Weighing in on Obesity Treatments and Kidney Disease

Brian Rifkin, MD; Hattiesburg Clinic Nephrology

Vidhya Gunasekaran, MD; PGY3 Internal Medicine, Merit Health Wesley

Mohammed Attaullah Khan, MD; PGY2 Internal Medicine, Merit Health Wesley

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Introduction

The surge in worldwide obesity rates are a result of the complex interplay of genetic, environmental, behavioral, and societal factors. Obesity is known to exacerbate various chronic conditions including diabetes, cardiovascular disease, sleep apnea, osteoarthritis and hypertension. In nephrology, understanding the intricate relationship between obesity and kidney health is a priority for disease management and patient well-being. Furthermore, obesity treatment and kidney disease should be a regular consideration in daily medical practice.

The impact of obesity is profound in patients with kidney disease. Studies indicate a strong association between obesity and the development and progression of chronic kidney disease (CKD). A review by Hsu et al demonstrated a higher risk of incident CKD in individuals with a higher body mass index (BMI). Additionally, a meta-analysis by Wang et al highlighted that one out of three cases of CKD in the United states may be attributed to obesity, reinforcing the necessity to address obesity in CKD management.

The challenges of obesity extend to the kidney transplantation arena, affecting both pre and post-transplant care. An elevated BMI may disqualify a patient for kidney transplantation, and maximum acceptable BMIs are determined by each transplant center. KDIGO suggests that candidates not be excluded from transplantation because of obesity (as defined by body mass index or waist-to-hip ratio; 2B recommendation), however, specific numbers are not discussed. A study by Shi et al found that obese kidney transplant recipients had an increased risk of delayed graft function as well as a higher incidence of surgical complications. Furthermore, obesity is associated with an increased risk of new-onset diabetes after transplantation (NODAT), adding further complexity to patient management. Addressing obesity in transplant candidates is crucial for optimizing opportunities, outcomes and long-term graft survival.

The rise in obesity rates has led to a pressing need for effective interventions, especially for patients with CKD and end stage renal disease (ESKD). Obese individuals are at a significantly higher risk of developing chronic conditions that can ultimately lead to CKD and ESKD. Obesity is also a major risk factor for mortality from cardiovascular disease, the number one cause of death in CKD, ESKD and transplant populations. Future research and targeted interventions are needed to effectively address the critical intersection of obesity and nephrology. A comprehensive approach that encompasses patient education, lifestyle modifications, medications, and surgery may be appropriate on a case-by-case basis.

Epidemiology

In 2010, the impact of obesity on global health was already substantial, resulting in an associated 3.4 million deaths, and accounting for 3.9% of years of life lost and 3.8% of disability-adjusted life years (DALYs) worldwide. This trend has only worsened over time, and currently about 13% of adults worldwide are considered obese, with another 39% of adults categorized as overweight. In fact, The World Obesity Federation predicts that 51% of the world’s population, or approximately 4 billion people, will be either obese or overweight within the next 10-15 years. This underscores the urgent need for focused attention on obesity, a critical risk factor for various chronic diseases affecting kidney health.

As stated previously, studies have shown an association between obesity and an increased risk of chronic kidney disease (CKD). First, metabolic disorders that may result from obesity including hyperglycemia, hypertension, and dyslipidemia, or the cluster of these disorders defined as the metabolic syndrome, are known contributors to the development and progression of kidney disease. Adipose tissue is an endocrine organ releasing cytokines and inflammatory mediators. Maladaptive persistent chronic inflammation can lead to oxidative stress and cellular damage. Furthermore, there is an intricate relationship between obesity and specific kidney pathologies like obesity-related glomerulopathy (ORG) and adaptive focal segmental glomerulosclerosis (FSGS) due to glomerular hyperfiltration. ORG is associated with glomerulomegaly, decreased podocyte density and mesangial sclerosis. Factors that may predispose obese individuals to ORG renal injury include the severity and number of obesity-associated conditions, and the mismatch of body size to nephron mass due to congenital or acquired reduction of glomeruli.

