With best wishes,
Dr Adina Abdullah
Organising Chairperson

For any enquires please contact:
Pn Norlia Abdul Rahman
Tel: 03 7949 2802
Email: norlia@ummc.edu.my
at Department of Primary Care Medicine,
University Malaya
or
Secretariat Ms Nalini or Ms Puva,
Pfizer Sdn Bhd
Tel: 03 5568 6688

Corresponding author: Craig J. Currie, currie@cardiff.ac.uk.

http://care.diabetesjournals.org/content/early/2012/04/15/dc11-1277.abstract?papetoc

Abstract

OBJECTIVE To assess the association of compliance with treatment (medication and clinic appointments) and all-cause mortality in people with insulin-treated type 2 diabetes.

RESEARCH DESIGN AND METHODS Data were extracted from U.K. general practice records and included patients (N = 15,984) who had diagnostic codes indicative of type 2 diabetes or who had received a prescription for an oral antidiabetic agent and were treated with insulin. Records in the 30 months before the index date were inspected for clinical codes (recorded at consultation) indicating medication noncompliance or medical appointment nonattendance. Noncompliance was defined as missing more than one scheduled visit or having at least one provider code for not taking medications as prescribed. Relative survival postindex date was compared by determining progression to all-cause mortality using Cox proportional hazards models.

RESULTS Those identified as clinic nonattenders were more likely to be smokers, younger, have higher HbA1c, and have more prior primary care contacts and greater morbidity (P < 0.001). Those identified as medication noncompliers were more likely to be women (P = 0.001), smokers (P = 0.014), and have higher HbA1c, more prior primary care contacts, and greater morbidity (all P < 0.001). After adjustment for confounding factors, medication noncompliance (hazard ratio 1.579 [95% CI 1.167–2.135]), clinic nonattendance of one or two missed appointments (1.163 [1.042–1.299]), and clinic nonattendance of greater than two missed appointments (1.605 [1.356–1.900]) were independent risk factors for all-cause mortality.

CONCLUSIONS Medication noncompliance and clinic nonattendance, assessed during routine care by primary care physicians or their staff, were independently associated with increased all-cause mortality in patients with type 2 diabetes receiving insulin.

Received July 5, 2011.
Accepted February 19, 2012.

© 2012 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

A B S T R A C T

Background
Prevention of childhood obesity is an international public health priority given the significant impact of obesity on acute and chronic
diseases, general health, development and well-being. The international evidence base for strategies that governments, communities
and families can implement to prevent obesity, and promote health, has been accumulating but remains unclear.
Objectives
This review primarily aims to update the previous Cochrane review of childhood obesity prevention research and determine the
effectiveness of evaluated interventions intended to prevent obesity in children, assessed by change in BodyMass Index (BMI). Secondary
aims were to examine the characteristics of the programs and strategies to answer the questions “What works for whom, why and for what cost?”

Search methods

The searches were re-run in CENTRAL, MEDLINE, EMBASE, PsychINFO and CINAHL in March 2010 and searched relevant
websites. Non-English language papers were included and experts were contacted.

Selection criteria

The reviewincludes data fromchildhood obesity prevention studies that used a controlled study design (with orwithout randomisation).
Studies were included if they evaluated interventions, policies or programs in place for twelve weeks or more. If studies were randomised at a cluster level, 6 clusters were required.

Interventions for preventing obesity in children (Review)
Copyright © 2011 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

Data collection and analysis

Two review authors independently extracted data and assessed the risk of bias of included studies. Data was extracted on intervention
implementation, cost, equity and outcomes. Outcome measures were grouped according to whether they measured adiposity, physical
activity (PA)-related behaviours or diet-related behaviours. Adverse outcomes were recorded. A meta-analysis was conducted using
available BMI or standardised BMI (zBMI) score data with subgroup analysis by age group (0-5, 6-12, 13-18 years, corresponding to
stages of developmental and childhood settings).

Main results

This review includes 55 studies (an additional 36 studies found for this update). The majority of studies targeted children aged 6-
12 years. The meta-analysis included 37 studies of 27,946 children and demonstrated that programmes were effective at reducing
adiposity, although not all individual interventions were effective, and there was a high level of observed heterogeneity (I2=82%).
Overall, children in the intervention group had a standardised mean difference in adiposity (measured as BMI or zBMI) of -0.15kg/m
2 (95% confidence interval (CI): -0.21 to -0.09). Intervention effects by age subgroups were -0.26kg/m2 (95% CI:-0.53 to 0.00) (0-
5 years), -0.15kg/m2 (95% CI -0.23 to -0.08) (6-12 years), and -0.09kg/m2 (95% CI -0.20 to 0.03) (13-18 years). Heterogeneity was
apparent in all three age groups and could not explained by randomisation status or the type, duration or setting of the intervention.
Only eight studies reported on adverse effects and no evidence of adverse outcomes such as unhealthy dieting practices, increased
prevalence of underweight or body image sensitivities was found. Interventions did not appear to increase health inequalities although this was examined in fewer studies.

Authors’ conclusions

We found strong evidence to support beneficial effects of child obesity prevention programmes on BMI, particularly for programmes
targeted to children aged six to 12 years. However, given the unexplained heterogeneity and the likelihood of small study bias, these
findings must be interpreted cautiously. A broad range of programme components were used in these studies and whilst it is not possible to distinguish which of these components contributed most to the beneficial effects observed, our synthesis indicates the following to be promising policies and strategies:
· school curriculum that includes healthy eating, physical activity and body image
· increased sessions for physical activity and the development of fundamental movement skills throughout the school week
· improvements in nutritional quality of the food supply in schools
· environments and cultural practices that support children eating healthier foods and being active throughout each day
· support for teachers and other staff to implement health promotion strategies and activities (e.g. professional development,
capacity building activities)
· parent support and home activities that encourage children to be more active, eat more nutritious foods and spend less time in
screen based activities
However, study and evaluation designs need to be strengthened, and reporting extended to capture process and implementation factors, outcomes in relation to measures of equity, longer term outcomes, potential harms and costs.
Childhood obesity prevention research must now move towards identifying how effective intervention components can be embedded
within health, education and care systems and achieve long term sustainable impacts.

Hepatitis B vaccine was first made available in 1982. The initial plasma derived vaccine was improved over the years and the current hepatitis B vaccines are manufactured using recombinant DNA technology and contains a portion of non-infectious hepatitis B virus gene coding for the HbsAg. Malaysia started routine Hepatitis B immunization for infants in 1989 using the three-dose regime with the first dose given shortly after birth, thereafter at 1 month and then at 5 months old to coincide with the third dose of DTP/OPV. Anti-HBs immunoglobulin is also given together with the first dose of hepatitis B vaccine (active-passive immunization) at different sites if the mother is found to be a carrier of Hepatitis B virus. Hepatitis B immunization prevents both vertical and horizontal transmission.

The immunogenicity and efficacy of current hepatitis B vaccines in preventing newborn babies from becoming infected and subsequently becoming chronic carriers of the hepatitis B virus (HBV) had long been established through many studies. This is important because a chronic carrier state is associated with the development of hepatocellular carcinoma. Studies conducted by the Malaysian Liver Foundation have found that 80% of the adults diagnosed to have hepatocellular carcinoma are chronic HBV carriers. Indeed, the hepatitis B vaccine is credited as being the first anti-cancer vaccine to be developed.

