Management of Obesity in Adults with CKD

Abstract

Obesity is a leading public health problem that currently affects over 650 million individuals worldwide. Although interest in the adverse effects of obesity has grown exponentially in recent years, less attention has been given to studying its management in individuals with CKD. This relatively unexplored area should be considered a high priority because of the rapid growth and high prevalence of obesity in the CKD population, its broad impact on health and outcomes, and its modifiable nature. This article begins to lay the groundwork in this field by providing a comprehensive overview that critically evaluates the available evidence related to obesity and kidney disease, identifies important gaps in our knowledge base, and integrates recent insights in the pathophysiology of obesity to help provide a way forward in establishing guidelines as a basis for managing obesity in CKD. Finally, the article includes a kidney-centric algorithm for management of obesity that can be used in clinical practice.

Obesity is a leading public health problem that currently affects over 650 million individuals worldwide.¹ Although interest in the adverse effects of obesity has grown exponentially in recent years, less attention has been given to studying its management in individuals with CKD. This relatively unexplored area should be considered a high priority in light of obesity’s rapid growth and high prevalence in the CKD population, its broad effect on health and outcomes, and its modifiable nature.

Guidelines for managing obesity exist,^2–4 but do not directly address patients with CKD. This gap has led to confusion about treatment options and even the value of treating obesity in people with CKD.^5,6 The purpose of this paper is to provide a comprehensive overview that critically evaluates the available evidence related to obesity and kidney disease and integrates recent insights into the pathophysiology of obesity to help provide a way forward in establishing guidelines as a basis for managing obesity in CKD.

Obesity Is Common in CKD

In clinical settings, obesity is usually estimated by simple anthropometric measurements that define excess body fat in a manner that is partly derived from their association with clinical risk in the general population.⁷ The body mass index (BMI), defined as weight (kilograms)/height (meters²), is the most commonly such used measurement. BMI has well-known limitations, including being influenced by extracellular volume expansion, but offers a reasonably good reflection of total body fat content in individuals with CKD and ESKD.^8,9 Although waist circumference more accurately reflects abdominal visceral adiposity, it is a less practical measurement in the clinical setting and is less accurate in patients with BMI>40 kg/m² due to variations in abdominal pannus distribution. Other anthropometric measurements offer only additional limited value. In fact, just as the size of a tumor may not necessarily correlate with its malignancy (in contrast to its metastases), neither is it certain that extra fat necessarily correlates with extra risk. Therefore, clinicians should be encouraged to look beyond BMI or other indices alone to instead focus on the potential complications of obesity related to the metabolic, mechanical, and psychologic domains. Newer techniques that can link measurement of fat to predictors of clinical risk in people with CKD would be of great benefit.

Granular data on the prevalence of obesity in persons with CKD are limited but consistent throughout the entire spectrum of kidney disease. In the 2011–2014 National Health and Nutrition Examination Survey, 44.1% of patients with CKD in the United States also had obesity (21.9% with class 1 obesity [BMI=30 to 34.9 kg/m²] and 11.1% each with class 2 [BMI=35 to 39.9 kg/m²] and class 3 obesity [BMI≥40 kg/m²]),¹⁰ with the overall percentage having increased by 5% over the preceding 12 years.¹¹ These levels are considerably higher than those in the general population during the same time period (36.5%),¹² during which time obesity was considered a major public health problem. Similar trends extend to kidney transplant recipients in whom the prevalence of obesity grew by 44% from 1999 to 2009 to include one third of all such patients.¹³ Individuals initiating dialysis have also had a persistent increase in BMI over time, with the mean rising from 26 to 28 kg/m² between 1995 and 2002.¹⁴ Identifying more recent trends not only in the prevalence of obesity in the CKD population but also in the prevalence of CKD in the greater obesity population would help frame the scope of the problem.¹⁵

Obesity Is a Predominating Global Mediator of Kidney Disease

Obesity is estimated to account for approximately 20%–25% of kidney disease worldwide. However, the true number is likely far higher after including intermediate disease states like type 2 diabetes (the most common global cause of CKD) and hypertension (the second most common cause in the United States).^16,17 In fact, diabetes and hypertension alone explain most obesity-associated kidney risk.¹⁸ The presence of obesity increases the lifetime risk of CKD by 25% compared with individuals with normal weight.¹⁹