From Tsboi N et al, The Renal Pathology of Obesity. KI Reports, 2017

Weight Loss Precautions

Weight loss in patients with CKD is not without associated health risks. In a study by Harhay et al, 2831 participants (median BMI 35.6), were followed for an average of 7 years. Of those patients, 82% were already trying to control or lose weight prior to enrollment. The highest mortality rate in the study cohort was characterized by early, steep BMI loss, early decline in serum albumin levels, and late systolic blood pressure increases. The authors concluded that among adults with CKD and obesity, BMI loss with concomitant serum albumin or fat-free mass loss was associated with a higher risk of death. Clearly, not all weight loss in patients with kidney disease is beneficial. In fact, there is an “obesity paradox” in patients with kidney disease, where larger muscle mass and higher body fat result in longevity in comparison to patients with a thinner body habitus and greater weight loss. Weight loss, while maintaining muscle mass, is particularly important in the CKD population. Visual abstract by Susan Thanabalsingam, MD.

Lifestyle modifications

Although modification of dietary and exercise habits may work for a variety of patients with obesity, patients with kidney disease deserve special consideration. High levels of physical activity, frequent monitoring of body weight, and consumption of a reduced calorie diet have been recommended for long-term weight loss. Appetite and body weight are regulated by a highly integrated gut-to-brain neuroendocrine system that tracks both short- and long-term changes in energy intake and expenditure. In patients with kidney disease there may exist alterion of this neuroendocrine pathway by means of dietary restrictions, medications, and gut microflora dysbiosis. Complex interactions of behavioral, cultural, economic, and environmental factors that influence an individual’s lifestyle, may need to be addressed to achieve weight loss goals. Interventions may be prescribed by health professionals, including registered dietitians, psychologists, or health counselors, as well as trained lay persons. The amount of time required for recurring counseling can be particularly challenging to patients with chronic diseases that require recurring doctor visits. Without further intervention, lifestyle modification alone typically results in regaining one-third of lost weight in the year following treatment, with continued weight gain thereafter. Moreover, participants have to work just as hard to maintain their weight loss as they did to achieve it; most report that maintaining weight loss is far less rewarding than losing weight. There are many physical and psychological barriers that may prevent patients with kidney disease from achieving and maintaining their weight loss.

Diet

For most people in developed nations, food is cheap, plentiful, highly processed, and palatable, with unending combinations of sugar, fat, and salt that are served up in ever-increasing portion sizes. Calorie restriction is essential to clinically meaningful weight loss. The Obesity Guidelines recommend consumption of a diet designed to achieve a deficit of 500–750 kcal/ day, with a resulting mean loss of 0.5–0.75 kg (1.0–1.5 lb) per week. The 2023 U.S. Dietary Guidelines recommend that approximately 15– 20% of daily calories be derived from protein, 20–35% from fat (with no more than 10% from saturated fat) and the remainder from carbohydrates, particularly fresh fruits, vegetables, and grains. Reducing portion sizes, as well as excess sugar and fat, are simple ways to achieve calorie deficits. Use of “conscious eating”, by means of a food diary or diet tracking app, can also help in activity reducing calorie intake. These general dietary restriction guidelines are appropriate for patients with CKD, without anorexia from uremia, as long as certain high potassium or high phosphorus legumes, fruits, and vegetables are avoided. Although the quality of evidence is limited, some physicians still recommend low protein diets for patients with advanced CKD.

Physical Activity

Lifestyle modification programs typically recommend 150–180 minutes per week of moderately vigorous aerobic activity, such as brisk walking or cycling. Regular aerobic activity is associated with numerous benefits including improvements in physical and mental health. Persons who report lack of time to exercise are encouraged to engage in multiple brief bouts (10 minutes) of activity throughout the day and to increase their lifestyle activity, such as by taking stairs rather than elevators. In patients requiring dialysis, exercise (by means of stationary bike pedals) has been shown to be beneficial for managing intradialytic hypotension and improving physical fitness. In fact, even a simple, personalized, home-based, low-intensity exercise program managed by dialysis staff has shown improvements in physical performance and quality of life in patients on dialysis. Physical activity alone produces minimal short-term weight loss even if not combined with calorie restriction. Thus, lifestyle modification participants are encouraged to exercise primarily for cardiovascular health benefits. However, high levels of activity are critical for maintaining weight loss. High intensity activities may not be possible in patients with CKD and ESKD, who often suffer from multiple comorbidities that may limit exertion.