Medical practitioners often face a dilemma over three practical issues, which this short article will try to address. The emphasis is to give a perspective of what is already known about the current hepatitis B vaccine and its use in protection against HBV infection so that practitioners can make an informed decision on advising their patients. Knowledge on immunization against hepatitis B and its duration of protection is still ongoing. Hence, the practice of hepatitis B immunization may change in the near future as new knowledge emerges. Medical practitioners therefore will need to keep abreast of such knowledge so that their practice can be current.

Pre-vaccination serologic testing

The need to have blood tested to document the presence of protective anti-HBs antibody is to identify those who do not need to be vaccinated unnecessarily and hence save cost on purchasing the vaccine. In the majority of cases in healthy infants, children and adults this is unnecessary and should be guided by the likelihood that the individual had been exposed to HBV and/or another family member had been found to be infected or a carrier of the HBV. The administration of the vaccine in an immune or infected individual will not result in any adverse outcome. In the event that pre-serologic testing is deemed necessary, a combination of tests for HBsAg, anti-HBsAb and anti-HBcAb will differentiate those who are currently infected or had past infection (detectable anti-HBc antibody) from a carrier state (HBsAg positive) who can then be followed up and treated.

Post-vaccination serologic testing

The current hepatitis B vaccines are highly immunogenic with > 95% of children and adolescents developing protective antibody following the recommended three doses of vaccines. Thus, routine post-immunisation serologic testing is not recommended except in the following situations:

• Infants whose mothers are HbsAg carriers
• Immunodeficient states
• Patients undergoing dialysis
• Medical and dental students
• Paramedical staff

Post-vaccination serologic testing is usually carried out 1-3 months following the last dose of the vaccine. Anti-HBs antibody levels of = 10 mIU/L are considered protective against infection. Since low birth weight babies (< 2000 gm) respond poorly to the vaccine 1-3, one might even consider extending post-immunisation serologic testing in such situation. In a recent publication by WHO 4 it is recommended that this group of babies be given four doses of the vaccine, with the first dose given shortly after birth not considered as part of the primary series.

To boost or not to boost ?

Following the recommended three doses of vaccines the duration of immunity lasts at least 13-15 years 5 and seems to be longer in those with a higher post-immunisation antibody titre. The decline in the antibody titre is most rapid in the first year, after which the rate of decline slows down considerably. However, a low or undetectable anti-HBs Ab does not mean that there is loss of protective antibody 6.

Nevertheless, this observation of waning antibody level to < 10mIU/mL has generated some anxiety among practitioners and unwittingly brought about the controversial subject of whether a booster (fourth) dose of the vaccine is needed in 5-10 years after the last dose of the vaccine. In those subjects who have responded (anti-HBs antibody titre equal to or more than 10 mIU/mL) the duration of immunity is at least 15 years. Since the current hepatitis B vaccines are highly immunogenic in over 95% of immunocompetent vaccinees the large majority of children will retain long-term protection, unless there are reasons to believe otherwise. Protection against HBV is conferred by memory T-cells and B-cells, in those successfully vaccinated regardless of persistence of detectable antibody. This anamnestic response occurs on exposure to the HBV either naturally or by booster immunization. 7-12 Based on these observations regular booster doses of hepatitis B vaccine are not indicated for immunocompetent vaccinees. Indeed, currently none of the advisory bodies (Advisory Committee for Immunization Practices (ACIP) in the United States nor the European Consensus Group 13 on Hepatitis B Immunity) recommend a routine booster dose of hepatitis B vaccine following the primary series of three doses, regardless of whether or not the first dose was administered shortly after birth.

Summary :

1. Susceptibility testing is not indicated before immunization in immunocompetent children
2. Routine post-immunisation testing for anti-HBs level is not necessary
3. Antibody testing is recommended 1-3 months after the third dose of active immunization in the following small group of individuals :
   1. Infants born to HBsAg positive mothers
   2. Patients undergoing haemodialysis
   3. Immunocompromised patients including HIV-infected individuals
   4. Adults at occupational risk from sharps injuries eg. health care workers
   5. Spouses or sexual contacts of HBsAg positive persons

References

• Blondheim O, Bader D, Abend M, et al. Immunogenicity of hepatitis B vaccine in preterm infants. Archives of Disease in Childhood: Fetal & Neonatal Edition 1998;79: F206-8.
• Golebiowska M, Kardas-Sobantka D, Chlebna-Sokol D, Sabanty W. Hepatitis B vaccination in preterm infants. European Journal of Pediatrics 1999;158:293-7.
• Belloni C, Chirico G, Pistorio A, et al. Immunogenicity of hepatitis B vaccine in term and preterm infants. Acta Paediatrica 1998;87:336-8.
• Weekly epidemiological record No. 28, 2004.
• Watson B, West DJ, Chilkatowsky A et al. Persistence of immunologic memory for 13 years in recipients of a recombinant hepatitis B vaccine. Vaccine. 2001;19:3164-68.
• Banatvala J, Van Damme P, Oehen S. Lifelong protection against hepatitis B – the role of vaccine immunogenicity in immune memory.; Vaccine 2001;19:877-85.
• European Consensus Group on Hepatitis B Immunity. Are booster immunisations needed for lifelong hepatitis B immunity? Lancet 2000;355:561-5.
• Williams JL, Christensen CJ, McMahon BJ, et al. Evaluation of the response to a booster dose of hepatitis B vaccine in previously immunized healthcare workers. Vaccine 2001;19:4081-5.
• Greub G, Zysset F, Genton B, et al. Absence of anti-hepatitis B surface antibody after vaccination does not necessarily mean absence of immune response. Medical Microbiology & Immunology 2001;189:165-8.
• Moyes CD, Milne A, Waldon J. 1990. Very low dose hepatitis B vaccination in the newborn: anamnestic response to vaccine at four years. J Med Virol 30: 216–8.
• West DJ, Calandra GB. 1996. Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination. Vaccine 14: 1019–27.
• Mahoney FJ, Kane M. 1999. Hepatitis B vaccine. In: SA Plotkin, WA Orenstein (eds) Vaccines (3rd edition). Philadelphia: WB Saunders Company.
• European Consensus Group on Hepatitis B Immunity. Are booster immunizations needed for lifelong hepatitis B immunity? Lancet. 2000; 355:561–565.

Prepared by Dr MT Koh 5 Dec 2004
Modified and corrected : April 2005

Clinicians often do not initiate or intensify therapy appropriately in their patients with diabetes. More aggressive treatment is necessary and should include earlier introduction and appropriate intensification of insulin therapy in patients with type 2 diabetes. Unfortunately, earlier initiation of insulin is hindered by fear of hypoglycemia, weight gain, and injections. Fear of hypoglycemia remains a major challenge for both physicians and patients and is a significant barrier to achieving optimal glycemic control.

Physicians treating patients with diabetes need to be comfortable with the use of insulin, as well as confident about integrating new formulations of insulin into their diabetes treatment plans.

Neutral protein Hagedorn (NPH) insulin is associated with a distinct peak at 6 hours, which may cause hypoglycemia, does not provide 24-hour control, and is associated with high inter- and intra-individual variability.