In a variety of epidemiologic studies, obesity is independently associated with the development of proteinuria, AKI, CKD, and ESKD both in otherwise healthy individuals and in higher-risk groups, like persons with prehypertension.^20–28 Two large studies deserve special attention. In a global database of over 5.4 million healthy individuals, the risk of a decline in the eGFR linearly and progressively increased as BMI rose above 25 kg/m².²⁹ Risk also extends to the pediatric population, where the prevalence of obesity continues to rise.³⁰ In 1.2 million adolescents, overweight or obesity was independently associated with the development of ESKD over an average follow-up of 25 years, with the relationship being especially pronounced for diabetic ESKD (hazard ratio 39.95 [14.5 to 110.0]) in youths in the >95th percentile of BMI).³¹ Obesity is also an independent risk factor for accelerated CKD in certain monogenic (i.e., polycystic) and glomerular (i.e., IgA nephropathy) kidney diseases whose underlying pathophysiology is seemingly unrelated to weight^32–35 and for AKI in critically ill patients or those undergoing cardiac surgery.^36,37 However, not all studies of IgA nephropathy or other primary glomerulopathies are in accord.³⁸

The causal link between obesity and kidney disease is biologically plausible and believed to be mediated through direct and indirect mechanisms, with the actual pathways requiring further elucidation.¹⁸ Development of obesity leads to increased abdominal pressure and fat infiltration of the kidney,³⁹ intraglomerular hypertension with resultant glomerular shear-related stress,⁴⁰ podocyte damage and depletion leading to segmental sclerosis,⁴¹ activation of the renin-angiotensin-aldosterone⁴² and sympathetic systems leading to tubular sodium avidity and altered hemodynamics,⁴³ and lipotoxicity of kidney parenchymal cells.⁴⁴ Adipocyte secretory products, like leptin, contribute to sympathetic activation and may have separate nephrotoxic effects.⁴⁵ Individuals may also develop obesity-related glomerulopathy (ORG), which is characterized in certain instances by proteinuria and FSGS. Why only a relatively small percentage of people with obesity appear, on the basis of admittedly limited data, to develop ORG or other obesity-related kidney diseases is unknown. Reduced nephron endowment at childbirth with resultant stress on remaining nephrons over time could explain the susceptibility to ORG.^46–48 Population-based studies are indicated to better understand the prevalence of ORG. Indirect adverse effects via disease states that can arise from obesity, like diabetic nephropathy and hypertensive nephrosclerosis,¹⁸ but also cardiorenal processes (e.g., heart failure, pulmonary hypertension, and obstructive sleep apnea) are major causes of obesity-related CKD.^18,49

It should be noted that when estimating GFR in people with obesity, standard creatinine-based equations will for the following reasons offer less accurate results.^50–53 The equations themselves were not derived in populations with obesity, so their validation in this subgroup is not as strong. Serum creatinine will fluctuate independent of GFR as weight (and muscle mass) is gained or lost, and therefore, change in weight will throw off the results. The equations also include an adjustment for body surface area due to the observed relationship in mammals that GFR is proportional to body size. This observation is presumably due to the increasing load of metabolic by-products that larger organisms need to excrete.⁵⁴ Yet, it is lean (and not fat) mass that generates the metabolic waste that is filtered, so adjusting for fat mass introduces systemic bias.⁵⁵ In general, GFR estimating equations that combine serum creatinine and cystatin C are more accurate in individuals with obesity, although direct GFR measurement would be the ideal strategy.^56,57

Obesity Increases the Burden of Disease and Disability in CKD

The independent association between obesity and a variety of chronic physical and mental illnesses, more hospitalization and mortality, and reduced quality of life is well documented in the general population,^58,59 but data on these associations among the CKD population are sparse. A recent global survey found a heavy disease burden in persons with obesity and CKD that has grown significantly since 1990.⁶⁰ For example, in 2015 overweight and obesity in persons with CKD helped account for 24.4% of all disability-adjusted life years and 7.2% of all deaths worldwide. However, controversy surrounds the precise effect of obesity on mortality in patients with CKD. Numerous observational studies have found a protective association between obesity and survival, a phenomenon known as the obesity paradox, that is particularly pronounced in older patients on hemodialysis.^61–63 The obesity paradox is controversial, with detractors concerned about multiple residual confounders and biases, whereas supporters point to the consistency of the findings in the literature.⁶⁴ Regardless of which view is correct, the obesity paradox does not directly address the question of whether patients with CKD and obesity would benefit from weight reduction. That question was recently informed by observations that bariatric surgery, now more commonly referred to as metabolic surgery, was independently associated with a 31% lower all-cause mortality at 5 years compared with usual care (hazard ratio, 0.69; 95% confidence interval, 0.60 to 0.78) in patients with severe obesity on dialysis.⁶⁵ Similar studies in the pre-ESKD population are currently ongoing.

