**4. Discussion**

This is the first report in Colombia to provide an account of the factors affecting HRQOL in patients with mild to moderate renal impairment. It is also the first to point out the advantages that a renal protection program may have over conventional treatment regarding its impact on patient HRQOL. This study's results are presented to comply with the demands that appear in international literature regarding the need to determine the impact on HRQOL in early stages of renal impairment (Chandban et al., 2003; Perlman et al., 2005) and to insist that current interventions must emphasize the preservation of renal functioning in order to decrease the negative impact of kidney failure on HRQOL (Chandban et al., 2003; Fukuhara et al., 2007; Valdebarrano et al., 2001).

Health-Related Quality of Life in Chronic Renal Predialysis

corroborated for each case with the medical staff.

measurements.

Patients Exposed to a Prevention Program – Medellín, 2007-2008 441

Regarding age, patients older than 65 had a lower HRQOL. Physical functioning was the most affected domain for the two groups both at the start of the study and one year later. This could be explained by the strong negative association between the state of physical health and old age. Such association was reported in literature by studies on this and other chronic diseases (Chandban et al., 2005; Hopman et al., 2000; Yepes et al., 2008). The RPP patients younger than 65 showed an increase in four of the domains one year after the start of the study. The rest of the domains also decreased, but not significantly, except for the role-physical domain. For the CT group, all the domains values decreased in the second measurement, and four of them did so significantly. The difference found in physical functioning between the age groups in CT according to the effect size (> 0.60) can be considered to be clinically important. This must be

It is imperative to adjust the differences found in the final HRQOL scores for the variables that can influence such results. As for general health and change in health, upon adjusting for the respective value of the initial score, an increase of more than five points of HRQOL was generated in the difference that favors the RPP over CT in both domains. In the PCS1 and vitality domains, adjusting scores for gender yielded an important increase of the difference in favor of the RPP in both cases (Yepes et al., 2008). In physical functioning, adjusting scores for

In short, exposure to a RPP has a positive impact on the HRQOL of CRF patients from the early stages of their condition. The initial HRQOL score, gender, and age are fundamental characteristics to take into account for measuring the HRQOL of patients upon exposure to an intervention. It seems that early detection of CRF patients and interdisciplinary control of risk factors have a significant influence in the outcome of both physical and mental HRQOL

HRQOL values have been proposed as an important outcome in patients with high death, hospitalization, and depression risks. Measuring the HRQOL with validated instruments such as the SF-36 allows it to become a strong indicator of the health-related quality of life in ambulatory patients. In fact, it is considered a mortality and morbidity predictor in elderly and CRF patients (DeOreo, 1997; Han et al., 2009; Kalantar-Zadeh, 2005; Mapes et al., 2003). Assessing the well-being of CRF patients periodically with the SF-36 is important for measuring response to treatment and for improving healthcare. In fact, improving the

This study's main limitation is its short follow-up period, which could not provide an appropriate account of the characteristics of a slow, progressive disease while explaining that many changes are not significant enough. Another limitation is that demographic variables like marital status, socioeconomic level, occupation, educational level, income, etc., were disregarded. Some studies state that both PCS1 and MCS1 are closely associated with demographic characteristics that are likely to have a deeper impact than clinical

Data loss due to patient death and other causes was expected for the second application of the SF-36 one year later. Like many other health scales, the SF-36 has no clear directions regarding how deaths within a studied population should be analyzed. This has limited the analysis in research. This issue is most frequently addressed by excluding these cases from the study or by analyzing these data separately. Paradoxically, if two study groups are compared, the

age increased the difference in HRQOL scores, favoring CT (Yepes et al., 2008).

HRQOL of CRF patients is a key objective in the U.S (Kalantar-Zadeh, 2005).

characteristics themselves (AASK, 2002; Fukuhara et al., 2007).

The study's data were collected from 293 patients in the early stages of CRF. Patients followed two kinds of medical treatment during one year. The groups showed no differences for the main comorbidities, but it was evident that the RPP collected more patients in earlier stages of CRF due to its active search. The higher proportion of male patients in CT could be due to the faster progression of CRF in males (Silbiger & Neugarten, 1995). This could explain the gender and age disparities found between the groups at the start of the study.