The advent of the long-acting insulin analogues in the past decade has revolutionized insulin therapy by offering flexibility in dosing and more options for tailoring therapy.

Next-generation basal insulin analogues are being studied, addressing the major challenges in diabetes care. The furthest along in development is degludec, with an elimination half-life longer than 24 hours. It is associated with significantly less pharmacodynamic variability which may be directly related to the drug’s lower rate of hypoglycemic episodes.

Another basal insulin analogue designed to deliver improved clinical features is LY2605541, which has just moved into phase 3 clinical development.

Full Link…

Archana Chatterjee; Catherine O’Keefe

Posted: 06/04/2010; Expert Rev Vaccines. 2010;9(5):497-502. © 2010 Expert Reviews Ltd.

Abstract and Introduction
Abstract

As a result of the vaccines discovered in the 20th Century, parents and many healthcare providers of the 21st Century have limited or no experience with the devastating effects of diseases such as polio, smallpox or measles. Fear of disease has shifted to concerns regarding vaccine safety. Scientific evidence has refuted many of the misconceptions regarding vaccine safety; however, parental refusal of vaccines is increasing. Here we review six of the most prevalent controversies surrounding vaccine safety: the proposed causal relationship between receipt of the measles–mumps–rubella vaccine and autism; thimerosal as a potential trigger for autism; religious objection based on some vaccine viruses being grown in cell lines from aborted fetal tissues; parental worries that use of the human papillomavirus vaccine may lead to youth promiscuity; fears regarding the purported association between pertussis vaccination and adverse neurological outcomes; and concerns regarding too many vaccines overloading or weakening the infant immune system. Healthcare providers are ideally positioned to correct these misconceptions, but they must recognize and acknowledge parents’ concerns, educate themselves on the latest scientific research that addresses these, and dedicate sufficient time to discuss vaccine safety with worried parents.

Introduction

Historical evidence suggests that there is a predictable inverse relationship between the levels of vaccine-preventable diseases and safety concerns, with safety concerns likely to emerge as first-hand experience with vaccine-preventable diseases decreases.[1] Today, vaccines represent one of the most important medical advances of all time and are responsible for preventing several vaccine-preventable diseases, and untold human suffering and disability.[101] As a consequence of the vaccine discoveries of the 20th Century, parents and many healthcare providers of the 21st Century have limited or no experience with the devastating effects of diseases such as polio, smallpox or measles. This has contributed to an uneasy relationship between the lay public and stewards of public health. In a recent survey of pediatricians and family practitioners, 11% of the physicians did not recommend to parents that children receive all available vaccines.[2] Thus, controversies surrounding safety have clouded the successes reaped by these life-saving vaccines. Fear of disease has shifted to fear of vaccine safety. Ironically, vaccines have become victims of their own success.

Scientific evidence has refuted many of the misconceptions regarding the safety of vaccines;[3] however, a distressing increase in parental refusal of vaccines has been reported.[4-6] A 2001–2002 National Immunization Survey indicated that 1% of parents believe vaccines are unsafe and another 6% have a neutral opinion on vaccine safety. Both groups had similar low vaccination coverage.[4] The 2003–2004 National Immunization Survey revealed an increase in vaccine refusal rates to 6%, with a total of 28.3% of respondents indicating that they were unsure or delaying vaccines due to concerns about vaccine safety.[7] Recent outbreaks of measles, Haemophilus influenzae type b invasive disease and pertussis have been attributed to vaccine refusal resulting in underimmunized infants and children.[8–11] These outbreaks underscore the need for continued efforts to educate the community regarding the safety and efficacy of currently licensed vaccines.

In this review, current common vaccine controversies in the USA will be addressed. In addition, the extant scientific evidence will be discussed within the context of the ongoing public health debate regarding the recommended vaccination schedule for infants and children.
Neurodevelopmental Concerns: Disconnecting Autism

One of the most contentious vaccine controversies to date is the proposed causal relationship between the receipt of the measles–mumps–rubella (MMR) vaccine and autism. Andrew Wakefield, a gastroenterologist in the UK, was the first to postulate the so-called ‘leaky-gut’ theory. Wakefield’s theory was supported by studies that identified measles virus nucleic acid sequences in the blood cells and intestinal tissue of some children who had experienced severe behavioral regression.[12,13] A similar investigation with a larger sample failed to reveal persistence of measles virus nucleic acids in the peripheral blood of children with autism-spectrum disorder.[14] Subsequently, results of several large population- and ecologic-based studies have failed to provide any support for Wakefield’s theory.[15] In light of the compelling evidence refuting Wakefield’s contention, most of his coauthors have published a formal retraction of the findings of the original article and the journal Lancet has recently fully retracted the original publication based on several elements of the paper being proven to be false.[16,17] Further details about this controversy and autism research have been published in a recent book.[18] The Institute of Medicine (IOM) in a report on vaccine safety has stated that “the committee concludes that the evidence favors rejection of a causal relationship between MMR vaccine and autism”.[19] Although there are rare side effects such as immediate hypersensitivity reactions and febrile seizures, as well as mild fever and rash that occur relatively commonly in association with its use, the MMR vaccine continues to be safe, efficacious and recommended by the Advisory Committee on Immunization Practices (ACIP) of the US CDC, and endorsed by the American Academy of Pediatrics (AAP) and the American Academy of Family Practice (AAFP).

Thimerosal is another hot button issue that has been debated in relationship to the onset of autism. Thimerosal has served as a preservative in vaccines since the 1930s. It is added to multidose vaccine vials for its bactericidal properties to preserve the sterility of the contents. In the late 1990s, the government became aware of and concerned about mercury exposure in the general population and the Environmental Protection Agency (EPA) published standards of safe limits of methylmercury exposure.[20] Thimerosal contains 49.6% mercury by weight and metabolizes into ethylymercury and thiosalicylate.[15] The use of thimerosal came under fire as more thimerosal-containing vaccines were added to the recommended infant and child immunization schedule. The possibility of subsequent neurodevelopmental problems related to the cumulative amounts of thimerosal that a child was receiving in the first 2 years of life, the total amount of mercury being administered at a single clinic visit, especially for the very smallest of infants (including premature infants in whom safety data were unavailable at the time) were raised as concerns.[20,21]

In 1999, the AAP and the US Public Health Service (USPHS) took a cautionary stance and issued a joint statement calling for the removal of thimerosal from pediatric vaccines.[22] At that time, the risks of low-dose ethylmercury in vaccines were unknown, although there was no evidence that thimerosal-containing vaccines contributed to toxic mercury levels. Studies conducted subsequently suggest that ethylmercury behaves very differently to the more concerning environmental neurotoxin methylmercury.[21] The action taken by the AAP and USPHS had a significant ripple effect on the general public’s acceptance of vaccine safety. The birth dose of hepatitis B vaccine, which at the time contained thimerosal, was subsequently withheld by many healthcare providers and the hepatitis B vaccination campaign experienced a serious setback. The removal of thimerosal from vaccine vials has also increased production costs, which are ultimately passed on to the consumer. At present, with the exception of some influenza vaccines, none of the routinely recommended pediatric vaccines contain thimerosal as a preservative.

