**3. Elevated risk for fracture in early stages of CKD**

**2. Elevated risk for fracture in end-stage kidney disease**

higher for 3 years after kidney transplantation [16].

Table 1 Elevated fracture risk in ESKD

**326,464 dialysis patients**

**1,272 dialysis patients in the US hip**

**12,782 HD patients in 320 HD facilities from 12 countries**

**128,141 HD patients in**

**Retrospective cohort study**

78 Updates in Hemodialysis

**Retrospective cohort study**

**Prospective cohort study**

**Retrospective cohort study**

**Table 1.** Elevated fracture risk in ESKD

Compared with general population, the risk for fracture is reported to be much higher in endstage kidney disease (ESKD) (Table 1) [10-14]. A multicenter cohort study in the US having more than 320,000 dialysis patients, 13.6 in women and 7.5 in men had an incident hip fracture among 1,000 person-years [10].The incidence ratio standardized with age was about 4.4 times higher than that of healthy subjects. Another study in a single institution in the US having 1,272 dialysis patients, 13.9 (24.1 in women and 11.7 in men) had an incident hip fracture among 1,000 person-years, which was 17.4 times higher than that of general population [11]. Increased risk of hip fracture was shown among Japanese hemodialysis (HD) patients, in which the risk was about 5 times higher than that of general population [12]. Facture risk of HD patients was increased in the west part of Japan, which showed similar results to the general population [12, 15]. A multicenter prospective study (DOPPS II) in 12,782 patients from 12 countries showed that 8.9/1,000 person-years had a hip fracture [13]. In addition, risk for fracture may even be

CKDにおける骨折リスク

**Japan hip men 7.57 6.2 (5.7-6.8)**

Mean age of incident fracture in dialysis patients is reported to be 61.4 in women and 64.4 in men, which are much younger than those of general population (74 and 80, respectively),

**in the US hip men 7.45 4.44 (4.16-4.75)**

**and RR (95%CI) for general population Reference**

**[11]**

**[13]**

**women 13.63 4.40 (4.17-4.64) [10]**

**women 17.43 4.9 (4.6-5.3) [12]**

**men 11.7 14.2 (9.3-28.6) women 24.1 17.2 (7.1-19.4) all 13.9 17.4 (12.4-34.0)**

**men, 15-54 1.00 (Ref) men, 55-64 2.15 (1.06-4.57) men, 65-74 2.38 (1.07-5.26) men, 75- 5.05 (2.36-10.82) women, 15-54 0.85 (0.30-2.35) women, 55-64 1.85 (0.75-4.59) women, 65-74 4.67 (2.22-9.83) women, 75- 7.79 (3.69-16.43)**

**all 8.9 (8.4-9.4) men, 15-54 1.00 (Ref) men, 55-64 1.25 (0.84-1.85) men, 65-74 1.65 (1.10-2.48) men, 75- 1.86 (1.24-2.77) women, 15-54 1.07 (0.67-1.69) women, 55-64 2.36 (1.56-3.54) women, 65-74 2.58 (1.79-3.63) women, 75- 3.43 (2.33-5.06) all 25.6 (24.4-27.0)**

**Study design Subjects Fracture type Fracture incidence of 1,000 person-years**

**hip**

**any**

Although considerably high risk for fracture has been shown in ESKD patients, recent epidemiological studies indicate that the risk for fracture is elevated in CKD patients, even in early stages (Table 2). Nickolas et al. reported that CKD was an independent predictor of prevalent hip fracture [22]. When categorized 6,270 participants by estimated glomerular filtration rate (eGFR) using MDRD formula, prevalent hip fracture was found in 5.2% and 2.0% of those with eGFR 15-60mL/min/1.73m2 and eGFR>60mL/min/1.73m2 , respectively. Odds ratio of prevalent hip fracture in those with CKD was 2.12 (95%CI: 1.18-3.80), compared with those with eGFR>100mL/min/1.73m2 . Multiple logistic analysis for prevalent hip fracture showed that osteoporosis (OR=2.52, 95%CI: 1.08-5.91), low activity (OR=2.10, 95%CI: 1.03-4.27) and CKD (OR=2.32, 95%CI: 1.13-4.74) were the risk factors independent of age, sex, body weight, race, BMD, history of hip fracture in mother, dietary calcium intake, and 25(OH)D blood level and propensity score to CKD. In ≥75 years subjects with and without prevalent fracture, the ratio of CKD suffered was 32.1% and 32.2%, respectively, whereas in < 75 years subjects, the ratio was 19.2% and 6.2%, respectively. This finding suggests that the younger patients with prevalent fractures suffer from CKD almost 3 times more frequently, compared to those without fractures. Thus, CKD (eGFR: 15-60mL/min/1.73m2 ) is an independent risk of hip fracture, especially in subjects with <75 years old.

