Obesity-mediatedhypertension and renal

dysfunction

Gergely Bodor Szegedi Tudományegyetem

Marion Hervouet Université de Nantes

Nicky Honnef VU Amsterdam

Mariarosaria Magaldi Seconda Universita di Napoli

Julie Robert Université de Angers

Tutor : Alina Parvu, Cluj-Napoca

1

Content

Introduction ........................................................................................................................3

Renal structural and functional changes in obesity .......................................................4

Role of adipocytes mediators in obesity .........................................................................6

Renin angiotensin aldosterone system in obesity …......................................................8

Sympathetic nervous system in obesity …......................................................................8

Obesity paradox …..............................................................................................................9

Conclusion ….......................................................................................................................9

Abstract …...........................................................................................................................11

References …......................................................................................................................12

Acknowledgements …........................................................................................................13

2

Introduction

In the past corpulence was considered a sign of good health and being fat an advan-

tage. The potential of harmful effects of excess body weight were appreciated in the 19th

century, but only in the 20th century the complications, increased morbidity and mortality of

obesity began to be documented. Since then, it was indicated that fat cells provide not

merely energy storage but that components of excess adipose tissue function as an en-

docrine organ with multiple detrimental health consequences. Furthermore, it was found that

obesity frequently contributes to the pathogenesis, complicates the course, and increases

the risk of diabetes, hypertension, cardiovascular disease, metabolic syndrome, certain ma-

lignancies, and kidney disease.

The biological mechanisms whereby obesity contributes to chronic kidney disease

(CKD) remain incompletely understood, but it is known that obesity may promote kidney

damage through direct and indirect mechanisms.

Direct mechanisms include renal changes due to some hemodynamic and hormonal

effects. In obesity the presence of large adipocytes is associated with functional and struc-

tural abnormalities of adipose tissue. These include: 1) an insufficient capacity to accommo-

date excess energy-intake related increases in serum lipids, leading to ectopic fat storage in

tissues, which, in turn, enhances insulin resistance and hyperinsulinemia; 2) the increased

production of bioactive molecules, such as adiponectin, leptin, resistin, angiotensinogen,

proinflammatory cytokines, and reactive oxygen species (ROS); (3) augmented macrophage

infiltration of the adipose tissue enhancing the production of proinflammatory cytokines and

ROS. This “dysfunctional” adipose tissue may, in turn, induce activation of the rennin-an-

giotensin-aldosteron system (RAAS) and sympathetic nervous system (SNS), and enhance

systemic oxidative stress, all of which promote the development of obesity-associated hyper-

tension (HT) and CKD.

Indirect mechanisms of CKD development in obesity include coexisting conditions

such as diabetes and HT, the two most common causes of CKD. In obesity HT and diabetes

may interact synergistically to increase the risk of chronic kidney disease (CKD). In the same

time there are also evidences that obesity may cause CKD independent of diabetes and

HT(1), and CKD further increases in blood pressure.

3

Renal structural and functional changes in obesity

Overweight and obesity are heterogeneous

conditions, defined by the World Health

Organization (WHO) as abnormal or excessive fat

accumulation that may impair health, and are

classified according to the calculation of body mass

index (BMI) of weight for height (table 1). BMI has

some limitations as it considers that adipose tissue

is distributed evenly over the body.

Indeed, body shape and more specifically the regional distribution of adipose tissue is

more important than the total amount of body fat in predicting disease-causing complications

associated with obesity. Other markers of adiposity have been evaluated, including waist

circumference and magnetic resonance and computed tomography imaging of visceral fat

and specific ectopic fat depots.

Abdominal obesity is defined as a waist circumference >102cm in men or >88cm in

women. It is part of a phenotype that includes dysfunctional subcutaneous adipose tissue

expansion and ectopic triglyceride storage closely related to clustering cardio-metabolic risk

factors. Visceral obesity refers to the excess intra-abdominal adipose tissue accumulation.

Today, there are evidences that excess visceral fat is the main driving force for most of the

disorders associated with obesity.

CKD was defined by the National Kidney Foundation Kidney Disease Outcomes Quality

Initiative as “the presence of reduced kidney function, or kidney damage, for a period of 3

months or greater”. It was classified in 5 stages, according to the estimated GFR (eGFR),

which is calculated based on the serum creatinine (table 2). CKD is characterized by its

chronicity, because the loss of kidney function persists, and by its constant progression,

because CKD leads to more kidney damages. CKD has also systemic consequences due to

the HT, hemodynamic injury, albuminuria and toxic ions or molecules accumulation.

