The biological consequence of obesity on the kidney
Abstract
Obesity is a worldwide epidemic that is associated with several health issues, including kidney diseases. A specific kidney disease, referred to as obesity-related glomerulopathy, has been described in earlier publications. Obesity can affect the prognosis of other types of kidney diseases. Body-weight reduction with caloric restriction is an essential therapy, although strictly controlling food intake coupled with an appropriate evaluation is challenging. Low birthweight can be an important factor for obesity and results in kidney dysfunction. In this review, we analyse the consequences of obesity on kidney prognosis and potential strategies for combating obesity-associated kidney injury.
Key words
INTRODUCTION
Obesity, defined as a body mass index (BMI) of > 30 kg/m2, is a significant worldwide health epidemic [1]. The World Health Organization estimates that of more than 1 billion overweight adults, at least 300 million people are obese. Changes in our socioeconomic environment and the worldwide nutrition transition have been hypothesized as drivers of the obesity epidemic in recent decades. Modernization, urbanization and globalization of food markets are several contributors to the obesity epidemic. From a global standpoint, the workplace has become less physically demanding because of technological advancements.
For decades, researchers have investigated an association between obesity and kidney disease. In 1923, Preble [2] studied a series of 1000 obese patients and discovered that 410 of these patients exhibited albuminuria without nephritis. In 1974, Weisinger et al. [3] described the first association between massive obesity and nephrotic syndrome in four patients. The development of glomerulomegaly and focal segmental glomerulosclerosis (FSGS) has been generally associated with massive obesity and recognized as obesity-related glomerulopathy (ORG) [4]. In humans and experimental animal models, the impact of obesity on renal outcome includes structural and functional adaptations, such as increased glomerular filtration rate (GFR), increased renal blood flow and renal hypertrophy [5].
EPIDEMIOLOGY
Although obesity-related proteinuria, especially histological evidence associated with FSGS and glomerulomegaly, is well-known, the majority of the publications on this issue include case reports or autopsy analyses on a small sample of individuals. Therefore, definitive epidemiological data regarding ORG are insufficiently available. From a single-centre review of 6818 kidney biopsies during a 14-year interval, Kambham et al. [4] reported an important retrospective study on ORG. In their study, obese (BMI ≥30 kg/m2) proteinuric patients were found to have ORG when they had glomerulomegaly with FSGS without other causes of FSGS, such as human immunodeficiency virus, heroin abuse and reduced renal mass (n= 57), or glomerulomegaly alone (n = 14) [4]. Other defined primary and secondary glomerular diseases, including diabetic nephropathy and hypertensive nephrosclerosis, were eliminated. They found that the incidence of ORG was increased from 0.2% of the total biopsy in 1990–1996 to 2.0% in 1996–2000 [4]. Such increased trends of ORG in renal biopsy have been described in a Chinese cohort that showed increased trends of ORG from 0.62% in 2002 to 1.0% in 2006. The mean BMI in ORG was 41.7 in the study of Kambham et al. [4], 35.0 in a Spanish cohort [6], 33.6 in a Chinese cohort [7] and 32.4 in a recent report from Japan [8].
ORG is often associated with FSGS-like histological characteristics. While the well-known idiopathic FSGS (i-FSGS) is one of the most severe prognoses in kidney function, ORG-associated FSGS is a less progressive disease and is qualitatively different from i-FSGS. Kambham's study showed that when compared with 50 patients with i-FSGS, ORG patients displayed a significantly lower incidence of nephrotic range proteinuria (48% versus 66%; ORG versus i-FSGS) and of nephrotic syndrome (5.6 versus 54%), higher serum albumin level (3.9 versus 2.9 g/dL), lower serum cholesterol (229 versus 335 mg/dL) and lower ratio of oedema (35 versus 68%) [4]. When renal histology was analysed, ORG patients exhibited fewer segmental sclerotic lesions compared with patients with i-FSGS (10 versus 39%), more glomerulomegaly (100 versus 10%), and less evidence of foot process effacement (40 versus 75%) [4]. In a long-term follow-up analysis (ORG, 27 months; i-FSGS, 38 months), significant renal end points were milder in ORG patients than in i-FSGS patients: serum creatinine doubling (14.3 versus 50%) or end-stage renal disease progression (3.6 versus 42%) [4]. In a Spanish cohort in whom longer kidney survival was analysed, kidney survival of patients with ORG (biopsy-proven evidence of FSGS lesion) was 77% after 5 years and 51% after 10 years, in contrast to kidney survival of patients with i-FSGS, which was 52% after 5 years and 30% after 10 years [6]. Both Chinese [7] and Japanese [8] cohorts showed that ORG is progressive, but not likely as progressive as i-FSGS. Several obese individuals have exhibited subclinical kidney diseases, defined as sclerotic lesions in a few glomeruli in patients with little or mild proteinuria and a normal GFR [9].