Ensrud et al. conducted a prospective study to examine risk for fracture in 9,704 women with >65 years, stratified by CCr (Cockcroft-Gault formula) corrected with body surface area [23]. During 6 years observational period, hazard ratios of hip fracture were 2.32 (95%CI: 1.15-4.68) in CCr<45 mL/min/1.73m2 and 1.57 (95%CI: 0.89-2.76) in CCr45-59 mL/min/1.73m2 , compared to CCr≥60 mL/min/1.73m2 . These results suggest that decreased kidney function is a risk for incident hip fracture independent of age, body weight and calcaneal BMD. However, signifi‐ cant difference disappeared after adjustment by healthy status, smoking, walking excise,

Table 2 Elevated fracture risk in CKD

**Table 2.** Elevated fracture risk in CKD

diabetes mellitus (DM), and history of fracture occurred after 50 years old. On the other hand, only a tendency was observed using eGFR by MDRD formula instead of CCr. Moreover, the analysis of fracture sites shows that the risk for fracture was elevated at the trochanter not at the femoral neck, indicating that hip fracture in CKD patients could be associated with the frailty [24].

Since sarcopenia or protein-energy wasting (PEW) is commonly seen in CKD patients, eGFR derived from creatinine often underestimates actual kidney function. Cystatin C is more accurate estimate for kidney function than eGFR calculated from creatinine, especially in elderly people whose muscle mass is reduced. Fried et al. demonstrated a significant associa‐ tion between cystatin C blood level and hip fracture risk in 4,699 subjects in their prospective study. Women with eGFR<60 mL/min/1.73m2 have an increased risk for fracture even after adjusting the covariates [25].

So far, few studies are performed to evaluate the relationship between kidney function and vertebral fractures. In a case-control study of 659 postmenopausal osteoporotic women with an average age of 64.5 years, 45.3% of those with eGFR<60 mL/min/1.73m2 had prevalent vertebral fractures and the ratio was significantly higher than those with eGFR 60-89 mL/min/ 1.73m2 (25.3%) and eGFR≥90 mL/min/1.73m2 (23.8%) [26]. Multiple logistic regression analysis showed that CCr was selected as a significant predictor of prevalent vertebral fracture after adjustment for years after menopause, smoking, drinking, and BMD at vertebrae (OR=0.359, 95%CI: 0.168-0.765, p=0.01). There were significant positive correlations between eGFR and BMD at the femoral neck and the radius. These findings suggest that the reduction of BMD and the elevation of risk for fracture may start during early CKD (eGFR<90 mL/min/1.73m2 ).

However, Ensrud et al. could not find a significant association of incident vertebral fractures with kidney function calculated by C-G as well as MDRD formulas [23]. The discrepancies of these two reports could be derived from the differences of participants' background such as race, age, and kidney function, and the methodology. In the latter study, 150 patients, who had incident vertebral fractures, were relatively older (mean age: 73.1 years) than those of the former study. In addition, the second X-ray was not performed in 22% of women possibly due to bed rest or death. Thus, such limitation should be taken into account when the results of prospective study are assessed.

