Correspondence *VA North Texas Health Care Systems, Dallas Veterans Affairs Medical Center, 4500 South Lancaster Road, Dallas, TX 75216, USA

Email devasmita.dev@med.va.gov

Introduction

Renal disease increases the complexity of preventive health care. The term 'preventive care' implies taking measures to avoid morbidity and mortality. In patients with kidney failure, preventive strategies frequently focus on the renal-disease-related issues of anemia, mineral metabolism, hypertension, and vascular access for dialysis. Addressing more-general health issues, such as vaccination, cancer screening, control of diabetes mellitus, and lipid management can be postponed in order to prioritize acute issues such as infection, bleeding, malnutrition, volume overload, vascular thrombosis and unstable blood pressure, all of which are common in patients with renal failure. This prioritization of care could be one reason why fewer Centers for Medicare & Medicaid Services health claims for pneumococcal and influenza vaccines have been made for patients with chronic kidney disease (CKD) than for those without the condition, despite adequate access to health care resources.¹

The importance of ongoing health maintenance in the CKD population cannot be overemphasized. Disadvantaged by abnormalities of immune function, patients with kidney disease are more susceptible to infections and malignancies. The traditional cardiovascular risk factors of diabetes and dyslipidemia plague most patients with renal disease. Of a cohort of Medicare patients with CKD and diabetes who progressed to end-stage renal disease (ESRD), only 50% had their lipid or glycated hemoglobin (HbA_1c) levels tested in the year before, or after, initiation of dialysis.² Preventive health measures are underutilized in patients with renal failure.³ Vigilance with regard to screening and treatment can prevent acute issues from arising. Preventive goals and treatment strategies specific to patients with CKD or ESRD can differ from those for the general population. As such, useful general preventive health measures that are specific to the CKD and ESRD population and that complement the complexities of managing renal dysfunction are discussed herein.

Infection risk

Renal failure is accompanied by immune insufficiency; several immune functions, including phagocytosis, B-cell response and T-cell response, are abnormal. The degree of renal impairment at which immune dysfunction develops is not known; nonetheless, outcomes after hospitalization for infection are 3–4 times worse in people with CKD than in those without the condition.⁴ Polymorphonuclear chemotaxis and the phagocytic function of monocytes and/or macrophages are abnormal in people with kidney failure. There is, therefore, an increased incidence of bacterial infections of the lung, intestines, peritoneum, urinary tract and skin among uremic individuals.^{5, 6} Mucocutaneous barriers are frequently disrupted in renal patients secondary to skin excoriations that result from pruritus, xerosis and atrophy of sweat glands. In addition, gastrointestinal ulceration and diminished mucociliary and alveolar clearance of macrophages are common.⁷

Infections caused by common microorganisms such as Staphylococcus sp. and Escherichia coli can be severe.⁸ Individuals with hemodialysis catheters are particularly susceptible to infection with Staphylococcus sp. as violation of the patient's mucosal barriers frequently leads to bacteremia.⁹ Sepsis in patients with ESRD is associated with an annual percentage mortality that is 100–300-fold higher than that in the general population.¹⁰ Infective endocarditis can be devastating and fatal in the former group.⁹ The urinary tract of anuric patients is an important source of infection. Pyocystis can present as urinary frequency with or without dysuria, and can lead to sepsis and death.^{11, 12, 13} The mortality associated with pulmonary infection in patients with ESRD is 14–16-fold higher than in the general population. Aerobic Gram-negative organisms such as Klebsiella are not uncommon in patients with CKD who are hospitalized for pulmonary infections.¹⁴

Renal failure also heightens susceptibility to tuberculous, fungal and viral infections. The capacity to respond to intracellular infections such as those caused by Mycobacterium tuberculosis and viruses is impaired by abnormal T-cell-mediated immunity in patients with renal failure. Perturbed T-cell activation and proliferation, lymphopenia with suboptimal response to mitogens, depressed antigen-specific T-cell-mediated antibody responses and increased suppressor cell activity are noted in patients with renal failure.¹⁵ As a result, vaccination in this population is associated with decreased IgG production, despite total antibody levels being within normal ranges. Renal disease is, therefore, associated with lower rates of seroconversion and a greater need for revaccination.^{7, 15, 16, 17} For these reasons, optimum screening and vaccination schedules for patients with kidney dysfunction need to be clarified.