In spite of overwhelming scientific evidence to the contrary, the debate rages on with media reports fueling the general public’s fear and erosion of confidence in vaccines. In March 2008, the story of Hannah Poling, a 9-year-old child whose parents claimed that she developed severe neurodevelopmental problems after receiving the MMR and other vaccines, found its way to front page news. The MMR–autism ‘link’ and the hypothesis that multiple vaccines cause autism were given ‘new life’ when the Polings were successful in their litigation under the Vaccine Injury Compensation Program (VICP). The VICP was developed to fairly compensate individuals who feel they have been harmed by a vaccine. Unlike most US legal claims, the VICP only requires a biologically plausible theory and not irrefutable proof.[23]

The following year on 12 February 2009, the US Court of Federal Claims denied damages for three families who were seeking redress for what they believed to be MMR vaccine-associated neurodevelopmental harm to their children. The three cases were considered ‘test cases’ for the almost 5000 families with pending claims. The hearings were conducted over 2 years and included 5000 pages of expert testimony and 939 medical articles.[102] This was a landmark decision that was criticized by antivaccine activists and lauded by the Department of Health and Human Services (DHHS). Once again, the purported link between MMR, as well as thimerosal, and autism had been disconnected.
Moral & Religious Concerns

Some parents have refused certain vaccinations for their children based on religious objections. The moral opposition to these vaccines is due to the acquisition of the initial cell lines in which vaccine viruses are grown, from voluntarily aborted fetuses. The specific vaccines are:

Single-antigen vaccines against rubella
Multiantigen vaccines against MMR
Single-antigen vaccine against chickenpox
Vaccines against hepatitis A[24]

In response to these concerns, the US Conference of Catholic Bishops has issued statements relieving parents of the obligation to refuse this vaccine based on the Catholic Church’s opposition to voluntary abortion. The Catholic Bishops have noted that the source of the cell line for the vaccines was not the choice of the parents and the only viable option to protect their child and the community from serious illness is to take the vaccine.[25]
Human Papillomavirus Vaccine: A Battle between Policy & Parents

Human papillomavirus (HPV) is the most common sexually transmitted disease and is most widely known for its association with cervical cancer. There are more than 120 genotypes of HPV with approximately 30 affecting at least half of sexually active individuals. Of the 30 types, 12 can cause cervical cancer.[26] Four HPV genotypes have been targeted for vaccine development: 6, 11, 16 and 18. HPV-6 and -11 cause anogenital warts and, if transmitted vertically from a mother to her infant, may cause juvenile recurrent respiratory papillomatosis.[26]

The first HPV vaccine was licensed by Merck, NJ, USA (Gardasil®) in 2006 and was heralded by many as the most important anticancer vaccine since the hepatitis B vaccine. A second bivalent (HPV types 16 and 18) vaccine, Cervarix® (GlaxoSmithKline, London, UK), has recently been licensed by the US FDA. However, controversies and questions concerning safety as well as parental attitudes have contributed to the relatively low HPV vaccine uptake – 17.9% of vaccine-eligible young women aged 13–17 years and 9.9% aged 18–26 years.[27,103]

Gardasil is a quadrivalent vaccine (serotypes 6, 11, 16 and 18) and approved for use in females, ages 9–26 years. It has been recommended by the Advisory Committee on Immunization Practices (ACIP) of the CDC and endorsed by the AAP and the AAFP since 2007.[28]

Follow-up studies have revealed a 98–99% efficacy rate for Gardasil.[29,30] Post-licensure safety data for this vaccine as reported by the federal Vaccine Adverse Event Reporting Systems has been similar to other vaccine post-licensure data.[31] The question arises as to the acceptability of any vaccine risk with a disease that can be prevented by an active screening process. The answer lies within a medical system that has been unsuccessful in reducing the incidence of HPV-associated disease through routine screening.[32]

Public health, politics and parents have clashed and created a significant obstacle to the widespread acceptance of the HPV vaccine. Shortly after the licensure of the HPV vaccine, several states began introducing legislation to mandate HPV vaccination for school-aged girls.[33] This action prompted a groundswell of opposition from the lay public and immersed the HPV vaccine in controversy. Parents and some healthcare providers argue that receipt of the HPV vaccine should be a matter of individual choice, particularly since the vaccine is designed to prevent a sexually transmitted infection. Opponents proclaim that the HPV vaccine promotes early initiation of sexual activity and/or increased promiscuity.[104]

The reality is that young people engage in risky sexual behavior that can have devastating effects on their health well into adulthood.[34] A government study of abstinence-only education in middle schools revealed that within 4–6 years after the program, an equal number of participants versus controls had experienced sexual activity with the mean age of 14.9 years of age for first sexual activity.[105] The 2005 US Youth Risk Behavior Survey has reported similar findings with a median of 3.6% of females reporting experiencing their first sexual encounter before 13 years of age.[35] The National Health and Nutrition Examination Survey (NHANES) interviewed adults regarding sexual behavior and reported that 20% of 20–29-year-olds had engaged in sexual activity before 15 years of age.[106] An even harsher reality is that young children can become infected with HPV after being subjected to involuntary sexual activity due to rape, incest or other unwanted genital contact.[34]
Nervous System Disorders: Encephalopathies

The licensure of whole-cell pertussis vaccines in the 1940s marked the beginning of a dramatic decrease in the morbidity and mortality associated with Bordetella pertussis infection. Prior to the widespread use of the pertussis vaccine, hundreds of thousands of children every year contracted this debilitating respiratory infection and thousands of infants died.[36] However, despite routine use of this vaccine and, subsequently, the less reactogenic acellular pertussis vaccines, pertussis remains endemic in the USA.[37] This situation can partly be attributed to an increase in vaccine refusals as well as the modest efficacy (70–90%) of these vaccines, and an increasing adolescent and adult pool of susceptible individuals in whom immunity has waned over time.

The history of the pertussis vaccine debate dates back nearly 35 years. This controversy was first ignited by a study published in 1974 suggesting neurological complications associated with the pertussis vaccine.[38] Reports of post-vaccine febrile seizures added fuel to the fire.[39] These vaccine safety studies created significant anxiety among the general public, so that pertussis vaccine coverage plummeted in the UK from over 70% to approximately 30%.[39] Japan and Sweden also observed dramatic decreases in pertussis vaccine uptake as national mandates were lifted. The benefit of the pertussis vaccine soon became apparent as these countries quickly experienced widespread pertussis epidemics.[40] A case–control study entitled the National Childhood Encephalopathy Study (NCES) was conducted in the UK from 1976–1979, that suggested that the risk of permanent brain injury from pertussis vaccination might not be zero but was still extremely low (1 in 300,000).[41] Immunization rates began to recover after the NCES data were published. Unfortunately, the findings of the NCES were interpreted by some people as supporting a causal relationship between pertussis vaccine use and encephalopathy. Over time, this interpretation has been refuted.[42,43] In 1988, a London High Court of Justice ruling attempted to put an end to the speculation that pertussis vaccine caused serious neurological events but the damage had already been done in terms of pertussis vaccine acceptance.[39] Several well-designed studies have since been conducted that show no evidence of an association between the whole-cell diphtheria–pertussis–tetanus vaccine and encephalopathy.[44,45]
An Overwhelmed or Healthy Immune System?