Previous studies suggest that the risk for fracture is elevated in parallel with a decrease in kidney function. We estimated the risk for fracture with the assessment tool FRAX® (http:// www.shef.ac.uk/FRAX/) in 1,935 community-dwelling healthy Japanese people (1,123 women and 812 men, mean age: 68.9) [27]. Estimated risk of hip fracture for 10 years was 2.1% in men and 4.6% in women, respectively (Figure 1), and the risk was inversely proportionate to eGFR. Significant increase of the risk for fracture was observed in men with eGFR<60 ml/min/ 1.73m2 and women with eGFR<75 ml/min/1.73m2 . Major risk of osteoporotic fracture (verte‐ brae, hip, radius and humerus) for 10 years was estimated as 6.8% in men and 14.0% in women, which was also elevated as a loss of kidney function. As we have shown the elevated risk for fracture in CKD population using FRAX®, this tool has originally been developed for the screening of patients with high risk for fracture. Indeed, Jamal et al. have recently reported the utility of FRAX® in CKD patients [28]. Figure 1

diabetes mellitus (DM), and history of fracture occurred after 50 years old. On the other hand, only a tendency was observed using eGFR by MDRD formula instead of CCr. Moreover, the analysis of fracture sites shows that the risk for fracture was elevated at the trochanter not at the femoral neck, indicating that hip fracture in CKD patients could be associated with the

**women in Japan CCr 60**~**89mL/min vertebra 2.79(1.31–5.95) [26]**

CKDにおける骨折リスク

**CCr 45**~**59mL/min CCr** <**45mL/min CCr 45**~**59mL/min CCr** <**45mL/min CCr 45**~**59mL/min CCr** <**45mL/min**

**eGFR**<**60mL/min/1.73m2 Cystatin C 1SD above**

**the US eGFR** <**60mL/min/1.73m2 hip 2.32 (1.13–4.74) [22]**

**CCr** <**45mL/min all 1.3(1.0–1.6)**

**design Subjects Kidney function Odds ratio of fracture risk (95%CI) Reference**

Since sarcopenia or protein-energy wasting (PEW) is commonly seen in CKD patients, eGFR derived from creatinine often underestimates actual kidney function. Cystatin C is more accurate estimate for kidney function than eGFR calculated from creatinine, especially in elderly people whose muscle mass is reduced. Fried et al. demonstrated a significant associa‐ tion between cystatin C blood level and hip fracture risk in 4,699 subjects in their prospective

So far, few studies are performed to evaluate the relationship between kidney function and vertebral fractures. In a case-control study of 659 postmenopausal osteoporotic women with

vertebral fractures and the ratio was significantly higher than those with eGFR 60-89 mL/min/

 (25.3%) and eGFR≥90 mL/min/1.73m2 (23.8%) [26]. Multiple logistic regression analysis showed that CCr was selected as a significant predictor of prevalent vertebral fracture after

an average age of 64.5 years, 45.3% of those with eGFR<60 mL/min/1.73m2

have an increased risk for fracture even after

**hip 1.57 (1.18–2.09) radius 1.79 (1.39–2.31) vertebra 1.31 (1.19–1.55)**

**femoral neck 1.24 (0.60–2.56) femoral neck 1.41(0.59–3.36) trochanter 3.69(1.21–11.24) trochanter 5.04(1.38–18.45) vertebra 1.08(0.61–1.92) vertebra 1.33(0.63–2.80)**

**hip 1.38(0.99–1.94) hip 1.16(1.01–1.33) [25]**

**eGFR**<**60mL/min/1.73m2 hip 2.50(1.32–4.72) [67]**

**vertebra 2.5(1.6–3.9) [66]**

**[2]**

**[23]**

had prevalent

frailty [24].

 Elevated fracture risk in CKD

**aged >65 in Germany CCr** <**65mL/min**

Table 2 Elevated fracture risk in CKD

1.73m2

study. Women with eGFR<60 mL/min/1.73m2

adjusting the covariates [25].

**Figure 1.** Association between eGFR and 10 year-hip fracture incidence calculated by FRAX® In 1,935 communitydwelling healthy Japanese people (1,123 women and 812 men, mean age: 68.9), association between eGFR (MDRD for‐ mula) and 10 year-hip fracture incidence calculated by FRAX® was shown. \*; p<0.001and \*\*; p<0.005 (vs eGFR 90 ml/min/1.73m2 ), Post-hoc test (Fisher's PLSD) (modified by ref. [27])

In this part, terms such as eGFR and CCr were used followed by the original reports. Moreover, CCr was corrected with body surface in some reports and not in others. Kidney function is prone to be underestimated in C-G formula and overestimated in MDRD, which may lead confusion and the discrepancy among study results as described by Ensrud et al. [23].