One year later, the RPP group's scores for the different HRQOL domains were slightly lower, but these differences were not significant. Conversely, the CT group showed a significant decrease in four of the eight domains after the same time. This accounts for the effect of the RPP even in a short follow-up period. It is worth noting that general health was the most affected domain in both groups. After one year, the initial value for the RPP remained unchanged, but decreased drastically for CT.

The results obtained from data collected from predialysis patients confirm that HRQOL is affected from the early stages of CRF and continues to decrease as the condition evolves. Even after only one year, the scores for most domains decreased. This conclusion is shared by other studies whose patients lacked RRT. The population assessed in such studies was Japanese (Fukuhara et al., 2007), African-American (African American Study of Kidney Disease and Hypertension Trial Group [AASK], 2002), Australian (Chandban et al., 2005), Korean (Chin et al., 2008), and Dutch (Korevaar et al., 2000).

In this study, the physical health of predialysis patients was found to be more affected than their mental health. This was true for both study groups. These findings are in accordance with the conclusions reached in other publications on the same topic (Chandban et al., 2005; Fukuhara et al., 2007; AASK, 2002; Korevaar et al., 2000; Hopman et al., 2000). Regarding mental health, CT patients initially showed significantly superior values compared to the RPP patients. This result is consistent with the ideas exposed in other studies, which suggest that older patients —or those with an older diagnosis— have better mental health. This proves that mental health is worse in young or recently diagnosed individuals (Hopman et al., 2000). Nevertheless, one year later, the scores for the mental component of HRQOL increased within the RPP group, whereas CT scores decreased, and the initial differences between the RPP and CT disappeared.

Gender was a key factor for the SF-36 scores since its first application. It was observed that the scores for women were lower and had significant differences regardless of the group. However, these differences disappeared within the RPP group one year later. In CT, however, the differences remained and values in men decreased statistically. Other researchers also recognized this affectedness of HRQOL by gender. They also proposed that women may be particularly more vulnerable (Yepes et al., 2008). This was also done in the AASK study (AASK, 2002), which focused on the need for exploring the mechanisms allowing HRQOL in female CRF patients to decrease quickly. In studying the HRQOL of the Australian population suffering from kidney failure Chandban (Chandban et al., 2005) described similar worsening patterns for both genders.

After one year, women's HRQOL in most domains continued to be worse than that of men. However it is worth noting that differences between the values obtained at the start of the study and after one year could be indirectly considered as clinically important in the vitality values for the RPP (ES=0.69) and the bodily pain values for CT (ES=0.61).

The study's data were collected from 293 patients in the early stages of CRF. Patients followed two kinds of medical treatment during one year. The groups showed no differences for the main comorbidities, but it was evident that the RPP collected more patients in earlier stages of CRF due to its active search. The higher proportion of male patients in CT could be due to the faster progression of CRF in males (Silbiger & Neugarten, 1995). This could explain the gender

One year later, the RPP group's scores for the different HRQOL domains were slightly lower, but these differences were not significant. Conversely, the CT group showed a significant decrease in four of the eight domains after the same time. This accounts for the effect of the RPP even in a short follow-up period. It is worth noting that general health was the most affected domain in both groups. After one year, the initial value for the RPP

The results obtained from data collected from predialysis patients confirm that HRQOL is affected from the early stages of CRF and continues to decrease as the condition evolves. Even after only one year, the scores for most domains decreased. This conclusion is shared by other studies whose patients lacked RRT. The population assessed in such studies was Japanese (Fukuhara et al., 2007), African-American (African American Study of Kidney Disease and Hypertension Trial Group [AASK], 2002), Australian (Chandban et al., 2005),

In this study, the physical health of predialysis patients was found to be more affected than their mental health. This was true for both study groups. These findings are in accordance with the conclusions reached in other publications on the same topic (Chandban et al., 2005; Fukuhara et al., 2007; AASK, 2002; Korevaar et al., 2000; Hopman et al., 2000). Regarding mental health, CT patients initially showed significantly superior values compared to the RPP patients. This result is consistent with the ideas exposed in other studies, which suggest that older patients —or those with an older diagnosis— have better mental health. This proves that mental health is worse in young or recently diagnosed individuals (Hopman et al., 2000). Nevertheless, one year later, the scores for the mental component of HRQOL increased within the RPP group, whereas CT scores decreased, and the initial differences