The number of recommended childhood vaccines has increased exponentially in the last 50 years. A fully immunized child by the age of 2 years will have received 14 different vaccines and up to 26 injections. Some healthcare visits may require five injections at a single visit. Understandably, parents have voiced concern about too many vaccines overloading or weakening the fragile immune system of their infant.[46] This notion may be based upon reports that certain live viral vaccines, such as those containing attenuated measles virus, can cause a decrease in protective immune responses to varicella vaccine[47] and that the high-titered measles vaccine (Edmonston–Zagreb strain) can cause an excess of cases of invasive bacterial infections in developing countries.[48] It should be noted that current vaccines (including the highly attenuated Moraten strain of measles vaccine) do not appear to cause clinically relevant immunosuppression in healthy children.[3]

The neonate’s immune system begins to develop and is primed in utero.[49] There is evidence that fetuses have the capacity to form antibodies in the presence of intrauterine infections.[50] Infants can generate functional T cells as well as the full range of B-cell responses.[51] Continued maturation of the immune system is observed as the neonate, within hours of life, begins to colonize his/her intestinal tract and respond to a whole host of environmental antigenic stimuli. Infants in fact have an amazing capacity to respond to a vast array of antigens, including vaccines. However, the infant’s immune system is not capable of responding with adult efficiency. Maturation of the immune response occurs in an orderly fashion from approximately 16 weeks gestation and slowly gains momentum in the first year of life. This, along with the presence of maternal antibodies provided passively, may account for the need for multiple injections to complete the primary series of several vaccines.[49,50] Data suggest that, theoretically, the intact immune system could respond to 109–1011 different antigens.[51] Today’s vaccines contain far fewer antigens than the immune system is designed to respond to. Medical advances in vaccinology have contributed to the decline in the number of antigens in modern vaccines. For example, the whole-cell pertussis vaccine contained approximately 3000 proteins compared with the two to five proteins found in the current acellular pertussis vaccines.[51]

Thus, parents and caregivers should be reassured based on these data that vaccines will not overwhelm or weaken the infant immune system.
Expert Commentary

Parents today are overwhelmed with the vaccine controversies and the decisions they face regarding their children’s health and well being. They are inundated with media reports of profit-driven pharmaceutical companies that cannot be trusted, internet blogs hosted by antivaccine activists and internet misinformation. They are in need of trusted expert advice. Although some parents distrust the experts, a majority identify their healthcare provider as the person with the most influence over their decision to vaccinate their child.[52] Healthcare providers are positioned to correct misconceptions and alleviate anxieties; but first they must recognize and acknowledge parents’ fears. They must educate themselves on the latest scientific research that addresses these issues. They also need to dedicate time to discuss concerns regarding vaccine safety with worried parents. To achieve these two things, training programs for healthcare providers need to include coursework on quality communication, and third-party payors need to reimburse immunization providers for education related to vaccination.[3] Providers also need to familiarize themselves with programs such as the Vaccine Safety Datalink, a collaborative effort between CDC’s Immunization Safety Office and eight managed-care organizations (MCOs).[107] The Vaccine Safety Datalink project was established in 1990 to monitor immunization safety and address the gaps in scientific knowledge regarding rare and serious events following immunization. Ultimately, it is imperative for all stakeholders to recognize that the overall health and well-being of US children is dependent on a robust vaccination program in which parents and providers are partners, not adversaries.
Five-year View

Although well-designed, statistically valid, scientific research studies have refuted many of the claimed adverse effects associated with vaccines, a portion of the public remains concerned regarding the safety of these life-saving products. Unfortunately, these controversial claims are not likely to disappear in the future. As medical science progresses and new vaccines are introduced, it is only to be expected that more controversies surrounding their safety will develop. Particular interest is likely to be focused on vaccine additives and adjuvants such as aluminum and squalene. While the vaccine–MMR/thimerosal debate appears to be abating, new concerns have arisen regarding the possible association between vaccine adjuvants/multiple vaccines given simultaneously and the development of autism spectrum disorders. Fears regarding vaccines and various disorders without clear-cut etiologies such as Alzheimer’s disease, other forms of dementia, neuropsychiatric illnesses, learning disabilities, rheumatoid diseases, macrophagic myofasciitis and Gulf War Syndrome[108–110] are also gaining attention. It is, therefore, imperative that healthcare providers be prepared to respond to patient and parent anxieties related to these emerging concerns.
Sidebar
Key Issues

The schedule of vaccines currently recommended for infants, children and adolescents has expanded in the USA within the societal context of increased concern with environmental risks.
Incidence of vaccine-preventable
Fear of disease has been replaced by fear of vaccines.
High vaccination coverage rates at the community level are necessary to protect individuals who cannot receive the vaccine(s) or those who are too young to be fully protected.
Public health departments, government agencies and medical professional organizations have responded to parental concerns regarding immunizations via educational campaigns and by providing instructive materials in print and online.
Healthcare providers need to be fully aware of the current scientific evidence and available educational material for lay people that support the currently recommended vaccine schedule.
A trusting relationship must be forged between the consumer and healthcare provider that facilitates open communication.

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•• Good review of several studies reporting no relationship between measles–mumps–rubella (MMR) vaccine and autism (1999–2007).
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Websites
101. Ten great public health achievements – United States 1900–1999 www.cdc.gov/mmwr/preview/mmwrhtml/mm4850bx.htm
102. US Court of Federal Claims. Autism decisions and background information www.uscfc.uscourts.gov/node/5026
103. Heyman KM, Barnes PM, Schiller JS. Early release of selected estimates based on data from the 2008 National Health Interview Survey. National Center for Health Statistics (2009) www.cdc.gov/nchs/nhis.htm
104. Cancer sluts. Does the HPV vaccine ‘promote’ promiscuity? www.slate.com/id/2174850/105
105. Impacts of four Title V, Section 510 abstinence education programs: final report www.mathematica-mpr.com/publications/pdfs/impactabstinence.pdf
106. Drug use and sexual behaviors reported by adults: United States, 1999–2002. Advance Data from Vital and Health Statistics www.cdc.gov/nchs/nhanes.htm
107. Vaccine Safety Datalink (VSD) project www.cdc.gov/vaccinesafety/Activities/vsd.html
108. Aluminum in vaccination-associated cognitive decline, motor neuron disease, autism www.generationrescue.org/binstock/090928-aluminum-als-alzheimer-autism.htm
109. Mercury and aluminum and squalene, oh my! http://holisticmomsnational.blogspot.com/2009/10/mercury-and-aluminum-and-squalene-oh-my.html
110. Squalene www.novaccine.com/vaccine-ingredients/results.asp?sc=27

Papers of special note have been highlighted as:
•• of considerable interest

Financial & competing interests disclosures
Archana Chatterjee has received research grants from Merck, GlaxoSmithKline, Sanofi Pasteur, Novartis, Wyeth and MedImmune. She has also served on the Speakers Bureau for Merck, GlaxoSmithKline, Sanofi Pasteur, Wyeth and MedImmune. She has served on ad hoc Advisory Boards for Merck, GlaxoSmithKline, Novartis, Sanofi Pasteur and MedImmune. Catherine O’Keefe is involved in research studies funded by Merck, GlaxoSmithKline, Sanofi Pasteur, Novartis, Wyeth and MedImmune. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Expert Rev Vaccines. 2010;9(5):497-502. © 2010 Expert Reviews Ltd.

