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

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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.

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Oral Complications of Chronic Kidney Disease - Key Concepts Bite by Bite

Written by: Patrícia Sousa M.D., António Barbosa M.D., Shweta S. Shah, M.D.

Infographics by: Shweta S. Shah, M.D. Salar Bani Hani, MD

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Chronic kidney disease (CKD) is a ​​progressive and irreversible deterioration of kidney function marked by systemic manifestations. Both the disease itself, and therapeutics used to treat disease progression, uremia and ESKD may affect oral health. Before we bite off more than we can chew, let's nibble away at this gnawing topic or oral complications of chronic kidney disease. Unfortunately, this subject might leave a bad taste in your mouth, as there is conflicting evidence regarding CKD and oral health with limited pediatric literature. CKD can lead to a dysregulation of the vitamin D-parathyroid axis, affecting tooth development and eruption, craniofacial growth, dental occlusion, and function. On the positive side, uremia may result in an alkaline oral pH that inhibits cariogenic bacteria, decreasing the risk of dental caries. However, an alkaline oral milieu may promote dental calculus accumulation, which can raise aesthetic concerns. If proper dental hygiene is not in place, the risk of dental caries rises following a kidney transplant. Both metabolism alterations and systemic medication may cause oral manifestations, such as oral pigmentation, stomatitis, gingivitis, gingival overgrowth, malodor (halitosis), dry mouth (xerostomia), and distorted taste (dysgeusia). In severe cases, there may be an increased risk of developing oral candidiasis, and oral cancers.

Chronic Kidney Disease

Tooth Development and Position

Dental impacts will occur during the tooth development timeframe, which spans from birth until the 25th year of life. Secondary parathyroid disease and bone metabolism have important roles in the different phases of tooth development. Hypocalcaemia, decreased 1,25-dihydroxycholecalciferol, elevated inorganic phosphate, elevated serum parathyroid hormone, and elevated serum fluoride can lead to defects in enamel quality and quantity, variation in the number of teeth, as well as the position of erupting teeth. Enamel defects can lead to rapid tooth destruction and an increased risk of caries. Teeth position may be influenced by the number of teeth and bone quality, leading to abnormal craniofacial development and altered occlusion (contact between upper and lower teeth). Teeth abrasion can be prevented by using fluoride toothpaste with a 1000-1500 ppm concentration, a dental split or guard during sleep and avoiding hard foods.

Dental-craniofacial development may be affected by protein and caloric deficits, metabolic acidosis, growth hormone resistance, anemia, and renal osteodystrophy. These factors may have a synergistic effect, contributing to altered occlusion. Manifestations include decreased cranial base length, more obtuse mandibular angle, and shorter mandibular length. Studies support the use of growth hormone to improve the facial profile and occlusion in selected cases. Use of growth hormone does not, however, accelerate teeth eruption. As such, growth hormone is not widely adopted in clinical practice for this indication.

Dental caries are the most frequent preventable infectious disease in the world. The pathogenesis is multifactorial, involving the host, microflora environment, food intake, and duration of risk factors. The acid produced by oral bacteria (e.g., lactobacilli) lowers oral pH resulting in demineralization of the tooth surface, allowing Streptococcus mutans proliferation in caries. Pediatric patients with CKD may be predisposed to the development of dental caries due to insufficient oral hygiene, xerostomia, and a carbohydrate-rich diet that promotes harmful microflora. In spite of this, some studies suggest these patients have lower concentration of cariogenic bacteria when compared with healthy individuals, due to an alkaline oral pH and higher salivary buffering capacity (caused by the higher concentration of ammonia from urea hydrolyzation in the mouth). Thorough dental hygiene is paramount for prevention.

Oral soft tissue manifestations like halitosis, dysgeusia, xerostomia, gingivitis, calculus accumulation, oral stomatitis, and leukoplakia are some of the reported soft tissue oral manifestations of CKD. The prevalence of these conditions is not well established but tends to increase as the patient moves towards end-stage kidney disease and kidney replacement therapy. Uremic odor, dysgeusia (metallic taste), xerostomia, and dental calculus (tartar) accumulation due to calcium deposition from saliva are more commonly observed.