Moderate weight loss through lifestyle modification can bring about clinically meaningful improvements in cardiovascular disease (CVD) risk factors, including lowering blood pressure and triglycerides. Improvements are generally dose dependent, with greater weight loss (>10%) producing greater benefits. At present, however, there are no randomized control trials that show that intentional weight loss reduces CVD mortality, despite improving individual CVD risk factors. By contrast, numerous medications for hypertension, hyperlipidemia, and type 2 diabetes have been shown to significantly reduce CVD mortality. Thus, with moderate to severe levels of obesity, lifestyle modification is recommended in combination with well established medication therapies for CKD and CVD.

Medications and Weight Loss

Medications should be seen as part of a broader strategy that includes a balanced diet and regular physical activity. Importantly, close monitoring by a healthcare professional is essential, to ensure the safety and efficacy of medication treatment in patients with CKD, ESKD or kidney transplantation. A meticulous approach is necessary, given the altered pharmacokinetics, potential interactions, and safety profiles associated with impaired renal function. Medications like orlistat, liraglutide, and bupropion/naltrexone (combination that targets the central nervous system to suppress appetite), have been investigated and shown to be potentially beneficial in non-dialysis CKD and post-transplant settings. However, it's crucial to underscore that a personalized approach is essential, considering individual comorbidities, concurrent medications, and CKD stage. This tailored approach ensures the selection of appropriate medication and dosage, striving to strike a delicate balance between effective weight management and preserving kidney health.

Adapted from: Friedman AN et al. Management of Obesity in Adults with CKD. J Am Soc Nephrol 2021.

Biguanides

Metformin remains the first-line treatment for type 2 diabetes (T2DM) in patients with CKD, but should be used with caution in patients with more advanced disease. Currently, metformin is contraindicated in patients with an eGFR < 30 cc/min due to the risk of lactic acidosis.Patients treated with metformin lost on average 10-14 pounds (5.6% to 6.5% of body weight) over 6 months compared to controls who gained 6-8 pounds during the same time period. Emerging evidence suggests that metformin-associated weight loss is due to modulation of hypothalamic appetite regulatory centers, and alteration in the gut microbiome.

Adapted from Use of Metformin in Mild to Moderate Renal Insufficiency

Incretins

Medications including the Glucagon-like peptide-1 receptor agonists (GLP-1) and Gastric Inhibitory Peptide (GIP) are part of a class of drugs known as incretins.

Different medications in this class differ in their recommendations for use in CKD, depending on their route of elimination. Albiglutide, dulaglutide, and semaglutide, all GLP-1 receptor agonists, do not require a dose adjustment with impaired kidney function. Liraglutide is not eliminated through the kidneys but carries a cautionary recommendation for use with other diabetes medication due to hypoglycemia, increased risk of pancreatitis and limited data in CKD/ESKD.

When considering weight loss pharmacotherapy in patients with CKD, incretin-based medications can be considered first-line therapy. For patients with obesity, T2D, and CKD, GLP-1 receptor agonists are recommended by the American Diabetes Association (ADA) as preferred if the HbA1c is above target or if sodium-glucose cotransporter-2 inhibitors (SGLT2i) are contraindicated. For patients who wish to achieve both weight loss and glycemic goals, the ADA lists multiple incretin-based medications as very high (semaglutide and tirzepatide) or high efficacy (dulaglutide and liraglutide).

A meta-analysis of 8 trials found that GLP-1 receptor agonists reduced major adverse cardiovascular events (MACE) by 14% as well as a composite kidney outcome (including development of albuminuria ≥ 300 mg/g) by 21%. The beneficial effects on MACE were similar among patients with and without CKD. Additionally, clinical trials demonstrated that semaglutide 2.4 mg per week resulted in a 12.7 kg weight loss at week 68 compared to placebo.