Obesity Impairs Management of CKD

Independent of any adverse effects on kidney function, the presence of obesity poses an impediment to optimal care of CKD. Placement of permanent dialysis access is one such example. Accesses that fail to work well require great expenditure of resources and expose patients to discomfort, inconvenience, and risk. Obesity can make placement of arteriovenous fistulas (AVFs) more challenging and complex.⁶⁶ Obesity may also limit the successful placement and function of AVFs particularly in more severe obesity, possibly by physically compressing the AVF and impeding its maturation,⁶⁷ although not all studies in this area are in agreement.^68–71 In patients on peritoneal dialysis, obesity may predispose to more (and more severe) episodes of peritonitis and thus, shorten the life of the dialysis catheter and peritoneal membrane.^72–74 More severe obesity may also reduce access to outpatient hemodialysis therapy due to weight limitations that constrain transportation and chair size options and make necessary ambulation difficult.⁷⁵

Obesity Impedes Access to Kidney Transplantation

Patients with obesity who undergo kidney transplantation will have superior outcomes compared with those remaining on dialysis.^76,77 Unfortunately, the presence of obesity impedes access to kidney transplantation. Because of concerns over higher rates of wound complications, longer hospital stay, delayed graft function, graft failure, and even higher mortality, many transplant centers do not offer transplants to individuals who are above certain BMI cutoffs.^78–83 Although data on cutoffs are scant, in one survey 29% of respondents stated their cutoff for listing was a BMI>35 kg/m².⁸⁴ These restrictions are controversial as some of the concerns may be outdated and are contradicted by other reports.^76,78,85,86 Establishing an evidence-based consensus on this important issue will improve transparency and possibly outcomes for donors and recipients.

An Updated Paradigm for Obesity and Implications for Treatment

The traditional understanding of obesity was that it resulted from the passive accumulation of excess calories. Research over recent decades has revised this thinking. Evidence now indicates that obesity is a disorder of energy homeostasis in which the body “defends” against fat loss by returning the subject to a set point of fat after every period of self-induced starvation.⁸⁷ The mechanisms through which body fat is defended are still unclear and may involve complex interactions between genetic, developmental, and environmental factors that seem to involve adipocyte-gut-neuroendocrine crosstalk.^87–89 The revised model helps explain why only about 20% of individuals with obesity are able to achieve sustained significant weight loss using lifestyle changes alone⁹⁰ and why targeting the hormonal mediators that defend against fat loss using medications or surgery may be a more effective strategy for most individuals. How or even if the uremic milieu contributes to the defense of excess fat requires further research.

Treatment for obesity includes lifestyle interventions, antiobesity medications, and metabolic surgery.⁵⁸ Lifestyle interventions, which incorporate various combinations of modified diet, physical activity, stress reduction, improved sleep health, and normalization of circadian rhythms, are low cost, have minimal risk, and can easily be integrated into a weight loss program. However, as mentioned above, they are only successful in achieving substantial sustained weight loss in a small minority of patients.⁹⁰ Renal-specific restrictions on macronutrients (e.g., high protein) or micronutrients (e.g., high potassium/phosphorus/sodium) may further limit dietary obesity treatment options. Medications that induce weight loss and improve obesity by modifying neuroendocrine regulation of body fat hold great potential, although the options for persons with CKD are currently more limited. Four Food and Drug Administration (FDA)–approved antiobesity drugs are available (Table 1). Of these, orlistat has fallen out of favor due to its long-term effectiveness and significant risk of steatorrhea and mild incontinence, as well as a low risk of oxalate-related acute kidney disease and CKD.^91,92 Of the remaining three drugs, only the glucagon-like peptide-1 (GLP-1) agonist liraglutide, which lowers mean weight by approximately 8 kg over several years,⁹³ can potentially be safely used in all CKD classes, although dose adjustments may be necessary.

Table 1.

FDA-approved antiobesity medications

Drug (Brand Name)	Mechanism of Action	Common Adverse Effects	Kidney-Related Precautions	Dosing Adjustments by eGFR, ml/min per 1.73 m2
				Stage 3–5 CKD	ESKD
Orlistat (Xenical, Alli)	Lipase inhibitor, thus inhibiting absorption	Fecal incontinence, oily spotting, fat-soluble vitamin deficiency	Reports of AKI and chronic kidney injury possibly from oxalate nephropathy	None	None
Phentermine (Adipex-P, Lomaira)	Sympathomimetic, anorexic	Hypertension, ischemia, palpitations, dry mouth, constipation	Excreted primarily via the urine	15–29: maximum 15 g/d	<15: avoid use (not been studied)
Phentermine/Topiramate (Qsymia)	Sympathomimetic, anorexic	Tachycardia, paresthesias, dry mouth, constipation, paresthesias, proximal (type 2) renal tubular acidosis, upper respiratory infections	Excreted primarily via the urine	CrCl<50 ml/min: maximum dose 7.5/46 mg once daily	Dialysis: avoid use (not been studied)
Buproprion-Naltrexone (Contrave)	Inhibits NE/dodopamine uptake, opioid antagonist	Nausea, constipation, dry mouth, dizziness, transient increase in BP, contraindicated in uncontrolled hypertension	Excreted primarily via the urine	“Moderate or severe impairment”: one tablet (8/90 mg) twice daily	Not recommended
Liraglutide (Saxenda)	GLP-1 agonist	Nausea/vomiting, diarrhea, anorexia	None	Use with caution in severe impairment—limited data available	Use with caution due to limited data