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Table 2:

Stage Description eGFR(mL/min/1.73 m2)

1 CKD with normal or increased GFR >90

2 Mild GFR loss 60–89

3 Moderate GFR loss 30–59

4 Severe GFR loss 15–29

5 Kidney failure <15 or dialysis

Increased visceral obesity causes renal structural changes due to the increased in-

trarenal physical forces. Ectopic fat accumulation in and around the kidney (“fatty kidneys”)

and increased extracellular matrix deposition within the kidney compresses renal medullary

region. The consequences are increased tubular reabsorption and reduced pressure na-

triuresis. The compensatory responses to the increased tubular sodium reabsorption is a

marked afferent renal artery vasodilatation and increased glomerular filtration rate. Chronic

renal vasodilation causes increased hydrostatic pressure and wall stress in the glomeruli,

and may progress to glomerulosclerosis and loss of nephron function in obese patients. Obe-

sity related glomerulopathy was described as a focal segmental glomerulosclerosis and

glomerulomegaly in patients with a BMI of over 30 kg/m2. It progresses with a low incidence

of nephritic syndrome, and milder foot process fusion (2).

Increased intra-abdominal pressure and resulting changes in renal dynamics may be

a cause for systemic HT in those with central obesity.

Obesity may have additive or synergistic effects to worsen renal function in patients

with pre-existing glomerulopathies or even more subtle renal injury.

Figure 1: Pathophysiological implications of obesity in hypertension and chronic kidney disease

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Role of adipocytes mediators in obesity

Visceral adipose tissue is recognized as an endocrine organ which secretes its own

local and systemic bioactive factors, called adipokines. The most important are: adiponectin,

leptin, resistin, and visfatin. Adipokines have many regulatory functions in different

processes, such as lipid metabolism, inflammation, atherosclerosis, insulin resistance,

immune-stress response, cell adhesion and migration, vascular homeostasis (3). They also

seem to be a linkage between obesity and development of CKD by modulating renal tube

function and the GFR.

Adiponectin is a cardioprotective protein, improving insulin sensitivity and

suppressing ROS production. Adiponectin receptor 1 is mainly expressed in skeletal muscle,

and moderately in other tissues. AdipoR2 is expressed in the liver. With binding to both two

receptors adiponectin icreases the activation of the downstream signaling mediator AMP

activated protein kinase. In the podocytes the AMPK activation downregulates podocyte

NADPH oxidase, and mediates oxidative stress. Interestingly, adiponectin levels are

negatively correlated with percent of body fat and positively with albuminuria. It is decreased

in insulin resistance, type 2 diabetes, cardiovascular diseases and HT. However chronic

kidney disease and type 1 diabetes are associated with elevated adiponectin levels,

unknown why (4).

Leptin belongs to the interleukin-6 family of proinflammatory cytokines. It crosses the

blood-brain barrier, and reaches the brain via a saturable, receptor-mediated transport. Lep-

tin is cleared from the bloodstream by the kidney through glomerular filtration and metabolic

degradation in the proximal tube, where the receptor is the megalin. Leptin is important in

regulating appetite, body weight, and energy balance. Moreover, leptin has a wide range of

biologic actions: effects on the SNS, glucose and insulin metabolism, lipolysis, vascular tone,

the hypothalamic-pituitary-adrenal axis, and reproduction. Normally, leptin alters energy in-

take by decreasing appetite and increasing energy expenditure via SNS stimulation. Leptin

deficiency, or abnormal leptin signaling in the hypothalamus, can lead to obesity. Plasma lep-

tin levels are typically elevated in obese people and are positively correlated with the amount

of adipose tissue. The failure of high levels of leptin in most obese individuals to promote

weight loss is thought to be because of hypothalamic insensitivity to leptin action. It was pro-

posed that hypothalamic leptin resistance in obesity is selective, meaning the appetite-con-

trolling and weight-reducing effects of leptin are disrupted while the excitatory effects on SNS

are maintained. In the cardiovascular the predominant vascular effect of chronic hyper-

leptinemia is a pressor effect mediated by increased SNS activity. Leptin has been found to

increase ROS and ET-1, which might contribute to HT. The leptin level is elevated in patients

with CKD, caused by the decreased clearance (5), (6).