**5.7. Stillbirth**

Advanced maternal age has been associated with an increased incidence of stillbirth [91]. A mechanism under this increase is placental dysfunction, which accounts for around 65% of stillbirths, and it has been observed more frequently in mice models and humans with age. Placentas from older mothers (35–39 and ≥ 40 years old) are less efficient in the sense that foetal/placenta weight ratio was lower than placentas from controls under 30 years old. They seem to be bigger in size and display mechanisms to ameliorate function, like increased relaxation of myometrium arteries and increased amino acid transport, but this does not correlate with a higher birth weight in the offspring. The hypothesis is that an increased size could be an adaptive mechanism trying to make up for placental dysfunction [92]. It has also been suggested that the greater contribution to stillbirth in older mothers could arise from their increased risk of chromosomal abnormalities [80].

Twin pregnancies are also high risk for stillbirth and neonatal death, increasing thirteenfold in monochorionic and fivefold in dichorionic pregnancies compared to singletons [93, 94].

Although this is not under the scope of this chapter, advanced paternal age has also been associated with stillbirth and death of the child before 5 years of age [95, 96]. The risk might be linked to a higher rate of sperm chromatin or chromosomal aberrations. Interestingly, this association dissolves when adjusting for paternal education level, when the association between advanced maternal age and the risk of stillbirth is independent of socioeconomic and educational levels.


*11.3.3. Vaccination schedule*

All of several vaccination schedules consist of primary (basic) vaccination followed by booster doses. Complete primary (basic) vaccination comprises three doses, usually given with an interval of 1–3 months between first and second dose, and 5–12 months between the second and third dose. When protection is wanted to be achieved in a short time, "fast schedule" (second dose is administered earlier, usually 14 days instead of 1–3 months after the first dose) can be used in accordance with the manufacturers' instructions [12, 42]. The first booster dose is administered 3 years after completion of the primary vaccination; after that, one dose is required every 5 years except for persons aged >60 years (FSME IMMUN) or >50 years (Encepur) for whom boosters are recommended at 3 years intervals [131]. Immunization with the first two doses is preferably accomplished during the winter months to achieve protection before tick activity; however, vaccination can start at any time. A person who had not received the recommended doses according to the schedule but with longer intervals does not need to start vaccination again from the very beginning but just to continue with missing doses. Longer intervals between doses generally do not reduce antibody concentrations after completion of TBE vaccination, but protection in the period before the delayed dose is less consistent [137].

## *11.3.4. Mode of application and dosages*

TBE vaccine is administered intramuscularly into the deltoid muscle; in young children, it can be given in the muscles of anterolateral thigh. It may be administered simultaneously with other vaccines (live or inactivated) but not on the same place [131]. Doses (0.25 or 0.5 ml) depend upon the age of the recipient. The age limits for vaccines available in Europe differ. In persons <16 years old, the dose of the FSME‐IMMUN vaccine is 0.25 ml, whereas for persons ≥16 years, 0.5 ml is advised; the corresponding age limits for Encepur vaccine are <12 and ≥12 years, respectively.

## *11.3.5. Efficacy and safety*

Both European vaccines are safe and effective. Fourteen days after the second dose of basic vaccination protective antibodies develop in about 85% of the subjects, whereas after three doses, more than 98% of persons with normal immunity are protected [131]. As a rule the effectiveness of protection after vaccination against TBE is not verified by the detection of antibodies against TBEV in serum. However, the manufacturers of the vaccines and some authors recommend that in persons with immunodeficiency, the response to vaccination is assessed by serological testing approximately 4 weeks after the second dose, and that — if antibody response was not adequate — the second dose is repeated and followed by the third dose in accordance with the regular TBE vaccination timetable. Along with some proposals similar procedure may possibly refer also to the following doses. While such practice may appear reasonable, no convincing clinical data corroborate its usage.

TBE vaccine field effectiveness is estimated to be >98% in persons vaccinated in line with the advocated schedule, and >90% for those who received basic vaccination, but were later not vaccinated according to the planned timetable [138].