Although ORG with glomerular sclerosis has been described elsewhere, massive obesity is not necessarily associated with the presence of glomerular sclerosis; glomerular sclerosis-associated obesity is rare [9]. Autopsy studies have revealed the presence of glomerulomegaly in obese individuals, although glomerular sclerosis has not been frequently detected. Such information indicated that massive obesity alone is not sufficient to induce kidney injury and that potentially the mechanisms underlying the pathogenesis of glomerular sclerosis are not uniformly present in obese people. Alternatively, the unknown genetic background conducive for the development of glomerular sclerosis can contribute to the metabolic and mechanistic stresses. Similarly, the majority of hypertensive individuals never reach end-stage renal failure, with <1% of hypertensive individuals progressing to end-stage renal failure.
PATHOGENESIS OF ORG
Any of the single mechanisms, such as neurohumoral, metabolic, structural and haemodynamic abnormalities that have been linked to the onset of microalbuminuria and decreased renal function, displays a limited potential to initiate overt glomerulosclerosis in obese people. Glomerular hyperfiltration and hypertrophy have been hypothesized to lead to segmental glomerulosclerosis in the obese population [4, 10], as described in patients with reduced renal mass and compensatory states [11]. Haemodynamic factors appear to be pathogenetically important in the association between severe obesity and FSGS, as demonstrated by studies in animals and humans. Hypertension can play an important role in the pathogenesis of secondary FSGS; secondary FSGS is the characteristic of pathological lesions observed in obesity [5]. The prevalence of hypertension can be directly attributed to obesity [12], and such obesity-associated hypertension is believed to play a pathological role in obesity-associated secondary FSGS [13]. Although hypertension is an important candidate mechanism in the pathogenesis of obesity-associated glomerulopathy, mild-to-moderate hypertension is often found in obesity and does not lead to substantial proteinuria or FSGS, in the absence of other contributing factors [14]. In this section, we discuss each candidate mechanism that is likely to be associated with obesity-related kidney injury.
HYPERFILTRATION AND HYPERTROPHY IN GLOMERULI
Frequent associations of obesity and increased GFR in both experimental animal models and humans have been demonstrated. Therefore, we acknowledge that increased metabolic demands in obese individuals lead to glomerular hyperfiltration [11], with compensatory hypertrophy of kidney and glomerulus [15]. Human studies also exhibited obesity-associated abnormal renal haemodynamics, such as increased GFR and renal blood flow. Chagnac et al. [16] reported that obese individuals display 61% higher GFR with 28% higher renal plasma flow and 29% higher filtration fraction than control subjects. Increased filtration fractions would result in haemoconcentration of post-glomerular circulation and increased plasma oncotic pressure of the peritubular capillaries. Such high oncotic pressure in the peritubular capillaries can promote proximal tubular sodium reabsorption, which leads to salt retention and systemic hypertension [17]. Obesity-associated glomerular hypertrophy, hyperfiltration and systemic hypertension might enhance an individual's susceptibility to hypertensive renal damage and barotrauma [5].
RENIN–ANGIOTENSIN SYSTEM
Similar to other proteinuric kidney diseases, the enhanced renin–angiotensin system (RAS) contributes to the pathogenesis of ORG; therefore, blockade of RAS provides blood pressure-independent renoprotection in ORG [5]. Angiotensin II can display deleterious effects via either haemodynamic or non-haemodynamic direct tissue damage-dependent pathway [18]. Although such a hypothesis of deleterious effects of angiotensin II on the renal system has been described elsewhere, we lack the direct mechanistic evidence to show specific pathogenic effects of angiotensin II on ORG [5], because we have derived information from non-obese experimental and clinical settings rather than from obesity models [5]. Nevertheless, RAS blockade with the appropriate use of diuretics might be effective in controlling blood pressure and reducing proteinuria in most individuals with ORG.
DYSLIPIDEMIA
Dyslipidemia has been linked to the development of i-FSGS because of glomerular lipid deposition and foam cell formation [19]. Low-density lipoprotein-aphaeresis has been shown to ameliorate steroid-resistant i-FSGS by reducing proteinuria and increasing serum albumin levels in a short interval [20]. Clinically, dyslipidemia and lipotoxicity might be relevant in the pathogenesis of ORG and might be a therapeutic target, although most of the results were obtained from preclinical analyses. Zucker fatty rat (ZFR), used in the analyses [21], displayed marked dyslipidemia; intervention with lipid-lowering drugs substantially ameliorated the onset of proteinuria and glomerulosclerosis without curing glomerular hypertrophy [21].