Charlie Tomson, DM, FRCP; Pippa Bailey, MRCP, DTM&H

Management of chronic kidney disease (CKD) requires a systematic approach that includes all components of the chronic disease model. Some causes of CKD require specific additional management directed at the underlying cause.

Principles of Chronic Disease Management

Chronic kidney disease (CKD) is a prime example of a chronic disease requiring life-long management, involving the patient, the primary care team and specialists. Most people with CKD also have other long-term conditions (hypertension, cardiovascular disease, diabetes mellitus, atherosclerosis). Current disease-based clinical services (eg, nephrology clinics, hypertension clinics, diabetes clinics, heart failure clinics) seldom provide optimal care, with poor communication occurring between these ‘silos’ of care, and between hospital-based clinics, the primary care team, and the patient.

This lack of integration is harmful and can contribute to patients’ loss of control and to conflicting messages on what drug treatment the patient should be taking. The system is also wasteful, with much duplication of effort, tests, and wasted travel time. Research on systematic attempts to achieve improvement in the delivery of care for patients with chronic diseases has resulted in development of a framework, the ‘chronic care model’. Improvement is more likely if each component of the organization of care (self-management; decision support; delivery system design; clinical information systems) is addressed, and unlikely if, for instance, improvement efforts are confined to a hospital-based clinic.^1,2 Many of the components of the model, including national guidelines on identification, management and referral, are already in place for CKD.³

Early CKD is largely asymptomatic, so a balance has to be struck between ‘labelling’ patients as having ‘chronic kidney disease’ and ensuring that patients who are at increased risk of cardiovascular disease or progressive loss of kidney function are identified and offered the options of treatment that will reduce these risks.

Diagnosis of CKD

In this article, CKD will be defined according to the five-stage classification adopted in the UK.^3,4 This classification endorses the use of the four-variable Modification of Diet in Renal Disease (MDRD) equation to estimate normalized glomerular filtration rate (GFR) from serum creatinine, age, gender, and racial origin. The estimate provided by the laboratory should be used wherever possible, as this should include correction factors for the type of creatinine assay used.^4,5

Some patients will have other evidence of chronic kidney damage, such as:

• persistent microalbuminuria;
• persistent proteinuria;
• persistent haematuria (after exclusion of other causes, eg, urological disease);
• structural abnormalities of the kidneys demonstrated on ultrasound scanning or other radiological tests (eg, polycystic kidney disease, reflux nephropathy); or
• biopsy-proven chronic glomerulonephritis (most of these patients will have microalbuminuria or proteinuria, and/or haematuria).

In February 2007, a consensus conference in the UK⁶ approved two enhancements to this five-stage classification; dividing stage 3 CKD into stage 3A (estimated GFR [eGFR] 45–59) and stage 3B (eGFR 30–44), and adding the suffix ‘p’ to the GFR-based stage for patients with proteinuria (random urine protein to creatinine ratio > 100 mg/mmol).

These changes are endorsed by the National Institute for Health and Clinical Excellence (NICE),⁴ the Scottish Intercollegiate Guidelines Network (SIGN)⁷ and the American National Kidney Framework’s National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) guidelines.⁸ Proteinuria should be assessed by measurement of either the urinary protein to creatinine or albumin to creatinine ratio.⁹ Adoption of this enhanced classification system is likely to focus greater attention on those patients in stage 3 CKD, who are at greatest risk of complications of CKD and progressive loss of kidney function.

Limitations of MDRD and the CKD-EPI Formula

There are many limitations to the use of the MDRD formula to estimate renal function. First, the formula is less accurate when the GFR is more than 60 mL/minute/1.73 m². Second, its use has not been fully validated in the elderly, children or pregnant women, acute kidney injury (AKI), extremes of body size, or in ethnic groups other than Caucasians and African-Americans. There is therefore ongoing work to find a more accurate estimation of renal function than that offered by the MDRD; as a result, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was published in May 2009.

Preliminary work suggests that the CKD-EPI equation performs better (with less bias and greater accuracy) than the MDRD formula, especially at higher GFRs, but it has not been extensively validated in the elderly or in ethnic minorities. The formula is more complex to compute than the MDRD formula, and has not yet been adopted by UK laboratories for routine reporting of eGFR.

Specific Causes of CKD

Some cases of CKD are attributable to specific diseases, for which specific treatments are sometimes available to reduce the risk of progressive kidney damage. However, most patients with these well-defined causes of CKD will also benefit from the non-specific interventions discussed below.

Non-specific Causes of CKD

Many patients with reduced GFR do not have proteinuria, radiological abnormalities or other markers that suggest a specific underlying cause; in particular, elderly patients with reduced GFR commonly have no proteinuria. ¹⁰

There is controversy about the assessment of renal function in the elderly and how renal function changes as part of ‘normal ageing’.¹¹ The MDRD formula is not as well validated in the elderly, and any creatinine-based formula that incorporates assumptions about muscle mass at different ages will face the same problems. The apparent high prevalence of CKD in the elderly may occur because of:

• the presence of numerous risk factors for CKD, such as diabetes and hypertension;
• an age-associated decline in kidney function that is not explained by other known risk factors; or
• inaccuracy of creatinine-based estimating equations in the elderly population.

The Baltimore Longitudinal Study of Aging (BLSA) suggested that on average kidney function tends to decline with age even without co-morbidities, but this decline did not appear to be inevitable.¹² The majority of CKD in the elderly is non-progressive, and research is needed to identify those at risk of developing established renal failure. The increased relative risk for death associated with lower GFR (mostly due to cardiovascular disease) is more evident in younger people than in older people, largely because of fewer competing risks in younger people; patients aged over 75 years with moderate eGFR 45–60 mL/minute/1.73 m² were at no higher risk of death over 1–3 years’ follow-up than their age peers with levels of eGFR above 60 mL/minute/1.73 m².¹³

Reducing the Risk of Progressive Loss of GFR

In addition to specific therapy targeted at the underlying primary disease, recognition of the role of several modifiable secondary factors associated with progressive kidney damage is important clinically, as these can be treated effectively thereby minimizing renal injury. Most of these interventions also reduce the risk of cardiovascular disease.

Systemic Hypertension

The two main goals of antihypertensive therapy are cardiovascular disease risk modification and reduction of risk of progressive decline in GFR.

There is strong evidence that high blood pressure (BP) is associated with increased risk both of cardiovascular disease and of progressive kidney disease, and that these risks are higher amongst people with diabetes than in non-diabetic subjects at any given level of kidney function.

Several randomized controlled trials have shown that the risks of cardiovascular events and progressive kidney disease are reduced by BP-lowering treatment. However, studies comparing different intervention thresholds, different BP ‘targets’, and different strategies for patients with varying degrees of proteinuria, co-morbidity, and conduit artery compliance or pulse pressure are still required. Two important studies ‘targeted’ mean arterial pressure rather than systolic or diastolic,^14,15 in contrast to current clinical practice. Many of the existing guidelines, therefore, are based on post hoc analyses of randomized controlled trials and observational studies, and of ‘translation’ of mean arterial pressures into systolic and diastolic pressures. As a result, there is considerable confusion between the various guidelines and audit measures currently used in the UK. We suggest following the recommendations by the Renal Association and NICE (Figure 1).