Tirzepatide, a dual GLP-1 and GIP receptor agonist, has been shown to have synergistic effects with semaglutide in reducing HbA1c and weight in patients with T2D. Tirzepatide also resulted in favorable effects on kidney outcomes, including slowing eGFR decline, reducing albuminuria, and reducing the risk of reaching the composite kidney endpoint.

Incretins do not cause hypoglycemia on their own, but they may potentiate hypoglycemia when administered with other diabetic medicines (in particular sulfonylureas or insulin). In patients with well-controlled blood sugars, it is recommended that the dose of sulfonylurea should be reduced or the sulfonylurea stopped when incretin therapy is initiated. Similarly, a 15-20% reduction in the basal insulin dose is generally recommended to avoid hypoglycemia.

Sodium-Glucose Cotransporter-2 Inhibitors

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are another class of medications that are effective for weight loss and cardiorenal protection in patients with T2D and CKD. Combining SGLT2i in with incretin therapies resulted in additive weight loss effects. For example, dulaglutide 1.5 mg weekly in addition to an SGLT2i resulted in approximately 1 kg of additional weight loss, while the addition of weekly semaglutide at a relatively low dose of 1.0 mg resulted in 2.8 kg of weight loss in addition to that seen with SGLT2i alone. Clinical trials are underway to test the hypothesis that the combination of SGLT2i with incretin-based therapies may be even more effective than either group alone in preventing cardiorenal morbidity and mortality in patients at high risk. In addition, there are currently ongoing clinical studies to evaluate the safety and efficacy of SGLT2i in patients with eGFR < 20 cc/min and patients with ESKD.

Medications are an integral part of the armamentarium used to facilitate weight loss. As newer medications are developed it is the hope of nephrologists that patients with kidney disease are included in phase II and III trials. Although there is not a solitary magic bullet when it comes to weight loss, a comprehensive plan with cautious use of medications can be beneficial to many patients.

Bariatric Surgery

For patients with severe obesity who have not responded to lifestyle modifications or medical therapy, bariatric surgery remains a viable option. While it is an invasive intervention, it can provide significant benefits to patients with extreme obesity when other approaches have failed. It is important to note that bariatric surgery may increase the complexity of managing nutritional and electrolyte disorders in patients with CKD and ESKD. Careful patient selection and thorough evaluation are essential before considering surgical weight loss. Bariatric surgery has been used extensively in patients with CKD in an attempt to get patients to a goal BMI prior to transplantation. In addition, there is observational cohort data that suggests bariatric surgery resulted in significant improvements for up to 3 years in eGFRs for patients with stage 3 and 4 CKD. Unfortunately, more advanced kidney disease was also associated with increased complications after bariatric surgery, including infections. However, even for the population with advanced CKD, the absolute rates of postoperative complications were low. The mounting evidence for bariatric surgery as a renoprotective intervention in people with and without established kidney disease suggests that bariatric surgery should be considered an effective option for certain patients with CKD. Bariatric surgery is associated with a reduction in mortality in pre-dialysis patients, regardless of the patient developing ESKD. These findings are significant because patients with CKD are at relatively high risk for death with few interventions available that improve overall survival.

Conclusion

In conclusion, managing obesity in patients with CKD, ESRD, and kidney transplantation presents a complex challenge for the nephrologist. Individualized treatment plans, tailored to the patient's renal function, glycemic status, comorbidities, and concurrent medications, are necessary to achieve optimal weight control while minimizing the risk of adverse events. Furthermore, a multidisciplinary approach involving nephrologists, dietitians, therapists and pharmacists is helpful in creating a patient-centered plan. Continued research, collaborative efforts, and enhanced clinical guidelines are needed to refine our understanding and optimize the management of weight loss in patients with kidney disease. Ultimately, with the evolving landscape of drug therapies and a deeper understanding of the genetic and physiological triggers of weight gain, we are moving closer to achieving a comprehensive guide to weight management. This will help nephrologists to assist in preservation of kidney function, while improving the overall health and quality of life for our patients at various stages of kidney disease.

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.