CrCl, creatinine clearance; NE, norepinephrine; GLP-1, glucagon-like peptide-1.

Renoprotective medications not specifically approved by FDA to treat obesity, such as other GLP-1 agonists and the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors, may also have weight-lowering effects in persons with CKD. The GLP-1 agonist dulaglutide lowers weight by 2–3 kg at 52 weeks in patients with CKD stages 3 and 4.⁹⁴ SGLT2 inhibitors are less effective, with an average weight loss of 0.8 kg in CKD stages 2–4.⁹⁵ Of note, the American Diabetes Association currently recommends combining SGLT inhibitors and GLP-1 agonists in people with CKD and type 2 diabetes whose glycemic control is not adequate.⁹⁶ However, benefits of this drug combination on glycemic control, weight reduction, and treatment of CKD are not well established and warrant further attention. Metformin is recommended in patients with type 2 diabetes or prediabetes with an eGFR>30 ml/min per 1.73 m². Because the variability of weight loss is high with metformin (average of 2%, as high as >10%^97,98) and because there are other medications that have may also have a beneficial effect on CKD, metformin should be considered a third- or fourth-line agent in people without type 2 diabetes or prediabetes. Although the weight-lowering effects of antiobesity medications have traditionally been fairly modest, some of the more recently approved agents now average 7%–9% weight loss, including the combination of topiramate and phentermine and the use of liraglutide alone. Newer agents appear to be even more effective. The recently reported results of phase 3 studies of the GLP-1 agonist semaglutide demonstrated an average of 16%–18% weight loss. Phase 2 studies of cagrilinitide, a novel amylin agonist, and terzepatide, a GLP-1/glucose-dependent insulinotropic polypeptide agonist, hold the promise of even greater effectiveness, yielding average weight loss approaching or exceeding 20%.

Metabolic surgery offers the most effective treatment for obesity and encompasses several types of procedures, the most common being sleeve gastrectomy and Roux-en-Y gastric bypass.⁹⁹ Metabolic surgery has been demonstrated to induce profound and sustained weight loss, including in patients with CKD stages 3 and 4¹⁰⁰ and ESKD.¹⁷ Drawbacks of metabolic surgery in patients with CKD include initial up-front costs, slightly higher risk of adverse events (reoperation, readmission, and AKI) compared with the general populace, and nephrolithiasis and oxalate nephropathy (on the basis of isolated reports in the literature).^65,101–104 Although metabolic benefits of metabolic surgery, such as remission of diabetes, were initially attributed wholly to postsurgical reductions in caloric intake and absorption, there is growing evidence that changes in secretion of gut hormones like GLP-1, gut nutrient–sensing mechanisms, the gut microbiome, and circulating plasma bile acids may also be contributing, particularly to the long-term improvements.¹⁰⁵

Mitigation of Kidney Disease through Weight Loss Strategies

Weight loss interventions, particularly metabolic surgery, ameliorate type 2 diabetes and hypertension, the two most common risk factors for CKD in the United States.¹⁷ A 5-year lifestyle intervention involving an average 5%–7% weight loss in people with prediabetes lowered the future risk of developing type 2 diabetes by 58% compared with placebo.¹⁰⁶ In patients with obesity and preexisting type 2 diabetes, metabolic surgery greatly reduces the need for diabetes medicines and improves glycemic parameters to a much greater degree than intensive medical therapy.¹⁰⁷ Metabolic surgery is also nearly seven times more likely to lower the need for antihypertensive medications compared with medical therapy.¹⁰⁸ In uncontrolled studies, metabolic surgery improves other risk factors for CKD, including glomerular hyperfiltration, pulmonary hypertension and sleep apnea, and cardiac disease.^109–112 There is little information on how weight loss improves metabolic parameters in people with CKD.