Gender was a key factor for the SF-36 scores since its first application. It was observed that the scores for women were lower and had significant differences regardless of the group. However, these differences disappeared within the RPP group one year later. In CT, however, the differences remained and values in men decreased statistically. Other researchers also recognized this affectedness of HRQOL by gender. They also proposed that women may be particularly more vulnerable (Yepes et al., 2008). This was also done in the AASK study (AASK, 2002), which focused on the need for exploring the mechanisms allowing HRQOL in female CRF patients to decrease quickly. In studying the HRQOL of the Australian population suffering from kidney failure Chandban (Chandban et al., 2005)

After one year, women's HRQOL in most domains continued to be worse than that of men. However it is worth noting that differences between the values obtained at the start of the study and after one year could be indirectly considered as clinically important in the vitality

values for the RPP (ES=0.69) and the bodily pain values for CT (ES=0.61).

and age disparities found between the groups at the start of the study.

remained unchanged, but decreased drastically for CT.

Korean (Chin et al., 2008), and Dutch (Korevaar et al., 2000).

between the RPP and CT disappeared.

described similar worsening patterns for both genders.

Regarding age, patients older than 65 had a lower HRQOL. Physical functioning was the most affected domain for the two groups both at the start of the study and one year later. This could be explained by the strong negative association between the state of physical health and old age. Such association was reported in literature by studies on this and other chronic diseases (Chandban et al., 2005; Hopman et al., 2000; Yepes et al., 2008). The RPP patients younger than 65 showed an increase in four of the domains one year after the start of the study. The rest of the domains also decreased, but not significantly, except for the role-physical domain. For the CT group, all the domains values decreased in the second measurement, and four of them did so significantly. The difference found in physical functioning between the age groups in CT according to the effect size (> 0.60) can be considered to be clinically important. This must be corroborated for each case with the medical staff.

It is imperative to adjust the differences found in the final HRQOL scores for the variables that can influence such results. As for general health and change in health, upon adjusting for the respective value of the initial score, an increase of more than five points of HRQOL was generated in the difference that favors the RPP over CT in both domains. In the PCS1 and vitality domains, adjusting scores for gender yielded an important increase of the difference in favor of the RPP in both cases (Yepes et al., 2008). In physical functioning, adjusting scores for age increased the difference in HRQOL scores, favoring CT (Yepes et al., 2008).

In short, exposure to a RPP has a positive impact on the HRQOL of CRF patients from the early stages of their condition. The initial HRQOL score, gender, and age are fundamental characteristics to take into account for measuring the HRQOL of patients upon exposure to an intervention. It seems that early detection of CRF patients and interdisciplinary control of risk factors have a significant influence in the outcome of both physical and mental HRQOL measurements.

HRQOL values have been proposed as an important outcome in patients with high death, hospitalization, and depression risks. Measuring the HRQOL with validated instruments such as the SF-36 allows it to become a strong indicator of the health-related quality of life in ambulatory patients. In fact, it is considered a mortality and morbidity predictor in elderly and CRF patients (DeOreo, 1997; Han et al., 2009; Kalantar-Zadeh, 2005; Mapes et al., 2003). Assessing the well-being of CRF patients periodically with the SF-36 is important for measuring response to treatment and for improving healthcare. In fact, improving the HRQOL of CRF patients is a key objective in the U.S (Kalantar-Zadeh, 2005).

This study's main limitation is its short follow-up period, which could not provide an appropriate account of the characteristics of a slow, progressive disease while explaining that many changes are not significant enough. Another limitation is that demographic variables like marital status, socioeconomic level, occupation, educational level, income, etc., were disregarded. Some studies state that both PCS1 and MCS1 are closely associated with demographic characteristics that are likely to have a deeper impact than clinical characteristics themselves (AASK, 2002; Fukuhara et al., 2007).

Data loss due to patient death and other causes was expected for the second application of the SF-36 one year later. Like many other health scales, the SF-36 has no clear directions regarding how deaths within a studied population should be analyzed. This has limited the analysis in research. This issue is most frequently addressed by excluding these cases from the study or by analyzing these data separately. Paradoxically, if two study groups are compared, the

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Due to the negative impact of CRF on HRQOL, it is necessary to determine potential areas for research and clinical intervention. Such areas include: psychological support for the most vulnerable population (women, young people, recently diagnosed patients, patients in early stages of the condition), early prescription of nephroprotectors, and complete physical therapy programs focusing on older patients and on those with high deterioration rates.