Screening and prophylaxis for bacterial infections

Given the predisposition of people with CKD or ESRD to developing bacterial infections, which are associated with high morbidity and mortality in this population, preventive measures are necessary to minimize both exposure and subsequent infection. Measures to prevent skin breakdown, including careful evaluation and treatment of pruritus and xerosis, need to be incorporated into follow-up visits with nursing or medical staff. Treatment of skin breakdown or wounds needs to be as prompt as it is for people with diabetes. As the incidence of bacteremia in ESRD patients with hemodialysis catheters is high, every effort should be made to establish mature arteriovenous fistulas before initiation of renal replacement therapy¹⁸ (Box 1).

Intranasal swabs and culture of the collected samples can be used to screen for Staphylococcus sp. and, thereby, to determine the carrier status of dialysis-dependent patients. Eradication of intranasal staphylococcal colonization by the use of antibacterial ointments, such as mupirocin applied twice daily for 5 days and once per week thereafter, can help to reduce the number of staphylococcal infections in dialysis patients.¹⁹ Applying antistaphylococcal or antibacterial ointments, such as mupirocin or gentamicin, at the exit sites of dialysis catheters decreases rates of infection and bacteremia.^{20, 21} Use of these agents can be considered for patients with either peritoneal or hemodialysis catheters,^{20, 21} and might be particularly useful for nasal carriers or those who have had repeated infections. It should be noted that emergence of resistant strains is a problem associated with long-term use of such topical agents.^{22, 23} Routine use of mupirocin in non-carrier catheter-dependent dialysis patients or in those without evidence of recurrent infection might not, therefore, be prudent. A recent retrospective study indicated that rates of catheter-associated staphylococcal bacteremia were reduced in patients taking 325 mg aspirin per day.²⁴ Salicylic acid inhibits S. aureus virulence genes, which affects endovascular pathogenesis.²⁴ As such, daily aspirin therapy could help to prevent staphylococcal infection in patients with CKD or ESRD. Prospective studies are needed to confirm this hypothesis before aspirin use can be routinely recommended for the prevention of catheter-related infections.

Poor oral health can cause chronic inflammation and infection in people with CKD. Untreated uremia is associated with severe stomatitis, and most patients on dialysis suffer from severe gingivitis and periodontitis (a chronic bacterial infection of the oral cavity).²⁵ Compared with patients with gingivitis who were otherwise healthy, odds ratios of 2.00 and 2.14 were found for the association of initial and severe periodontal disease, respectively, with CKD (glomerular filtration rate <60 ml/min per 1.73 m²) in the Atherosclerosis Risk in Communities study.²⁶ Given the relationship between chronic inflammation and cardiovascular disease, evaluation of oral health can be important for health maintenance in patients with CKD or ESRD and should be actively encouraged.

Data on the utility of antibiotic prophylaxis for the prevention of endocarditis specifically in patients with renal disease are not available. Extrapolating from American Heart Association guidelines on infective endocarditis prophylaxis for the general population,²⁷ antibiotic prophylaxis before invasive dental or periodontal procedures should be considered for patients with CKD or ESRD who have prosthetic valves or congenital cardiac defects and those with a history of endocarditis or cardiac transplantation. Infective endocarditis can complicate valvular and perivalvular calcification of the mitral annulus and aortic valve, which is common in people with ESRD; patients known to have these valvular abnormalities should, therefore, receive endocarditis prophylaxis.²⁸ Patients with hemodialysis catheters are at high risk of developing endocarditis; administration of single-dose oral amoxicillin (2 g) or single-dose oral clindamycin (600 mg) before dental procedures should be considered for those who are allergic to penicillin.²⁹ As high flow status resulting from arteriovenous shunting in hemodialysis patients can increase the risk of endocarditis, some practitioners advocate routine antibiotic prophylaxis before dental treatment for individuals with arteriovenous accesses³⁰ (Box 1). Current American Heart Association guidelines do not recommend prophylaxis for infective endocarditis before gastrointestinal or genitourinary-tract procedures²⁷ because the risk of bacteremia is low unless the patient has severe liver disease or carcinomatosis.^{31, 32} It should be noted, however, that recommendations specific to immunosuppressed individuals, such as those with CKD or ESRD, have not been made.