Xerostomia may arise from restricted fluid intake and is associated with an increased cariogenic risk, oral sensitivity, increased Candida infections, and loss of taste. Xerostomia can be relieved with topical oral products or by chewing sugar-free gum. Dental calculi accumulation leads to inflammation of the gingival tissue (gingivitis) which can evolve into periodontitis. Periodontitis is an infection of the gingiva and the bone, which supports the teeth, which may lead to systemic infection. Systemic inflammation caused by periodontitis can lead to adverse cardiovascular morbidity and atherogenesis, already well-documented in CKD patients.To avoid hemorrhagic risk, secondary to anticoagulants used during dialysis, oral procedures with high bleeding risk should be scheduled on non-dialysis days.

Kidney Transplant Recipients

Prior to kidney transplant, a dental evaluation is recommended to evaluate for any infections or caries that could worsen once immunosuppression is started. In the immediate post-transplant period, when immunosuppression is highest, dental work should be limited to only life-threatening oral conditions to limit the risk of infection. In the post-transplant maintenance phase, regular oral treatments can be resumed, and a periodic oral evaluation should be maintained.

Graft-versus-host disease following kidney transplant is rare, but may manifest in the oral cavity as lichenoid lesions, hyperkeratotic plaques, salivary gland dysfunction, and ulcers.

Antimicrobial Prophylaxis for oral procedures is not widely recommended in patients with CKD, nephrotic syndrome or immunosuppression following kidney transplant. However, on an individual basis under certain circumstances prophylactic antibiotics may be warranted. Antibiotic prophylaxis is advisable before invasive dental procedures are performed such as dental extraction or periodontal surgery, as transplant patients are more susceptible to infection.

Although rare, transplant patients may have a higher risk of oral cancers, which includes Kaposi Sarcoma and squamous cell carcinoma, due to long-term immunosuppression. Regular dental evaluation is essential in these patients, with routine follow-up to screen for these conditions. Avoiding smoking and alcohol consumption are also paramount to reduce risk factors.

Immunosuppressive Medication

Immunosuppressive medications may be used in kidney transplants and/or as a treatment for glomerular diseases such as nephrotic syndrome. They may be associated with white patches on the dorsal surface of the tongue that cannot be wiped away. Hairy tongue is benign and self-limited, and no treatment is required in most cases. In 4 to 43% of kidney transplant patients, oral Candida infection can be found in the form of oral candidiasis and angular cheilitis. Candida albicans is commonly found as part of the commensal oral flora, acting as an opportunistic pathogen following immunosuppression. Oral stomatitis or oral ulcerations may arise as a side effect of immunosuppressant medications such as sirolimus and everolimus. They tend to be self-limited and resolve in 10 to 15 days, but can be treated with topical steroids to minimize discomfort. In the case of severe and recurrent ulcers, immunosuppressant medications should be discontinued until the mucosa heals. Gingival overgrowth (GO) can be found as a consequence of immunosuppression. Cyclosporine causes GO in 25% of treated patients by inducing fibroblast production. Tacrolimus is a useful alternative in these patients. Azathioprine appears to have a protective effect in patients under cyclosporine or tacrolimus treatment, since its impact on GO is lower and allows for dose reduction of these drugs.

GO leads to delayed or ectopic teeth eruption, impaired speech, protruding appearance of the gingiva, and hinders teeth brushing. Gingivectomy is indicated when GO affects function and impairs orthodontic treatment. In selected cases, GO can be reduced or resolved by using an alternative immunosuppressant. Addressing these concerns is important to prevent patients from self-adjusting their medication and risking graft rejection.

Anti-hypertensive Medications

Gingival overgrowth may also be a side effect of anti-hypertensive medications, such as calcium-channel blockers (CCB) - e.g. nifedipine (6.3% of treated patients), amlodipine (2.2%), and diltiazem (1.7%). CCBs inhibit the zona glomerulosa, increasing the secretion of ACTH by negative feedback, which then promotes testosterone production leading to gingival hyperplasia. Increased risk is observed when cyclosporine is used simultaneously with CCB (51.9%), suggesting a synergistic effect.

Angiotensin-converting enzyme inhibitors (ACEIs) can lead to angioedema in 0.1 to 0.2% of patients, oral dysesthesia, oral lichenoid reaction, and xerostomia.

TAKE-HOME MESSAGE

• CKD has an important impact on oral health.

• Dysregulation of the vitamin D-parathyroid axis can cause dental-maxilo-facial dysmorphia.