6

Resistin is a recently discovered polypeptide that antagonizes insulin action (named

for resistance to insulin) and may play a part in the pathogenesis of insulin resistance. Re-

sistin is increased in diet-induced and genetic forms of obesity. It is predominantly produced

by macrophages, and with a lower release form adipocytes.

Some hypertensive patients have increased endothelin-1 (ET-1) dependent vasoconstrictor

tone. In addition to direct vasoconstrictor effects of ET-1, impaired nitric oxide bioavailability

as a result of elevated endogenous ET-1 may also contribute to endothelial dysfunction in

obesity.

Visfatin primary source are the adipocytes. Some researchers suggest that visfatin

should be classified as a marker of inflammation. It increases the production of the

inflammatory cytokines TNF-α, IL-6, IL-1B, and ROS. As superoxide production increase

oxidative stress it alters the cell permeability through oxidative stress pathways, leads to

renal pathology. In glomerular mesangial cells elevetad visfatin level resulted in increased

rennin and angiotensin mRNA expression. This changes likely alters the GFR. However, the

role visfatin plays in obesity-related CKD is poorly understood.(7)

Other factors such as oxidative stress and inflammation may also contribute to obesity-

mediated hypertension and renal dysfunction. It was demonstrated that oxidative stress is

evident in the kidney, as shown by 3-nitrotyrosine and protein radical adduct formation in the

glomeruli on high-fat diet, possibly mediated by the parallel increase in inducible NO

synthase (iNOS) and NOX-4 expression. The increased H2O2 emission in the mitochondria

suggests altered redox balance and mitochondrial ROS generation, contributing to the

overall oxidative stress. Oxidative stress was accompanied by morphological changes and a

proinflammatory transition in both the glomeruli and tubuli. Regardless of the oxidative stress

events, the kidney developed an adaptation to maintain normal respiratory function as a

possible response to an increased lipid overload. These findings provide new insights into

the complex role of oxidative stress and mitochondrial redox status in the pathogenesis of

the kidney in obesity and indicate that early oxidative stress-related changes, but not

mitochondrial bioenergetic dysfunction, may contribute to the pathogenesis and development

of obesity-linked chronic kidney diseases.

Adipose tissue has been recognized as an important endocrine organ producing

numerous hormones and cytokines, including proinflammatory factors such as interleukin-

6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and

others. Furthermore, production of proinflammatory cytokines is increased in obese patients,

suggesting the pathogenetic contribution of these factors in development of insulin

resistance, vascular disease, and possibly other related pathologies. Increased release of

proinflammatory factors from adipose tissue may contribute to a systemic subclinical

inflammatory response in patients with obesity and thus promote the development of

insulin resistance and atherosclerosis in these patients. Systemic proinflammatory state in

patients with CKD could accelerate the progression of renal dysfunction. The increase of the7

proinflammatory factors has been explained as the combination of increased systemic

production of these factors because of subclinical inflammation and decreased degradation

in the kidney because of renal insufficiency.

Renin angiotensin aldosterone system in obesity

In physiological conditions RAAS activation is tightly regulated from the total-body

sodium and blood pressure, and it has a crucial role in regulating fluid volume and vascular

tone. When the blood pressure decreases, first renin is produced though three mechanisms:

1) stimulation of the renal sympathic nerves (SNS) by cardio-pulmonar baroreceptor; 2)

stimulation of the Juxtaglomerular cells inside the afferent arteriolar wall; 3) stimulation of the

Macula densa inside the ascending loops of Henle. Then rennin activates angiotensinogen to

angiotensin I and angiotensin-converting enzyme (ACE) stimulates angiotensin II formation.

The angiotensin II main role is to stimulate aldosterone release and also to constrict

arterioles. Aldosterone is a mineralocoticoide hormone that acts on the distal convulated

tubule and the cortical collected ducts and stimulates sodium reabsorption. RAAS limitant

factor is the renin production.

Nevertheless, in case of obesity-related HT and CKD, despite elevated blood

pressure, RAAS activity is increased. Obesity is an expansion of adipose tissue and the

presence of large adipocytes is associated with a huge production of bioactive molecules.