In light of the increased risk of pulmonary infection that is associated with CKD and ESRD, influenza and pneumococcal vaccinations can be preventive and should be administered to preclude morbid complications. Response and dosing are discussed in the 'Immunizations and monitoring for viral infections' section below, and are presented in Box 2.

Screening and prophylaxis for tuberculosis

Insidious presentation of tuberculosis at extrapulmonary sites is common in patients with renal failure. Symptoms are frequently difficult to distinguish from the general complaints of malaise, fatigue, poor appetite and weight loss that are often associated with renal failure. Cutaneous reactivity to tuberculin skin testing is as high as 44% in the renal failure population,^{33, 34} probably as a result of diminished cell-mediated immunity and host response to intracellular pathogens. The cumulative incidence of tuberculosis in the US ESRD population is low (1.2–1.6%) relative to the reported incidence in developing nations (3.7–13.3%).^{33, 35, 36} Latent tuberculosis is 52.5 times more likely to be reactivated in patients with renal failure compared with the general population,^{33, 37} so screening is necessary. For patients considered to be at high risk of tuberculosis who do not initially react to the Mantoux test (exposure to 5 U of a purified protein derived from a sterile killed concentrate of human tubercle bacilli), repeat skin testing with a 250 U dose of purified protein derivative should be attempted³⁸ (Box 3). Repeat (two-step) skin testing can enhance sensitivity, but is associated with lower specificity.^{37, 39} It has also been noted that annual skin testing plus a routine chest radiograph improves detection of tuberculous infection.⁴⁰ When compared with skin testing alone, newer-generation interferon assays seem to be a promising means of improving detection of latent tuberculosis—particularly when combined with medical assessment—and should be considered as a screening tool for this high-risk group.³⁷ Careful screening and treatment for tuberculosis before renal transplantation can reduce post-transplantation mortality.⁴¹ Data indicate that routine tuberculosis screening should perhaps begin as early as stage 2–3 CKD so that treatment can be initiated and completed in at-risk individuals before progression to ESRD and transplantation.

Patients with a screening Mantoux skin test positive for tuberculosis with at least 10 mm of induration, and those with a chest radiograph indicating previous infection and at least 5 mm of induration following skin testing, should be treated for latent tuberculosis infection.^{33, 42, 43} Modified treatment regimens have been recommended for people with renal failure. The generally recommended prophylaxis for patients with stage 4 CKD (glomerular filtration rate <30 ml/min), stage 5 CKD and for those on dialysis is 300 mg isoniazid daily or 900 mg thrice weekly (15 mg/kg) for at least 6 months and up to 9 months, with concurrent pyridoxine (at least 25 mg daily) to combat adverse neurological effects. Supervised thrice-weekly dosing for patients receiving in-center hemodialysis can minimize noncompliance. For patients who cannot tolerate isoniazid, rifampicin (600 mg daily or thrice weekly for at least 6 months) has been recommended.³⁸ Combined regimens of rifampicin and pyrazinamide for 2 months have also been suggested; rifampicin and pyrazinamide should be administered thrice weekly (600 mg and 25–35 mg/kg, respectively) to patients with advanced kidney disease⁴³ (Box 3).

Immunizations and monitoring for viral infections

Monitoring and management of lipid levels

The risk of cardiovascular disease is high in patients with CKD or ESRD;⁸³ a distinctive 'atherogenic lipoprotein phenotype' of high LDL, low HDL and elevated serum triglyceride levels is associated with both conditions.⁸⁴ Observational data indicate that progression of CKD can be slowed by controlling lipid levels.^{85, 86, 87} In 2003, the National Cholesterol Education Program Adult Treatment Panel (ATP III) guidelines for treatment of dyslipidemia in the general population were adopted by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) for application to patients with stage 1–4 CKD. Subgroup analyses of several large studies that investigated the effect of statin therapy on cardiovascular outcomes have corroborated the cardiovascular benefits of lipid lowering for people with stage 2 or 3 CKD.⁸⁴ Specific outcome data for stage 4 CKD are not available. Nevertheless, as patients with CKD are known to be at high risk of developing cardiovascular disease, the target LDL level should be less than 2.6 mmol/l (100 mg/dl) for people with stage 1–4 CKD. The K/DOQI workgroup suggested an LDL target of less than 1.8 mmol/l (70 mg/dl) for patients who also have diabetes (Box 4). Aggressive lipid lowering (to an LDL level <2.6 mmol/l [100 mg/dl]) using statins in patients with ESRD and diabetes who were on hemodialysis had little effect on cardiovascular-related mortality in the randomized Deutsche Diabetes Dialyse Studie (4D) study.⁸⁸ By contrast, large observational studies in both diabetic and non-diabetic patients have found cardiac mortality to be decreased following statin therapy.^{89, 90} On the basis of current evidence, then, monitoring of fasting lipid levels and maintenance of LDL cholesterol levels below 2.6 mmol/l (100 mg/dl) should continue to be standard practice for all patients with CKD.