According to British Hypertension Society guidelines and NICE guidance, the threshold BP for intervention is 140/90 mm Hg for patients with CKD without diabetes, and 130/80 mm Hg for patients with CKD and diabetes. The target BP to be achieved is determined by the degree of proteinuria present. In people with CKD and a urine protein to creatinine ratio of 100 mg/mmol or lower, the target BP is systolic blood pressure less than 140 mm Hg (target range 120–139 mm Hg) and the diastolic blood pressure below 90 mm Hg. In patients with CKD and a urine protein to creatinine ratio more than 100 mg/ mmol, and for all patients with CKD and diabetes, aim to keep the systolic blood pressure below 130 mm Hg (target range 120–129 mm Hg) and the diastolic blood pressure below 80 mm Hg.⁴ Patients with proteinuria higher than 1 g/day may benefit from more rigorous BP control (< 125/75 mm Hg). Reduction of proteinuria is an additional therapeutic goal; dietary salt restriction amplifies the antiproteinuric effect of antihypertensive therapy.¹⁶

Currently, there is no good evidence to suggest that lowering BP below standard targets reduces mortality or morbidity.^17,18 There is some evidence that intensive BP lowering is of benefit in those who are high risk for cerebrovascular events, but in other patient groups a lower target BP may be harmful because of impaired perfusion of vital organs; these include patients who are at high risk of falls, especially those with postural hypotension, and those with concomitant coronary artery and peripheral vascular disease.¹⁹ Patients with multiple co-morbidities are unlikely to have been included in most of the informative randomized controlled trials. It is clear that antihypertensive therapy should be individualized for patients, having assessed the risks and benefits of intensive versus standard BP control, and taken into account the patient’s attitude to risk and medication. Given that arterial blood pressure is just one of several risk factors for cardiovascular and kidney disease, it would be more logical to adopt a ‘risk-based’ approach rather than one based on separate thresholds for blood pressure, serum cholesterol, etc; using this approach, more intensive treatment to reduce blood pressure (and other risk factors) would be recommended for patients at higher risk. This transition to a risk-based approach to risk factor modification is under way in many national and international guideline groups; it is likely to result in more coherent guidelines that will allow patients and their physicians to use the evidence base to come to shared decisions on which treatments to use. Such an approach is likely also to improve adherence to treatment.

Choice of Anti-hypertensive Agents

ACE inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) afford significant renal protection, in addition to that attributable to blood pressure lowering, and should be used as firstline agents in all patients with diabetes (with or without evidence of albuminuria), ²⁰ in non-diabetic kidney disease with proteinuria (random urine protein to creatinine ratio > 100 mg/mmol)²¹ and in those with heart failure.²²

The role of ACEIs and ARBs in non-diabetic kidney disease with less severe proteinuria is not as well established; although there is good evidence that these drugs reduce albumin excretion,²³ the benefits in terms of ‘hard’ clinical outcomes have not been established. In the absence of diabetes and/or albuminuria/proteinuria, the NICE Clinical Guideline 34 for hypertension should be consulted. Many patients need more than one agent to achieve target BP goals. Non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, have additional antiproteinuric effects and are preferred to the dihydropyridine agents, which may increase proteinuria. Many patients with CKD are fluid overloaded and may benefit from concomitant diuretic therapy, preferably a loop diuretic, as thiazide diuretics are less effective at GFR less than 30 mL/minute/1.73 m².

?-Blockers, ?-blockers and sympathetic antagonists may be needed in patients with resistant hypertension (ie, BP > 150/90 mm Hg despite three classes of antihypertensive agents).

Combination ACEI and ARB Therapy

There is some evidence that combination ACEI and ARB therapy offers a greater reduction in proteinuria compared with monotherapy.²⁴ However, the CO-OPERATE study, which appeared to support dual therapy, has now been withdrawn after the results of an academic investigation indicated serious concerns surrounding this publication.²⁵ The ONTARGET study suggests that combination therapy should be used with caution, especially in patients with vascular disease, owing to the greater risk of hypotensive symptoms, syncope and renal dysfunction.²⁶ An international, double-blinded, randomized, controlled trial is ongoing to assess the effect of combination reninangiotensin system blockade on CKD in diabetics.²⁷ Owing to the risks of serious adverse effects, dual blockade with an ACEI and an ARB should only be initiated under specialist supervision.

Patients commencing therapy with ACEIs or ARBs should have their serum creatinine and potassium checked within 2 weeks of initiation of therapy and after every increment in dosage. If the serum creatinine rises by more than 30% or the GFR falls by more than 25% from baseline, alternative causes of a deterioration in renal function should be investigated, dosage reduced to that previously tolerated or the agent withdrawn, and an alternative antihypertensive agent deployed. A significant fall in kidney function during ACEI/ARB inhibition can indicate haemodynamically significant renal artery narrowing, but the selection of patients who will benefit from revascularization remains problematic.

Reduction of Intraglomerular Hypertension

Proteinuric CKD (including diabetic nephropathy) is typically characterized by intraglomerular hypertension, caused by alterations in the regulation of vascular tone in the afferent and efferent glomerular arterioles, permitting greater transmission of systemic pressure to the glomerulus.

This increase in intraglomerular pressure is thought to be a major cause of progressive glomerular damage.

Although reduction of systemic BP helps to limit damage, some antihypertensive drugs (including ACEIs, ARBs, and non-dihydropyridine calcium channel blockers) directly reduce intraglomerular pressure by selective vasodilatation of the efferent arterioles, whereas others (including dihydropyridine calcium channel blockers) may increase intraglomerular pressure and worsen proteinuria. The benefits of ACEI/ARB treatment are, therefore, more evident if systemic blood pressure remains higher than optimal.²⁸

Inhibition of Renal Fibrosis

ACEIs and ARBs may have additional beneficial effects in progressive CKD, by inhibiting the actions of angiotensin II on glomerular permeability and tubulo-interstitial fibrosis. Several targets for anti-fibrotic agents have been validated in cellular and animal studies, but progress in translating these results to clinical practice has been disappointing. Nevertheless, drugs targeting the pathways of TGF-?, connective tissue growth factor, platelet-derived growth factor, Ki-Ras and NF-KB are all possible future therapeutic agents.²⁹

Smoking Cessation

Population-based studies have shown an association between tobacco smoking and increased incidence of CKD. Smoking has also been shown to increase the risk of progression of CKD to end-stage renal disease (ESRD), an effect independent of the primary renal disease. There is evidence that cessation of smoking reduces loss of kidney function amongst patients with progressive CKD.

Correction of Obesity

Weight loss has been shown to ameliorate obesity-induced glomerular hyperfiltration, and to decrease proteinuria in patients with chronic proteinuric nephropathies. Weight loss also reduces blood pressure, and the reductions are larger in patients taking antihypertensive treatment. Lastly, weight loss can improve glycaemic control amongst people with diabetes mellitus.³⁰

Glycaemic Control

The Diabetes Control and Complications Trial (DCCT) and the UKPDS trial provided evidence that improved glycaemic control prevents the development of microalbuminuria as well as other microvascular complications in patients with type 1 and 2 diabetes mellitus; long-term follow-up suggests that improved glycaemic control may have long-term beneficial effects on macrovascular disease as well.³¹ It is less clear whether improved glycaemic control slows down progressive renal injury once overt proteinuria has developed.