Although a growing literature suggests that weight loss interventions offer renoprotection, several important questions remain unanswered. The first is whether benefits are strictly related to weight loss or if weight-independent mechanism(s) play a role. One preclinical study found that metabolic surgery–induced weight loss has a superior antiproteinuric effect compared with weight-matched dietary restriction, supporting the latter possibility.¹¹³ A retrospective cohort study of 619 patients found no relationship between changes in BMI and eGFR up to a median of 2.8 years after metabolic surgery.¹¹⁴ However, a pilot study examining possible mechanisms that could explain changes in glomerular hyperfiltration after metabolic surgery found no relationship between circulating GLP-1 and measured GFR nor any changes in GFR immediately postmetabolic surgery before weight loss had occurred. This is in contrast to reports in other populations that describe metabolic improvements at this same time point.^115,116

Another question involves the relationship between weight loss and renoprotection. This question has not been directly addressed in the literature, but the studies in Table 2 suggest that as low as 2- to 4-kg weight loss using a variety of interventions may offer some degree of renoprotection. Improvements were observed in a wide variety of parameters, including surrogate markers of glomerular filtration, decline in eGFR, albuminuria/proteinuria, prognostic risk for CKD, development of CKD, and in one study,¹¹⁷ even the need for dialysis. It should be noted that these studies were heterogeneous and varied by intervention (diet, medications, or surgery), population (diabetic versus nondiabetic), baseline eGFR (few with baseline CKD), length (weeks to years), and weight loss achieved (approximately 2–38 kg). Randomized, controlled trials are restricted to one study that found a significantly higher rate of regression of microalbuminuria after metabolic surgery versus best medical care in persons with mild CKD.¹¹⁸ Progress in this area will ultimately require additional randomized, controlled trials in patients with established CKD that are adequately powered to detect surrogate end points of disease progression¹¹⁹ or ideally, hard event rates (i.e., initiation of dialysis or mortality). One such study is currently ongoing (NCT04626323). Comparative effects of weight reduction therapies on kidney-related end points or in patients with CKD are also lacking, as are prospective studies designed to measure metabolic benefits of weight loss in diseases, like diabetic kidney disease. Prioritization should be given to addressing these key clinically oriented questions.

Table 2.