Monitoring of the fasting lipid levels of patients on dialysis can be difficult; elevated nonfasting levels (LDL >4.9 mmol/l [190 mg/dl]; triglycerides >5.7 mmol/l [500 mg/dl]) should prompt determination of fasting levels. If fasting levels remain very high and the patient is known to have cardiovascular risk factors, treatment to optimize levels should be considered as per the ATP III guidelines. Lifestyle and dietary modifications should always be initiated, and tailored medical therapy commenced thereafter using lipid-lowering drugs such as statins, resins, niacin, ezetimibe, and fibric acid derivatives, as necessary. Statins are relatively well tolerated in the renal failure population. Combination therapy with statins plus fibric acid derivatives or ezetimibe might increase the risk of myositis and rhabdomyolysis; careful follow-up is, therefore, important.⁹¹ Patients with renal disease who use the calcineurin inhibitors ciclosporin and tacrolimus concurrently with statins must be monitored carefully because the serum concentration of statins can increase and raise the risk of myositis and rhabdomyolysis. Concomitant use of mTOR inhibitors and statins also requires vigilant monitoring because increased rapamycin levels have been reported.⁹² Measuring of lipid levels at least once per year is recommended for the renal failure population. Patients who require medical intervention and have not reached targets can benefit from follow-up 2–3 months after their therapeutic regimen is altered.

Monitoring and management of blood glucose levels

Diabetes is a primary cause of kidney failure worldwide. Progression of CKD and cardiovascular complications is associated with poor glycemic control.^{2, 83, 85} Good glycemic control can prolong the lifespan of patients with ESRD.⁹³ Every effort should be made, therefore, to maintain the HbA_1c level of all patients with CKD or ESRD to less than 7.0% (Box 4), as recommended by the American Diabetes Association and K/DOQI. For insulin-dependent patients, dose adjustment is frequently required as renal failure progresses because the rate of insulin clearance drops. The second-generation sulfonylureas glipizide and gliclazide, oral thiazolidinediones, as well as meglitinide, repaglinide and the incretin mimetic exenatide, require no dose adjustment. By contrast, doses of nateglinide, the dipeptidyl peptidase 4 inhibitor sitagliptin and the amylin analog pramlintide acetate must be adjusted in patients with advanced CKD. Use of metformin and the first-generation sulfonylurea agents chlorpropamide, tolbutamide and tolazamide, as well as the -glucosidase inhibitors acarbose and miglitol, should be avoided in patients with advanced CKD or ESRD, in light of their association with metabolic acidosis and prolonged hypoglycemia.^{94, 95} Treatment regulation in patients with fluctuating blood glucose levels and those receiving insulin can be assisted by home blood glucose monitoring. Those who are stable while being treated can benefit from having their HbA_1c level checked every 6 months to ensure ongoing control. As renal disease progresses, gluconeogenesis is further impaired and dietary intake is compromised; careful dose adjustment of antiglycemic agents and more-frequent monitoring to avoid hypoglycemic events could be required. Patients should be followed closely and have their HbA_1c checked within 3 months of any treatment change.⁹⁵

Cancer screening

In the CKD and ESRD populations, tumors develop in the genitourinary tract 4–5 times more frequently than at other sites such as lung, colon and/or rectum, or breast.^{96, 97} It has been suggested that impaired immune function, ineffective DNA repair, diminished antioxidant defenses with accumulation of toxins such as analgesics, and acquired cystic kidney disease (ACKD) contribute to the increased prevalence of malignancies among people with renal disease.^{98, 99} Regardless, the need for routine screening is still debated, particularly for the ESRD population, given that survival rates are poor for maintenance dialysis patients (more specifically, for those with marked cardiac comorbidity).^{100, 101} Although overall survival might be poor among those with numerous concurrent chronic illnesses, routine screening for at least renal cell, bladder and prostate cancer should be considered for patients with few comorbidities, those preparing for—but not yet receiving—dialysis, and those awaiting transplantation (Box 5).