Moreover, adipocytes express angiotensin type 1 and 2 receptor and all RAAS

components(8). In obesity angiotensinogen is produced by adipose tissue and plays a role in

local adipose tissue differentiation. The same angiotensinogen from the adipose tissue can

be released into the blood stream and induces an endocrine effect(9). This suggests that

high blood angiotensinogen and associated hypertension seen in obese patients may be

becaused of the increased fat mass. Furthermore, activation of systemic and tissue RAAS

can cause increased renal sodium reabsorption and a hypertensive shift of pressure

natriuresis. Plasma aldosterone levels are higher in obese subjects, and this change cannot

be explained by the impact of increased plasma rennin activity or other factors promoting

aldosterone production. Aldosterone increases blood pressure in obesity by its action on both

mineralocorticoid and glucocorticoid receptors located in different tissues, including brain,

heart, kidney, and vasculature.

Sympathetic nervous system in obesity

The SNS is important for the regulation of cardiovascular homeostasis. There are

several proposed mechanisms linking obesity with SNS activation: baroreflex dysfunction,

hypothalamic-pituitary axis dysfunction, hyperinsulinemia/insulin resistance, hyperleptinemia,

and elevated circulating angiotensin II concentrations. The increase in renal sympathetic ac-

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tivity in obesity may possibly be necessary for the development of hypertension in obese in-

dividuals, but not a sufficient cause, being present in both normotensive and hypertensive

obese individuals.

Obesity paradox

“Obesity paradox” or “reverse epidemiology” has been consistently reported, and

points out that a higher body mass index (BMI) is paradoxically associated with better

survival. This notion requires a chronic disease in the first place, such as chronic kidney

disease, chronic obstructive pulmonary disease, coronary artery disease, and other

conditions with critical illnesses. Compared with patients with normal weight, patients with

over-weight and even moderate obesity (BMI range between 25 and 35 kg/m2 but not

beyond that) seem to have a better future prognosis. Possible causes of the obesity paradox

include protein-energy wasting and inflammation, time discrepancy among competitive risk

factors (undernutrition versus overnutrition), hemodynamic stability, alteration of circulatory

cytokines, sequestration of uremic toxin in adipose tissue, and endotoxin-lipoprotein

interaction.

Conclusion

CKD is nowadays a public health problem, as its prevalence is still increasing. This is

why a systematic screening for at-risk individuals is recommended. Understanding the

mechanisms linking obesity and CKD is important not only because of the societal health

burden of both conditions but also because novel insights to underlying mechanisms may

lead to new strategies to treat or prevent CKD and its associated comorbidities.

The first treatment for obesity mediated CKD stages 1-4 is body weight reduction in

the form of physical exercise and calorie intake. Reduction weight by calorie restriction is

especially mandatory for patients who are on dialysis treatment. The decreased calories

intake and physical activity improve the insulin sensibility. The biggest part of the lost weight

is fat. The decreased amount of visceral adipose tissue leads to a new adipokine level in the

blood, which is closer to the level of lean individuals. This results decreased SNS activity,

and lower HT. The pathological process stops in the kidneys without high leptin, resistin, and

visfatin level. Since it correlates negatively with the body fat percentage the adiponectin and

its protective effects are increased and help the glomerular regeneration.

Pharmacological treatments are generally unsafe in these patients, and has modest

efficacy. RAAS is an important therapeutic target. This process alters the HT increasing

effects of the SNS, and results in lower blood pressure. Drugs that block this system have

been developed, such as ACE inhibitors and angiotensin receptor blockers (ARB). This

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blocking has been postulated as the first choice for treatment of hypertension in CKD

patients acording to the National Kidney foundation. However, some studies indicated that,

even under appropriate ACE inhibitors or ARB use, the renal end point was reached by

approximately one third of all patients. Several ACE inhibitor trials for CKD patients were

conducted and showed a slower decline in renal function with the use of this class of

antihypertensive medication. In another trial(10), was assessed whether ACE inhibitors

prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal

urinary albumin excretion .The study concluded that the trandolapril or combination of

trandolapril and verapamil reduced the incidence of microalbuminuria. Lately, research is

focussing on combinating treatments with RAAS blockading- and other blood pressure

reducing remedies, as such as a sodium restricted diet. There are studies that reveal the

positive effect of avoiding sodium intake in combination with RAAS blockade therapy(11),

(12). Aliskiren is the first direct renin inhibitor to receive approval for hypertension treatment,

reduces the production of all downstream products derived from angiotensinogen. In

addition, a clinical study reported that aliskiren reduces plasma and urinary excretion of

aldosterone and thus may provide additional renoprotec- tive effects. This drug has been

shown to be an effective antihypertensive agent. However, long-term studies are needed to

demonstrate the efficacy and safety of aliskiren in specific clinical settings(13).

