the WB Co and Cr level during a follow-up period?
2. How large proportion of patients’ measurements exceed the safe upper limits (SUL) of WB Co and Cr levels in the repeated measurement (thresholds WB Co 5.0 µg/L and Cr 7.4 µg/L) (Van Der Straeten et al. 2013).