The prevalence of renal tumors and cancers, based on pretransplantation evaluation of ESRD patients who have undergone nephrectomy, has been estimated at between 4% and 14%.¹⁰² ACKD has been observed in 7–22% of patients in CKD cohorts. The incidence increases with time on dialysis, reaching 90% among those with ESRD;^{103, 104} after 3 years on dialysis, the risk of developing ACKD is 80%.¹⁰⁵ Approximately 20% of patients with ESRD and ACKD progress to renal carcinoma, with 1% developing metastatic disease.¹⁰⁵ As such, some practitioners have recommended screening long-term maintenance dialysis patients for ACKD every 1–3 years.^{105, 106} The duration of renal disease and presence of acquired cysts are more likely than dialysis to affect the probability of developing renal cell carcinoma.¹⁰⁷ Prevention of renal cell transformation might, therefore, be facilitated by ultrasonographic screening of CKD patients who have ACKD, whether receiving dialysis or not, at least once per year.

The incidence of prostate cancer is increased in patients with renal disease compared with the general population.⁹⁶ Guidelines specific to those with renal disease are not available, so monitoring of patients older than 50 years whose life expectancy is at least 10 years^{108, 109, 110, 111} and of younger patients at high risk¹¹² should be as for the general population; that is, annual digital rectal examination and measurement of serum prostate specific antigen (PSA) level. Total PSA levels are not affected by renal failure or hemodialysis.^{113, 114} In addition, higher PSA levels are associated with a higher incidence of prostate cancer in this population compared with controls.¹¹⁵

Given that patients with renal disease are often anemic, and that iron deficiency can result from initiation of erythropoietin therapy, careful evaluation before erythropoietin administration should exclude gastrointestinal causes of iron loss including colorectal cancer, particularly among patients with CKD who are not dialysis dependent. The incidence of nonmalignant gastrointestinal abnormalities such as duodenopathy, gastritis, angiodysplasia, and diverticular disease is increased in the dialysis population,^{116, 117} so positive stool guaiac tests occur more frequently. The positive predictive value of fecal occult blood tests increases as renal function worsens,¹¹⁸ probably because screening is more frequent. Routine flexible sigmoidoscopy of all patients with renal failure does not seem to confer a survival advantage.¹¹⁹ As such, current general guidelines for colorectal cancer screening should be followed for patients with renal disease.¹¹²

Breast calcifications are more common in people with renal disease than in those without, contributing to an increased likelihood of investigations and an improved chance of detecting malignancy in the former.¹²⁰ In Canada, routine screening of women with ESRD for both breast and cervical cancer did not result in improved life expectancy.¹²¹ Screening mammography and routine pap smears should, therefore, be offered preferentially to those whose life expectancy is at least 5 years and to those at high risk.¹²²

Despite the increased prevalence of malignancy among patients with ESRD,⁷⁰ routine cancer screening is cost inefficient relative to survival time gained for this population as a whole.^{119, 123} Cost analysis of cancer screening specifically for patients with CKD or ESRD whose life expectancy when receiving dialysis exceeds 5 years has not been performed. Although cardiovascular disease and infection are the leading causes of poor survival among ESRD populations, basic cancer screening for patients with CKD or ESRD who are expected to live for at least 5 years should not be overlooked.¹²⁴ Individualized screening for any patient at high risk of developing a specific malignancy should be standard practice.

Conclusions

Prevention of renal-related comorbidities in patients with CKD or ESRD can be time-intensive and labor-intensive; nevertheless, general health maintenance should be incorporated into management strategies for such individuals. Decreasing the infection risk with careful screening, prophylaxis as applicable, and vaccinations should improve patient morbidity and reduce associated costs. Guidelines extrapolated from those for populations with comorbidities characteristic of renal disease patients provide basic standards for bacterial prophylaxis, glycemic control, lipid management and cancer screening. Given that people with CKD or ESRD usually visit health care providers more often than other patients, meeting current standards of preventive care is achievable. We encourage this endeavor as a means of preventing acute morbidity and mortality.

Acknowledgments

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Progression of renal disease