#### **5. Acknowledgment**

The authors would like to thank University of Antioquia, Colciencias and Sura EPS for sponsoring this research. We are also very grateful for the patients' cooperation, for the support provided by José Miguel Abad and José Ignacio Acosta, for the advice provided by Professors Rubén Darío Gomez and Juan Luis Londoño, and for Andrés Felipe Quintero Rave's thoughtful translation of this text.

#### **6. References**

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The authors would like to thank University of Antioquia, Colciencias and Sura EPS for sponsoring this research. We are also very grateful for the patients' cooperation, for the support provided by José Miguel Abad and José Ignacio Acosta, for the advice provided by Professors Rubén Darío Gomez and Juan Luis Londoño, and for Andrés Felipe Quintero

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*2.7. Quality Assurance/Quality Control*

A meadow soil collected from a cropland in Liaoning, China (123.90◦ E, 41.38◦ N) which was tested and demonstrated to be free of most of the studied PBDEs, was used as matrix blank and matrix spike samples. Twenty ng BDE 206, 207, 208, 209 and 4 ng of the other target PBDEs were spiked into 5 g meadow soil to evaluate the method performance. The recoveries for BDE-100, 154, 153, 183, 190, 208, 207, 206 and 209 were 60–107%. For BDE-28, 47, and 99, the recoveries were 32–58%. For all the target compounds, the relative standard deviations of duplicate samples were less than 14%. The recoveries of BDE-17, 66, 71 and 85 were lower than 20%, therefore they were not excluded from the statistically analysis. For the spiked surrogate 13C-PCB-208 and PCB-209, the average recoveries in all samples were 71% and 84%, respectively. The method detection limits (MDLs) values characterized as three times the signal-to-noise ratio were 8–164 pg/g for the target PBDEs (Supplementary Tables). The procedural blanks and solvent blanks were analysed simultaneously with samples to check for interferences and contamination. The reported results of PBDEs in the samples were corrected by recoveries of 13C-PCB-208. Three criteria were also used to ensure the correct identification of the target compounds [39]: (a) The GC (gas chromatography) retention times matched those of the authentic standards within ±0.1 min. (b) the signal-to-noise ratio was greater than 3:1; and (c) the isotopic ratios between the quantitative and confirmation ions were within ±15% of the theoretical values. Both 13C-PCB-208 and PCB-209 were used as surrogate to indicate the stability of the recoveries of each sample. In addition, this measure helps to monitor the recoveries of the target compounds at different concentration level.


**3. Results**

A total of 132 potentially eligible articles were identified using our search strategy. After the exclusion of 93 articles based on title and abstract for clearly not fulfilling inclusion criteria on the basis of the type of article, study design, population or outcome of interest, or due to being duplicates, 39 articles were left for full-length review. Eighteen of these were excluded from the full-length review as they did not report the outcome of interest, while six articles were excluded because they were not observational studies. Thus, 15 studies (10 cohort studies [58–67] with a total of 431 KTx recipients and 5 cohort studies [68–72] with a total of 108 living kidney donors) were included. The literature retrieval, review, and selection process are demonstrated in Figure 1.

**Figure 1.** Outline of our search methodology. Abbreviation: KTx, kidney transplant.

#### *3.1. Serum Klotho after Kidney Transplantation*

The characteristics of the included studies assessing serum klotho after kidney transplantation are presented in Tables 1 and 2. After KTx, there was a significant increase in serum klotho levels in recipients (at 4 to 13 months post-KTx) in reference to baseline levels before KTx with a mean difference (MD) of 243.11 pg/mL (three studies; 95% CI 67.41 to 418.81 pg/mL, I2 = 93%), Figure 2A. There were significant reductions in serum PTH and phosphate levels with MDs of −134.65 pg/mL (95% CI −176.09 to −93.21 pg/mL, I2 = 0%) and −2.81 mg/dL (95% CI −3.46 to −2.16 mg/dL, I2 = 97%), respectively. There was no significant change in serum calcium levels with a MD of 0.37 mg/dL (95% CI, −0.05 to 0.79 mg/dL, I2 = 83%). Although KTx recipients had lower serum klotho levels with a MD of = −234.50 pg/mL (five studies; 95% CI −444.84 to −24.16 pg/mL, I2 = 93%, Figure 2B) compared to healthy unmatched volunteers, one study demonstrated comparable klotho level between KTx recipients and eGFR-matched controls [66]. Two studies demonstrated high serum klotholevelsin deceased donors as a prognostic marker for good allograft function within one year after KTx (*p* < 0.05) [59,60].