Side effects are mild and relatively rare. They are more frequent after the initial than with later doses of TBE vaccine. The most common side effects are local pain and tenderness on pressure at the injection site; redness and swelling occur less often. Short-term fever after vaccination is relatively common in young children but rare in adults. Neurological complications are very infrequent [131].

## *11.3.6. Contraindications and limitations*

## *<IP_ADDRESS>. Contraindications*

1 and strain K23, respectively), are prepared in a similar way (viruses are grown in chick embryo fibroblast cells, are inactivated by formaldehyde and are purified, adjuvant is aluminum hydroxide), are registered for adults and children aged 1 year and older (vaccines for children are called FSME‐IMMUN 0.25 ml Junior, and Encepur Kinder, respectively), and effectively prevent TBE caused by the European as well as Far-Eastern and Siberian subtype of TBEV [131]. In addition to the European vaccines, three vaccines based on Far-Eastern subtype of TBEV are registered: two are produced in Russia (TBE‐Moscow and EnceVir) and one in China [131].

36 Meningoencephalitis - Disease Which Requires Optimal Approach in Emergency Manner

All of several vaccination schedules consist of primary (basic) vaccination followed by booster doses. Complete primary (basic) vaccination comprises three doses, usually given with an interval of 1–3 months between first and second dose, and 5–12 months between the second and third dose. When protection is wanted to be achieved in a short time, "fast schedule" (second dose is administered earlier, usually 14 days instead of 1–3 months after the first dose) can be used in accordance with the manufacturers' instructions [12, 42]. The first booster dose is administered 3 years after completion of the primary vaccination; after that, one dose is required every 5 years except for persons aged >60 years (FSME IMMUN) or >50 years (Encepur) for whom boosters are recommended at 3 years intervals [131]. Immunization with the first two doses is preferably accomplished during the winter months to achieve protection before tick activity; however, vaccination can start at any time. A person who had not received the recommended doses according to the schedule but with longer intervals does not need to start vaccination again from the very beginning but just to continue with missing doses. Longer intervals between doses generally do not reduce antibody concentrations after completion of TBE vaccination, but protection in the period before the delayed dose is less consistent [137].

TBE vaccine is administered intramuscularly into the deltoid muscle; in young children, it can be given in the muscles of anterolateral thigh. It may be administered simultaneously with other vaccines (live or inactivated) but not on the same place [131]. Doses (0.25 or 0.5 ml) depend upon the age of the recipient. The age limits for vaccines available in Europe differ. In persons <16 years old, the dose of the FSME‐IMMUN vaccine is 0.25 ml, whereas for persons ≥16 years, 0.5 ml is advised; the corresponding age limits for Encepur vaccine are <12 and ≥12 years, respectively.

Both European vaccines are safe and effective. Fourteen days after the second dose of basic vaccination protective antibodies develop in about 85% of the subjects, whereas after three doses, more than 98% of persons with normal immunity are protected [131]. As a rule the effectiveness of protection after vaccination against TBE is not verified by the detection of antibodies against TBEV in serum. However, the manufacturers of the vaccines and some authors recommend that in persons with immunodeficiency, the response to vaccination is assessed by serological testing approximately 4 weeks after the second dose, and that — if

*11.3.3. Vaccination schedule*

*11.3.4. Mode of application and dosages*

*11.3.5. Efficacy and safety*

The main contraindications are as follows:

## *<IP_ADDRESS>. Limitations*

*Pregnancy, breast‐feeding*: Because information on the safety of TBE vaccine during pregnancy and lactation is inadequate, pregnant and lactating women should receive the vaccine only after a careful individual assessment of the potential risks and benefits. There is also no sufficient data on the safety of vaccination during lactation. However, since TBE vaccines are based on inactivated virus, the harm of breast-feeding child or fetus is unlikely.

*Autoimmune diseases*: While there is no indication that vaccination may deteriorate the course of autoimmune diseases or trigger autoimmunity, caution is required in persons with an autoimmune disease because data on the safety of vaccination in this group are limited [131].

#### *11.3.7. Storage*

The vaccine must be stored in a refrigerator at a temperature between 2 and 8°C. Storage at higher temperatures and freezing are not suitable [131].