• Uremia decreases caries in CKD patients, but the risk can increase after a kidney transplant.

• Immunosuppressants (e.g., cyclosporine) and calcium channel blockers (e.g., amlodipine, nifedipine, diltiazem) may cause gingival overgrowth.

• Long-term follow-up for oral cancer screening is recommended in immunosuppressed patients.

Reviewed by S. Sudha Mannemuddhu, Brian Rifkin, Sophia Ambruso, Corina Teodosiu

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A BOLD Approach to Estimating Kidney Oxygenation in CKD

A New Strategy For Blood Oxygen Level-Dependent MRI Assessment of Hypoxemia

Written by: Gerren Hobby, MD

Expert reviewer: Pottumarthi Prasad, PhD

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INTRODUCTION

When talking about kidney disease, we often focus on glomerular disorders, but when it comes to the progression of chronic kidney disease, it's the combination of factors like a loss of parenchymal cells, chronic inflammation, diminished regenerative capacity of the kidney, and the final common path of fibrosis that pushes one towards dialysis. Glomerular injury leads to the loss of podocytes and the release of cytokines and growth factors. These, in turn, activate myofibroblasts responsible for producing the extracellular matrix (ECM). Nephrons are lost and replaced with scar tissue. This is the hallmark of chronic kidney disease progression. Multiple aspects of CKD progression are being studied, but interestingly kidney ischemia has been difficult to study or measure. Extracellular matrix (ECM) expansion increases the distance from blood vessels to tubule cells, resulting in hypoxia. Oxygen deprivation causes scarring of the glomerulus and interstitium, thereby driving CKD progression. Although its presence has long been suggested by the loss of peritubular capillaries on biopsies of CKD patients, firm proof of hypoxia in human kidneys has eluded us.

In the late 1990s, the chronic hypoxia hypothesis emerged and started with the fact that glomerular disease alters downstream blood flow in the peritubular capillaries. Altered gene activity and a cascade of other effects ensue, culminating in fibrosis. Hypoxia-inducible factors (HIF) comprise some of the key upregulated genes. As their activity increases, they alter the metabolism of tubular epithelial cells thereby causing extracellular matrix accumulation, interstitial collagen deposition, and matrix metalloproteinases suppression which normally breaks down said extracellular matrix.

The above processes provide a plausible mechanism for CKD progression from hypoxia. However, the question remains; does hypoxia actually exists in the kidneys of patients with chronic kidney disease? To begin, studies from animal models directly show that hypoxemia actually exists in animal models of chronic kidney disease. Utilizing oxygen microelectrodes, it was directly shown that hypoxia exists in CKD. For obvious reasons, these studies have not been performed in humans and because of this, our evidence base for the presence of hypoxia in humans with chronic kidney disease is more peripheral. Kidney biopsies of patients with chronic kidney disease reveal two important findings: rarefaction of peritubular capillaries and expansion of the extracellular matrix. These observations suggest a hypoxic environment. Additionally, studies using hypoxia-dependent pimonidazole protein adducts indicate hypoxia in CKD. Pimonidazole binds to thiol groups of protein, peptides, and amino acids at oxygen tensions below 10mmHg. Increased level of staining with this compound indicate lower oxygen levels. Pimonidazole protein adducts give more of a binary result though, and don’t allow us to quantify the degree of hypoxia. Lastly, proteomic studies show increased expression of HIF in patients with CKD.

In summary, we have concrete evidence in animals, and peripheral evidence in humans, to support the chronic hypoxia hypothesis. We have the biological plausibility of the role of hypoxia in fibrosis development, but we lack direct evidence of hypoxia in human chronic kidney disease patients.

What we need is a deeper understanding of hypoxia in human CKD to explore further the link between hypoxia, fibrosis, and chronic kidney disease. This brings us to the recent paper in Kidney International Reports, Quantitative Blood Oxygenation Level Dependent Magnetic Resonance Imaging for Estimating Intra-renal Oxygen Availability Demonstrates Kidneys Are Hypoxemic in Human CKD, which invites us into the world of magnetic resonance imaging (MRI).

visual abstract

We are all familiar with popular functional MRI studies that reveal changes in brain activity in response to a certain stimulus. Interestingly, these MRI studies, which utilize blood oxygen-dependent MRI (BOLD MRI), are an excellent tool to examine oxygen levels in CKD patients. The current KI Reports paper does just that, and provides the crucial missing piece of information we need for the hypoxia hypothesis.