At serious cases only the denervation of the kidneys could be an effective treatment.It

had been proven that adipokines takes their effects on the blood pressure through the SNS.

Renal denervation leads to diuresis and natiuresis. Although this treatment had a significant

effect of lowering the blood pressure and increasing the sensitivity for anti-hypertention

drugs. It was abandoned because of severe complications. Recently, the renal

sympathectomy has been revised and more specifisized. A catheter based device is

developed using radiofrequency energy for the removing of renal nerves via the lumen of the

renal artery. Two clinical trials, known as Symplicity HTN-1(14) and Symplicity HTN-2(15),

show promising results in decreasing the blood pressure without major side effects. Although,

both studies are small and non-randomised controlled.

In obesity, often, occurs an ectopic deposition of lipids into nonadipose tissues, such

as the kidney. This excessive lipid deposition into nonadipose organs can lead to

accumulation of toxic metabolites, such as diacylglycerols and ceramides, derived from

metabolism of fatty acids and sphingolipids. Some metabolites may lead to mitochondrial

dysfunction, endoplasmic reticulum stress, apoptosis, and eventually renal dysfunction and

injury. Supporting this hypothesis is the finding that treatment with 3-hydroxy-3-

methylglutaryl-coenzyme A reductase inhibitors may improve proteinuria and preserve renal

function(16).

There is now convincing evidence of a salutary effect of weight reduction or of

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pharmacological treatment, by bariatric surgery or dietary caloric restriction, on the

proteinuria of obese individuals. Bariatric surgery may be the only option in severe obesity, if

all other measures fail. For obese patients on dialysis treatment, who are eligible for kidney

transplantation, weight loss is mandatory to prevent obesity-related surgical complications

and improve patient and graft survival after transplantation. Interventions should place an

emphasis on exercise to increase muscle mass, and calorie but not protein restriction.

Bariatric surgery should be carried out by experienced surgeons due to the high risk of

complications(17).

Abstract

Obesity, hypertension and chronic kidney disease (CKD) are nowadays a public

health problem, as their prevalence is still increasing.The biological mechanisms whereby

obesity contributes to chronic kidney disease (CKD) remain incompletely understood, but it is

known that obesity may promote kidney damage through direct and indirect mechanisms.

Direct mechanisms include renal changes due to some hemodynamic and hormonal effects.

In obesity the presence of large adipocytes is associated with functional and structural abnor-

malities of adipose tissue. These include: an insufficient capacity to accommodate excess

energy-intake related increases in serum lipids, leading to ectopic fat storage in tissues,

which, in turn, enhances insulin resistance and hyperinsulinemia; the increased production of

bioactive molecules, such as adiponectin, leptin, resistin, angiotensinogen, proinflammatory

cytokines, and reactive oxygen species (ROS); augmented macrophage infiltration of the adi-

pose tissue enhancing the production of proinflammatory cytokines and ROS. This “dysfunc-

tional” adipose tissue may, in turn, induce activation of the rennin-angiotensin-aldosteron sys-

tem (RAAS) and sympathetic nervous system (SNS), and enhance systemic oxidative stress,

all of which promote the development of obesity-associated hypertension (HT) and CKD.

Indirect mechanisms of CKD development in obesity include coexisting conditions such as

diabetes and HT, the two most common causes of CKD. In obesity HT and diabetes may in-

teract synergistically to increase the risk of chronic kidney disease (CKD). In the same time

there are also evidences that obesity may cause CKD independent of diabetes and HT, and

CKD further increases in blood pressure. The treatment options for obesity mediated HT and

CKD are body weight reduction, pharmacological treatments that block the pathogenetic

mechanisms and renal denervation.

Keywords: obesity, hypertension, chronic kidney disease

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Acknowledgement

First and foremost, we would like to express our sincere gratitude and deepest thanks

to our dissertation supervisor Prof. Alina Elena Parvu for her availability in these weeks and

for her patient guidance, encouragement.

Mariarosaria Magaldi, Gergely Bodor, Julie Robert, Marion Hervouet, Nicky Honnef.

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