Weight reduction studies in adults with kidney-related outcomes

Intervention	Design	Baseline eGFRa (% eGFR<60)	Duration/Follow-Up	Weight Lost	Kidney Outcomesb
Lifestyle/diet based
Hypocaloric120	Prospective proteinuric DKD n=24	Mean GFR mid-60s (?)	12 mo	BMI ↓ 7.3 kg/m2	↓ Proteinuria (1.3–0.6 g/24 h, P=0.01)
					↓ Albuminuria (0.72–0.49 g/24 h, P=0.01)
					↑ Measured GFR (63–80 ml/min, P=0.01)
Hypocaloric121	Prospective proteinuric DKD n=22	Mean CrCl 41 (?)	4 wk	Mean 6.2 kg	↓ Proteinuria (3.27–1.5 g/24 h, P<0.001)
					No change in CrCl
Vegan122	Randomized T2DM n=7	?	12 wk	Mean 7.2 kg	Nonsignificant ↓ in albuminuria (435–155 mg/24 h)
Hypocaloric123	Prospective proteinuric nephropathy n=9	Mean CrCl 93	12 mo	BMI ↓ 4.5 kg/m2	↓ Proteinuria (2.9–0.4 g/24 h, P=0.05)
Hypocaloric124	Prospective proteinuric nephropathy n=30	Mean CrCl 68 (?)	5 mo	Mean 3.6 kg	↓ Proteinuria (2.9–1.9 g/24 h, P=0.05)
					No change in calculated CrCl
Hypocaloric and ketogenic125	Prospective DKD n=6	21 (100%)	12 wk	Median 14.2 kg	↓ sCr, cystatin C, eGFR
					Trend toward ↓ albuminuria/proteinuria
Intensive lifestyle intervention126	Randomized stages 3–4 CKD n=83	Mean eGFR 39 (100%)	12 mo	Mean 1.8 kg	No change in eGFR
Three distinct diets127	Randomized stages 1–3 CKD n=318	Stage 2 1–2: mean eGFR 79; stage 3: mean eGFR 53	24 mo	2.9–4.7 kg depending on diet	Stage 3 CKD: ↑ eGFR (7.1% [3.4 to 10.9]) across all diets
					Stages 1–2 CKD: ↑ eGFR (3.7% [2.1 to 5.4]) across all diets
Diet high in fruits/vegetables128	Randomized stage 3 CKD n=108	(100%)	3 yr	Mean 4 kg	In fruits/veggie arm, ↓ albuminuria (318–242 mg/g)
					In fruits/veggie arm, ↓ eGFR (42–37 ml/min per 1.73 m2)
Exercise training129	Randomized stages 3–4 CKD n=20	Mean eGFR 40 (100%)	12 mo	Mean 3.6 kg	Nonsignificant ↑ eGFR (2.3 ml/min per 1.73 m2) versus baseline
Intensive lifestyle intervention130	Randomized stages 3–4 CKD n=111	Mean eGFR 39–45 (100%)	4 mo	Mean 2.4 kg (diet/exercise arm)	No change in eGFR
Weight management program131	Prospective n=32	52 (100%)	24 mo	6.4 kg compared with usual care	Slower eGFR decline (11.5 ml/min per 1.73 m2) compared with usual care
Intensive lifestyle intervention132	Randomized T2DM n=5145	90 (5%)	Median 8 yr	4 kg compared with controls	↓ Very high-risk CKD (0.69 [0.55 to 0.87]), eGFR<45 (0.79 [0.66 to 0.960])
					No improvement in doubling sCr or RRT
Antiobesity medicationc
Liraglutide133	RCT secondary analysis n=9340	Mean 80 (23.1%)	Median 3.7 yr	2.3 kgd	↓ New-onset macroalbuminuria
					(0.74 [0.60 to 0.91])
					No improvement in doubling of sCr, RRT, renal death
Lorcaserin134	RCT secondary analysis n=12,000	Median 76 (19.6%)	Median 3.3 yr	Approximately 4 kgd	↓ New-onset micro-/macroalbuminuria
					(0.84 [0.76 to 0.97])
					↓ New/worsening CKD (0.81 [0.72 to 0.93])
					No improvement in doubling sCr, composite of ESKD/transplant/renal death, or eGFR≥30%/40%
Surgery based
BPD135	Retrospective n=35	? (?)	1 yr	39.8 kg	↓ Proteinuria (0.74 to <0.2 g/24 h, P=0.01)
RYGB >> SG136	Retrospective n=985	97 (4.7%)	Median 4.4 yr	34.2 kg	↓ Risk eGFR decline ≥30% (0.46 [0.36 to 0.60])
					↓ Risk doubling sCr or ESKD (0.49 [0.30 to 0.81])
RYGB, SG100	Retrospective n=714	48 (100%)	Median 3 yr	Approximately 27 kg (RYGB)	Slower eGFR decline compared with controls (9.8 [8.1 to 11.6] ml/min per 1.73 m2)
					↑ eGFR in RYBG versus SG groups (6.6 [3.4 to 9.80] ml/min per 1.73 m2)
RYGB > LAGB137	Prospective n=2144	Median 104 (N/A)	Up to 7 yr	38.2 kgd	Improvement in CKD prognostic risk
					↓ Albuminuria in moderate/high CKD prognostic risk groups
VBG > LAGB > RYGB138	Retrospective n=2010	Mean 92 (N/A)	Median 18 yr	N/A	↓ Risk of developing ESKD (= CKD5 + dialysi s+ transplant; 0.46 [0.24 to 0.90])
RYGB > LAGB139	Prospective T2DM n=737	Median 94 (12.2%)	Up to 5 yr	Median 25%	↓ In moderate/severe increase in albuminuria (0.66 [0.48 to 0.90])
					Stabilization of prognostic risk for CKD
					No effect on eGFR
RYGB > SG > LAGB140	Retrospective T2DM n=4024	Mean 97 (0%)	Median 4.3 yr	N/A	↓ Risk of developing diabetic nephropathy (0.41 [0.29 to 0.58])
RYGB > SG > LAGB > BPD141	Retrospective T2DM n=2287	Median 90 (N/A)	Median 3.9 yr	20.3 kg compared with controls	↓ Risk of developing diabetic nephropathy (0.40 [0.31 to 0.52])
					Lower eGFR/higher prognostic risk for CKD presurgery associated with lower likelihood of diabetes remission after surgery
RYGB117	Retrospective T2DM n=5321	Mean 99 (N/A)	Mean 4.7 yr	N/A	↓ Risk of halving of eGFR (0.58 [0.40 to 0.85]) and development of macroalbuminuria (0.55 [0.47 to 0.65]), AKI (0.57 [0.36 to 0.90]), CKD (0.45 [0.30 to 0.67]), diabetic nephropathy (0.22 [0.10 to 0.47]), or dialysis (0.25 [0.08 to 0.72])
RYGB142	Retrospective T2DM n=131	Mean 70 (26%)	Median 12.8 yr	N/A	↓ Risk of developing CKD compared with patients without bariatric surgery in full (0.53 [0.30 to 0.91]) but not propensity-matched cohort
RYGB118	RCT T2DM n=100	Median 100	2 yr	Relative ↓ in BMI of 7	49% improvement in microalbuminuria remission rate compared with best medical treatment
N/A143	Retrospective n=144	Mean 83	9.2 yr	N/A	1-ml/min per 1.73 m2 slower decline in surgery versus control groups over mean 8–9 yr as confirmed by multiple GFR markers
					Effects most pronounced in patients with lowest eGFR