HOW MRI WORKS

This paper is laden with technical details, so it’s worthwhile to spend some time discussing the physics of MRI. Figure 1 below is an overview of MRI physics, but also, be sure to check out this amazing video that gives a great introduction. You can find a more in-depth introduction to basic MRI physics in this video, as well as this one.

Figure 1: A: Protons are the basis of MRI imaging and are mainly found in water and fat in the body. They behave like small bar magnets, having one north pole and one south pole. In their normal state, their poles face different directions, and this random orientation cancels out their individual magnetization to create a net magnetization vector of zero. In addition, protons spin and their action of spinning is termed “precession”. Normally, protons spin (precess) out of sync with one another in a random fashion. B: The powerful fixed magnet of MRI aligns the poles of the protons along its Z axis, either in a parallel or antiparallel fashion, with a small majority aligning with the field of the MRI machine. Even though the fixed magnet aligns the protons along the Z axis, the second feature remains unchanged – they still spin (precess) out of sync with one another. C: When an MRI image is obtained, a radiofrequency (RF) pulse is applied at a 90-degree angle which tips the poles of the protons from the Z-axis 90 degrees into the X-axis. In addition, it causes the protons to spin (precess) in sync. D: When the RF pulse is stopped, the protons relax back to the Z-axis and they begin to relax and precess out of sync with one another.

When the RF pulse is removed, as shown in panel D, it creates what we think of as longitudinal relaxation (T1 relaxation) and transverse relaxation (T2 relaxation) which are due to regrowth of the longitudinal and decay of the transverse signal, respectively.

1. T1 relaxation is caused by protons relaxing from their X-axis orientation back to the longitudinal Z-axis

2. T2 relaxation is a bit more complicated. The transverse signal is maintained during an RF pulse when protons precess in sync with one another in addition to orienting their poles in the X-axis. Any loss in the synchronicity of proton precession or a return of the poles to the Z axis results in decay of the transverse signal and thus T2 relaxation.

Different body tissues have different T1 and T2 relaxation times and this forms the basis of MRI imaging and how images of different organs are formed. Placing an emphasis on the differing T1 or T2 relaxation times also forms the basis of T1- or T2-weighted imaging.

The current paper in KI reports utilizes an MRI parameter called R2*. As mentioned above, T2 is the time it takes for decay of the transverse signal. R2 refers to the relaxation rate and is simply the inverse (1/T2) of the T2 signal. A short T2 time provides a smaller denominator for R2 and thus a higher number – a faster relaxation rate. Conversely, a long T2 relaxation time gives R2 a large denominator and a smaller R2 value. The R2 relaxation rate is determined by the strength of the MRI fixed magnet as well as the intrinsic properties of the proton itself. In general, as the magnetic field increases, the transverse signal decays faster and the R2 relaxation rate increases. A strong fixed magnet pulls the protons back to their original orientation faster than a weak magnet does. The reality is, of course, more complicated. In addition to the fixed MRI magnet, any substances in the body with magnetic properties will increase the local magnetization of protons and increase the relaxation rate (R2). Deoxyhemoglobin, as opposed to oxyhemoglobin, contains unpaired electrons and displays these paramagnetic properties. The local magnetic field in a tissue increases along with increasing deoxyhemoglobin, and this speeds up the relaxation rate (R2). This true, or “observed relaxation rate (R2)” is termed R2*. For the purposes of understanding this paper, the higher the R2*, the higher percentage of deoxyhemoglobin we will find in the tissue, suggesting tissue hypoxia. By analyzing the overall amount of deoxyhemoglobin (via the R2* parameter) within a standardized volume of kidney tissue, called a voxel, we can estimate oxygenation levels on a spatial level in the kidney.

This is an incredible technique, but unfortunately, past studies utilizing BOLD MRI in CKD have revealed conflicting results due to the limitations of this technique. Firstly, biopsies in chronic kidney disease show rarefaction of the microvasculature, which reduces the total blood volume in the kidney. Secondly, we frequently encounter anemia in CKD patients. These two factors reduce the total amount of hemoglobin molecules within a voxel through pericapillary rarefaction and reduction in the concentration of hemoglobin in blood.