The target HbA1c for patients with CKD and diabetes continues to be debated. Although two large trials have found that intensive glucose control (target HbA1c < 6.5%; < 47 mmol/mol) compared with standard glucose control is associated with a reduction in new-onset microalbuminuria and macroalbuminuria,^32,33 and a reduction in the development of new or worsening nephropathy,³² in neither trial did intensive control have an effect on the doubling of serum creatinine. Intensive control is also associated with an increased risk of hypoglycaemia,³³ which is associated with an increased risk of death.³⁴ We would advise that clinicians individualize therapy after discussion with patients, taking into account life expectancy, overall cardiovascular and renal risk, aiming for a target HbA1c of less than 7.5% (< 58 mmol/mol) for most.

Treatment of Dyslipidaemia

Dyslipidaemia is a risk marker for progressive kidney injury and a risk factor for cardiovascular disease. Current evidence that treatment of dyslipidaemia reduces CKD progression is mostly restricted to post hoc subgroup analyses from large cardiovascular clinical trials, such as the Heart Protection study and the Cholesterol and Recurrent Events (CARE) study, where renal function was not the primary outcome studied. Results from the Study of Heart and Renal Protection trial (SHARP) have recently provided evidence that reducing serum LDL cholesterol (using a combination of simvastatin and ezetimibe) significantly reduced the incidence of ‘major atherosclerotic events’ (myocardial infarction, stroke and revascularization), with no adverse effects.³⁵ The size of the risk reduction was similar in patients with CKD and in patients on dialysis. Previous trials of cholesterollowering therapies in patients with kidney disease^36,37 were not able to demonstrate benefit, possibly because they lacked power or included a large number of non-atherosclerotic cardiovascular events, such as sudden cardiac death and haemorrhagic stroke—particularly common in patients with established renal failure. The SHARP study showed no significant difference in the number of patients with CKD reaching established renal failure.

Pharmacological Management

Many water-soluble drugs are cleared by the kidney and accumulate in CKD as a result of impaired excretion. For drugs with a high therapeutic index, reduced excretion is seldom a problem in stage 3 CKD, but can become important in stages 4 and 5. When using an estimate of GFR to decide on drug dosage adjustments in patients at the extremes of body size, it is also important to remember that the MDRD formula gives a normalized estimate of GFR (ie, what the GFR would be if the patient had a ‘normal’ body surface area of 1.73 m²; this is the best overall measure of the adequacy of renal excretory function, because metabolic rate—thus the need for excretion of waste products—varies with body size).

Actual GFR (which determines drug clearance) may be significantly lower than normalized GFR in small patients, and vice versa. Formula-based estimates of GFR should not, therefore, be used to adjust the dose of renally excreted drugs with a low therapeutic index.

The use of metformin presents particular problems, given the frequency with which CKD is found amongst people with type 2 diabetes. Metformin can cause type 2 lactic acidosis, and the risk of this very rare complication is probably greater amongst patients with reduced GFR. For this reason, the summary of product characteristics suggests that the drug is avoided in patients whose serum creatinine concentration is >150 ?mol/L. However, this corresponds to an eGFR of 67 mL/ minute/1.73 m² in a young black man, but to an eGFR of 33 mL/minute/ 1.73 m² in an elderly white female.

This illustrates the dangers of using serum creatinine concentration as the basis for drug dosage adjustment. It would be preferable to reach a decision that balances risk and benefit for each patient, based on the best available estimate of that patient’s actual GFR.

Nephrotoxic drugs are more likely to cause a clinically important reduction in GFR if GFR is already significantly reduced.

Avoiding Haemodynamic Insults

The ‘classical’ model of progressive, proteinuric CKD (for which diabetic nephropathy is the exemplar) does not fully explain the epidemiology of CKD; in particular, it is inconsistent with the frequency of stable stage 3 and 4 CKD.

The existence of so many patients with stable but significant kidney damage suggests an alternative model, in which kidney function deteriorates as a result of a series of step-wise ‘hits’ caused by episodes of nephrotoxicity, renal underperfusion, or renal atheromatous embolism. Clinical management of patients with CKD should, therefore, include precautions to minimize the risk of such insults. Patients taking ACEIs or ARBs should be advised to stop these temporarily during episodes of diarrhoea and/or vomiting, and during severe sepsis. Even more care should be taken in patients taking combinations of ARBs and ACEIs, as these agents significantly reduce the autoregulation of renal blood flow during episodes of renal underperfusion.

Treatment of Acidosis

There is increasing evidence from a number of small trials that alkali therapy in the form of sodium bicarbonate or sodium citrate slows the rate of progression of renal failure, delays the development of established renal failure and improves nutritional status.^38–40 Although larger, randomized, controlled trials are required to support this, alkali therapy appears to be of benefit at all stages of CKD regardless of the presence or absence of metabolic acidosis.⁴⁰ Supplementation with sodium bicarbonate (typically 1.5–3.0 g/day) is reasonable.

An approach to common ‘uraemic’ symptoms is outlined in Table 1.

Follow-up and Preparation for Renal Replacement Therapy

Patients with CKD should be offered life-long follow-up to ensure optimal management (as set out above) and to monitor changes in kidney function.

Suggested frequency of follow-up is given in Table 2.

The great majority of patients with CKD stage 3 will not progress to established renal failure and, even among CKD stage 4 patients, death from cardiovascular disease is more frequent than progression to established renal failure. However, there is evidence that patients who require renal replacement therapy have increased morbidity and reduced survival, and are more expensive to manage if they present to a nephrologist late in their illness.^41,42 It is essential that those who are at risk of progressive decline in renal function are identified early and referred to secondary care. NICE recommends that the following patients should be referred to a consultant nephrologist⁴:

• stage 4 or 5 CKD;
• heavy proteinuria (urine albumin to creatinine ratio ? 70 mg/mmol; urine protein to creatinine ratio ? 100 mg/mmol) unless known to result from diabetes and already appropriately treated;
• proteinuria (urine albumin to creatinine ratio ? 30 mg/mmol; urine protein to creatinine ratio ? 50 mg/ mmol) if accompanied by haematuria;
• rapidly declining eGFR (> 5 mL/ minute/1.73 m² in 1 year, or > 10 mL/ minute/1.73 m² within 5 years);
• hypertension that remains poorly controlled despite the use of at least four antihypertensive drugs at therapeutic dosage;
• people with or suspected of having rare or genetic causes of CKD;
• suspected renal artery stenosis.

Declaration of Interests

None.

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About the Author

Charlie Tomson is a Consultant Nephrologist at North Bristol NHS Trust, UK. As Chair of the Joint Specialty Committee on Renal Medicine of the Royal College of Physicians of London and the Renal Association, he led the development of UK guidelines for the Identification, Management, and Referral of Adults with Chronic Kidney Disease. His research interests include the causes of premature cardiovascular disease in patients with kidney disease, and quality improvement in healthcare. He is currently President of the Renal Association. Pippa Bailey is an Academic Clinical Fellow in Nephrology at Southmead Hospital, Bristol, UK.

Source: http://www.mims.com/Malaysia/pub/topic/Medical%20Progress/2011-12/Management%20of%20Chronic%20Kidney%20Disease