Abbreviations: eGFR, estimated glomerular filtration rate; iFGF23, intact fibroblast growth factor-23; KTx, kidney transplant; N/A, not available.

*J. Clin. Med.* **2020**, *9*, 1834

**Figure 2.** (**A**) Change in Serum Klotho in KTx Recipients after Kidney Transplant. (**B**) Serum Klotho in KTx Recipients Compared to Unmatched Healthy Volunteers.

#### *3.2. Serum Klotho after Living Kidney Donation*

The characteristics of the included studies assessing serum klotho after kidney transplantation are presented in Tables 3 and 4. A total of 108 living kidney donors were identified from five cohort studies. After kidney donation, there was a significant decrease in serum klotho levels post-nephrectomy (day 3 to day 5) with a mean difference (MD) of −232.24 pg/mL (three studies; 95% CI −299.41 to −165.07 pg/mL, I2 = 0), Figure 3A. At one year following the kidney donation, serum klotho levels remained lower than baseline before nephrectomy with a MD of = −110.80 pg/mL (two studies; 95% CI −166.35 to −55.24 pg/mL, I2 = 5), Figure 3B.

**Figure 3.** Changes in serum klotho after living kidney donation: (**A**) immediate post-donation and (**B**) one year post-donation.

**Table 4.** Characteristics of the included studies comparing serum klotho between living kidney donors and healthy volunteers.

There was no significant change in serum FGF-23 at one year post-donation with a MD of = 8.19 pg/mL (two studies; 95% CI −14.24 to 30.62 pg/mL, I2 = 85%), Figure 4A. Compared to unmatched healthy volunteers, living kidney donors had lower serum klotho levels with a MD of = −92.41 pg/mL (two studies; 95% CI −180.53 to −4.29 pg/mL, I2 = 44%), Figure 4B.

**Figure 4.** (**A**) Changes in Serum FGF-23 at one year post-donation and (**B**) Serum klotho levels in kidney donors compared to unmatched healthy controls.

#### *3.3. Evaluation for Publication Bias*

A funnel plot was not drawn because of the limited number of studies in each analysis. Generally, tests for funnel plot asymmetry should be used only when there are at least ten study groups, because the power of the test is too low to distinguish chance from real asymmetry [82]. Egger's regression test demonstrated no significant publication bias in all analyses (*p* > 0.05).


**9. Groups at risk for stigma and xenophobia associated with COVID-19**

People over the age of 65 suffer from the disease more severely due to the effect of other existing medical diseases. With the spread of the coronavirus and growing fear and anxiety, especially among older adults, the issue of coronavirus stigma in older

*Perspective Chapter: Psychosocial Impact of COVID-19 – Stigma and Xenophobia DOI: http://dx.doi.org/10.5772/intechopen.101527*

people has become a major social concern. Elderly people are accused of ignoring their own health and public health because they do not comply with protective measures sufficiently [64]. Disregarding their own will, they are the target of more prohibitive measures, and ageism has been exacerbated during this pandemic. The hypothesis that older people are more likely to have COVID-19 leads to the fact that people in the community are less likely to contact with older people. This led to the isolation of the elderly. This stigma can weaken social cohesion in the elderly and lead to social isolation among older adults [65]. In the first days of the epidemic, people living in China, even from all Asian countries, foreigners or foreigners were perceived as a possible threat. Refugees were included in the current risk group. Many names that affect the public, from heads of states to officials, made speeches accusing refugees of spreading the virus; discrimination and hate crimes against Mexicans in the USA, Africans in Italy, and refugee groups in Bosnia, Jordan, Singapore, and Greece took place in the press [66]. Health workers who are in close contact with patients may be excluded, and when people around them see them in shopping, in an apartment, or at home, they may exhibit discriminatory behaviors even when necessary physical distance and adequate precautions are taken. In May 2020, 13 humanitarian organizations such as the World Medical Association, Red Crescent, Red Cross and medical associations made a statement to draw attention to and prevent attacks against healthcare workers during the pandemic. In many different countries, from Mexico to India, healthcare workers are being attacked for fear of transmitting COVID [1]. Burnout is more common in healthcare workers who are faced with stigmatization [67].