DKD, diabetic kidney disease; DKD, diabetic kidney disease; CrCl, creatinine clearance (in milliliters per minute); T2DM, type 2 diabetes; sCr, serum creatinine; RCT, randomized, controlled trial; BPD, biliopancreatic diversion; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy; LAGB, laparoscopic adjustable gastric banding; N/A, not available; VGB, vertical banded gastroplasty.

^aeGFR is in milliliters per minute per 1.73 m².

^bMay include hazard ratio (95% confidence interval).

^cApproved by FDA for obesity treatment in 2020.

^dPublished in a separate dataset.

The criteria upon which patients are selected for obesity treatment also require refinement. Selection criteria will depend in part upon the severity of obesity and goals (e.g., metabolic benefits, slowing CKD progression, and disease regression), patient preference and tolerance of risk, and weight eligibility requirements for kidney transplant wait-listing if applicable. Unfortunately, little information is available to help guide recommendations. More advanced CKD has been associated with reduced efficacy of metabolic surgery¹⁴⁴ as well as a lower likelihood of diabetes remission¹³⁹ in retrospective studies that need to be prospectively confirmed. In summary, because of lack of rigorous evidence, management strategies are primarily opinion based at this time.

Figure 1 offers one possible kidney-centric management algorithm. The proposed algorithm balances severity of obesity, the presence of obesity-related uncontrolled modifiable CKD risk factors, and weight-related prohibitions on kidney transplantation in determining obesity management. The longer-term efficacy of any particular intervention is more likely to be reflected in the response to treatment at 3 months. We, therefore, recommend a stepwise approach that starts with lifestyle management, escalating to pharmacotherapy, then surgery, and ultimately, combination approaches. Clinicians can move rapidly from tier to tier if no response is noted within 3 months for each treatment modality. It should be recognized that at present, treatment options are fairly limited, and there is no way to determine which treatment pathway is most suited to a specific patient. If a patient responds to a particular treatment, then their obesity should be aggressively managed to optimize health benefits.

Figure 1.

Suggested algorithm for obesity management in persons with CKD. *Opinion-based recommendations for antiobesity medications include choosing from each of the following groups: group 1: orlistat, phentermine/topiramate, buproprion-naltrexone (all of these are dose adjusted as necessary with monitoring for renal side effects); group 2: GLP-1 agonists (dose adjusted as necessary); and group 3: sodium-glucose cotransporter 2 inhibitors (eGFR>30 ml/min per 1.73 m²). Adapted from Rubino et al.,¹⁴⁵ with permission.

A Multidisciplinary Approach to CKD Obesity Management

Nephrologists can play an active role in identifying and helping manage obesity in patients with CKD. This should be made somewhat easier by the fact that nephrologists are already comfortable in acting in many ways as primary physicians for their patients. Moreover, the incorporation into nephrology practice of SGTL2 inhibitors, GLP-1 agonists, and perhaps, other new drugs that have renoprotective effects but also induce weight loss will enable nephrologists to more comfortably and confidently participate in obesity management. Educating nephrologists on the importance of obesity as a pivotal risk factor for kidney disease and other major outcomes; the available weight reduction treatments and their efficacy, benefits, and risks; and how to communicate this information effectively to patients will help optimize obesity management. Introducing these concepts into nephrology training curricula will help reinforce these concepts and their importance. Although it is unrealistic given time constraints and other factors to expect that the majority of nephrologists will play a primary role in obesity management, they can help facilitate the process by establishing referral networks with local obesity medicine and metabolic surgery practices that can then take the lead. Active involvement of renal dietitians will also contribute significantly to the success of this endeavor.

A more aggressive push to treat obesity in CKD will also require greater familiarity and comfort on the part of obesity physicians in terms of the goals, benefits, risks, and limitations of weight reduction therapies in the CKD population. As many knowledge gaps remain in these areas, clinical judgement will be required. Possible treatment goals include remission of early CKD; halting progression of later stages of CKD; ameliorating risk factors for CKD, such as type 2 diabetes, systemic and pulmonary hypertension, and kidney inflammation; and improving the likelihood of obtaining a kidney transplant. Regular communication with nephrologists may be necessary, particularly with regard to the safety of treatment strategies and monitoring of kidney function and metabolic profiles.