Past studies of BOLD MRI used R2* to estimate oxygen levels in the kidney. However, as stated above, both pericapillary rarefaction and anemia lower the total amount of hemoglobin (and thus paramagnetic deoxyhemoglobin that MRI detects) in the volume of a voxel. This led to lower R2* levels which gave false impressions of higher oxygenation labels in the kidney. This assumption is due to the incorrect conclusion that if there are low levels of deoxyhemoglobin present, then there must be high levels of oxyhemoglobin. This gave the false impression of higher oxygen levels in CKD patients, thus this interpretation error led to conflicting results in the previous BOLD MRI literature in CKD patients. The current study, however, takes an intriguing approach by incorporating a contrast agent to measure the overall blood volume, thus removing the variable of pericapillary rarefaction in the kidney. Additionally, they measured the hematocrit from peripheral blood samples, taking into account the only other variable that adversely affects R2* for proper estimation of oxygenation in the kidney.

This study utilizes the IV iron medication, ferumoxytol to estimate blood volume. Why would they do this? It has parametric properties (order of magnitude higher strength of deoxyhemoglobin in magnetic properties) and thus increases the R2* signal. When injected, it goes into the bloodstream, and increases the R2* signal. Utilizing pre- and post-ferumoxytol imaging, the fractional blood volume of the kidney can be estimated.

METHODS

This study evaluated kidney oxygenation in CKD patients and healthy controls. BOLD MRI was used to image the kidneys of 9 healthy controls and 6 individuals with CKD and utilized R2* as the parameter to estimate oxygenation in the kidney.

Inclusion Criteria for all patients were as follows:

• Age ≥ 18 years

• Ability to give informed consent and willingness to follow study protocol

Exclusion criteria for all participants included:

• Contraindication for MRI

• Pregnant or nursing females

• History of heart failure

• History of renal artery stenosis

• History of ureteral obstruction

• NSAID use

• Iron overload (i.e. ferritin >800 ng/mL

• For CKD group: history of primary glomerular disease, primary interstitial disease, or polycystic kidney disease

Healthy participants had no history of HTN, DM, heart disease, or CKD. The CKD group had type 1 or type 2 diabetes and CKD G3-4.

MRI scans were completed with a 3.0 T MRI machine. qBOLD MRI data included both R2 and R2* measurements. After the initial R2* images were acquired, ferumoxytol was administered intravenously for estimation of blood volume.

RESULTS

Baseline characteristics of the participants are shown in Table 1.

When healthy controls and CKD patients were compared, we can see that the paramagnetic properties increased R2* values in the kidneys of both cohorts as expected (figure 1). After injection of ferumoxytol, the R2* increase is higher in healthy controls than CKD patients, which suggests a higher fractional blood volume in healthy controls.

When fractional blood volume is taken into account, it was found that the cortex is normoxic in healthy controls, but moderately hypoxemic in CKD. Next, the medulla was mildly hypoxemic in healthy controls and moderately hypoxemic in CKD (Figure 3).

DISCUSSION

This study gives us the first direct evidence of hypoxemia in human CKD. Since the chronic hypoxia hypothesis emerged, a number of pathogenic mechanisms connected hypoxia to the development of chronic kidney disease. Direct evidence from animal studies supported the presence of hypoxemia in CKD. Multiple layers of peripheral evidence also emerged from human studies, but we still lacked direct observations that hypoxemia existed in human CKD kidneys. Past studies utilizing BOLD MRI to examine hypoxemia revealed conflicting results due to methodological flaws. This study represents a significant step forward by using ferumoxytol to estimate blood volume to account for variables that affected oxygen estimation with the R2* parameter. There are a number of potential applications for this perfected technology. We now find ourselves in an era of nephrology with an increasing number of tools to affect the progression of chronic kidney disease. Testing the effect of a particular compound on kidney oxygenation could be one possible application. SGLT2 inhibitors slow CKD progression via mechanisms not fully explained by glucose lowering, blood pressure management, or a reduction in intraglomerular pressure. They have been shown to ameliorate hypoxia in the kidney and promote oxygen deprivation signaling, and this may partially mediate their kidney-protective effects. The utilization of BOLD MRI to fully understand these effects could be very useful. The authors additionally mentioned evaluation of oxygenation in the setting of renal artery stenosis, to determine which patients might benefit from interventions. In short, this is a tool that will be very helpful in studying chronic kidney disease, and it will be an exciting area of research to follow in the coming years.

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