Developing Clinical Practice Guidelines for Patients with CKD

Management of obesity in individuals with CKD is at an early stage. Despite increasing interest over the past two decades in the pathophysiologic effects and clinical impact of obesity on kidney disease, this topic is given little attention during fellowship training, in day-to-day nephrology care, or in nephrology clinical practice guidelines.^146,147 Contributing factors include a lack of understanding about the effect of obesity on kidney disease and its management, uncertainty on how to manage obesity and integrate its management into daily practice, and the important gaps in knowledge, including those listed in Table 3. Although clinical guidelines are not a panacea and have the potential to be harmful if used without application of adequate clinical judgment,¹⁴⁸ we think that developing practice guidelines for the management of obesity in CKD could improve quality and consistency of care, promote beneficial interventions, support quality improvement, improve medical education, empower patients, influence public policy, and identify gaps and limitations in the evidence. Ideally, such guidelines should be developed in collaboration with leading professional societies focused on obesity.

Table 3.

Research gaps related to obesity management in CKD

Topics
Techniques to more accurately measure clinically meaningful excess adiposity
Updated obesity trends in the CKD population
Understanding the pathophysiologic pathways linking obesity and CKD
Explaining the individual predisposition to obesity-related kidney disease and its prevalence
Developing consensus on weight-related contraindications to kidney transplantation
Determining the effect of obesity on mortality and other nonkidney-related clinical outcomes
Understanding the contribution of uremia to the defense of fat
Defining the precise relationship between weight loss and renoprotection
Comparing renoprotective effects of various weight loss strategies
Establishing evidence-based indications for antiobesity therapy

Despite its centrality as a risk factor for kidney disease, disability, and death and an obstacle for optimal management of CKD, obesity is relatively undermanaged and understudied by nephrologists. Improving obesity management for persons with kidney disease will require a concerted effort to integrate this topic into nephrology training curricula and standard clinical care, establish collaborative relationships with obesity experts, and address the many unanswered research questions to help fill current knowledge gaps. Establishing clinical guidelines in this area can help focus and advance efforts in this field.

Disclosures

A.N. Friedman is a member of the scientific advisory board for GI Dynamics and a consultant for Goldfinch Bio; reports ownership interest in Eli Lilly; is an editorial board member of the Journal of Renal Nutrition and Frontiers in Nephrology; is a council member of the International Society of Renal Nutrition and Metabolism; and is a Data Safety and Monitoring Board member of Watermark Research Partners. L.M. Kaplan is a scientific advisor to Boehringer Ingelheim, Fractyl, Gelesis, GI Dynamics, Johnson & Johnson, Lilly, Novo Nordisk, Pfizer, and Rhythm. C.W. le Roux is a member of the scientific advisory boards for Boehringer Ingelheim, GI Dynamics, Herbalife, Johnson & Johnson, Keyron, Novo Nordisk, and Sanofi; received research funding from the European Foundation for Study of Diabetes, the Health Research Board, the Innovative Medicine Initiative of the European Union, the Irish Research Council, and the Science Foundation Ireland; has ownership interest in Keyron; received honoraria from Boehringer Ingelheim, GI Dynamics, Herbalife, Johnson & Johnson, Keyron, Novo Nordisk, and Sanofi; is an editorial board member of Surgery for Obesity and Related Diseases and Obesity Surgery; and was on speakers bureaus from Boehringer Ingelheim, GI Dynamics, Herbalife, Johnson & Johnson, Keyron, Novo Nordisk, and Sanofi. P.R. Schauer is a member of the scientific advisory boards for GI Dynamics, Keyron, and Persona; has received consulting fees from Ethicon and Medtronic; and has received grant funding from Ethicon, Medtronic, and Pacira. L. Kaplan reports Consultancy Agreements with Eli Lilly & Co., Johnson & Johnson, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals; Ownership Interest in Fractyl, Gelesis, GI Dynamics, Rhythm Pharmaceuticals; Honoraria from Eli Lilly & Co., Johnson & Johnson, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals; Other Interests/Relationships as a Member of Executive Committee of The Obesity Society. P. Schauer reports Consultancy Agreements with GI Dynamics, Keyron, Persona, Mediflix; Ownership Interest in SE Healthcare LLC; Research Funding from Ethicon, Medtronic, Pacira, Persona; Honoraria from Ethicon, Medtronic, BD Surgical, Gore; Scientific Advisor or Membership as SE Healthcare Board of Directors. GI Dynamics Advisory Board, Keyron Advisory Board, Persona Advisory Board, and Mediflix Advisory Board.

Funding

None.