It is unclear how amelioration of lipid metabolism defects can inhibit the progression of glomerulosclerosis. To investigate this subject, Jiang et al. [22] analysed diet-induced obesity (DIO) models in C57Bl6 mice and found that increased renal expression of sterol regulatory element-binding proteins (SREBP-1 and SREBP-2) in C57Bl/6J mice was associated with cholesterol and triglyceride accumulation in the kidney; when fed the same diet, A/J mice displayed neither lipid accumulation in the kidney nor SREBP induction. These authors also found that SREBP-1c-deficient mice were protected from high-fat diet (HFD)-induced lipid accumulation in the kidney and fibrogenic molecule induction [22]. Recently, heart-type fatty acid-binding protein (H-FABP or FABP3) has been shown to be induced in ORG-affected kidney glomeruli [23], which suggests that H-FABP contributed to lipid dysregulation in ORG kidney.
HYPERLEPTINEMIA
Leptin levels in urine in Pima Indians have exhibited both a positive association with albuminuria and a negative association with GFR [24]. Leptin has been considered to stimulate fibrogenic cytokine expression, which contributes to glomerular sclerosis and tubule-interstitial fibrosis [25]. Leptin likely plays a pathogenic role in the onset of hypertension in obese individuals [25], although information about its fibrogenic role is limited. ZFR and db/db mice, with their leptin signalling completely shut down [1], exhibit a deficiency in leptin receptors and display significant obesity and glomerulosclerosis. Therefore, the phenotypes in these obese model animals were found to be independent of leptin receptor-mediated signalling. A pharmacological concentration of leptin in rats induced mild proteinuria and type II collagen expression (both 2–3-fold) via increased TGF-β1 production without altering blood pressure [26]. Nevertheless, leptin signalling cannot be the major inducer of ORG, but it can likely facilitate the phenotype.
ANIMAL MODELS
In addition to ORG, obesity exhibits a clear correlation with diverse chronic diseases. To understand the pathomechanisms in human disease, we need relevant animal models [1]. Interestingly, even in mouse models, different strains of mice exhibit different phenotypes: either genomic-mutation or HFD-induced DIO. Apart from rodent models, obese dogs have also been analysed as a model system to investigate ORG [15]. Medaka fish, Oryzias latipes, exhibits HFD-induced ORG [27]. We summarized ORG or relevant obesity animal models in Table 1.
Table 1.
Diverse obesity models and kidney phenotypes.
THERAPEUTIC FOR ORG
Body weight reduction and RAS blockade
Both weight reduction and an RAS blockade can dramatically reduce urine protein excretion (up to 80–85%) in patients with ORG [28]. A total of 63 patients with renal biopsy-proven ORG were subject to nutrition with exercise intervention in a physician-supervised weight loss programme [29]. After 24 months, a BMI reduction of ∼9% resulted in a 51.33% reduction of urine protein excretion [29]. The effects of body weight reduction were observed 6 months later, when an 8.29% reduction in BMI was reached [29]. In addition, body-weight reduction by bariatric surgery has been associated with reductions in both urine albumin excretion and creatinine clearance [30]. However, it is unclear whether such a body-weight reduction intervention can cure the histological FSGS in ORG.
Sleep apnoea
There are several pathogenic connections between ORG and obesity-associated sleep apnoea syndrome; a cure for sleep apnoea displayed total resolution of the proteinuria [31]. However, a follow-up study of patients with varying degrees of sleep apnoea could not demonstrate the association between proteinuria and the presence or severity of sleep apnoea [32]. Sleep apnoea has been shown to be associated with glomerulomegaly even without detectable proteinuria in an extremely obese cohort [33]. In patients with sleep apnoea, albuminuria was induced during sleep, whereas in control subjects, urine albumin levels were suppressed during sleep [34]. Continuous positive airway pressure (CPAP) reduced urine albumin levels during sleep, and the effects of CPAP were stronger in the population with non-dipping phenomenon of blood pressure [34]. Therefore, the renal effects of sleep apnoea itself may not be directly associated with kidney glomerulus structure, but they may be a secondary effect associated with haemodynamic alterations.
PERSPECTIVE: FOR THE NEXT GENERATION
Nephron number: possible connection with other kidney function
Hyperfiltration could contribute to the pathogenesis of ORG; however, the pathomechanisms and the general application of the hyperfiltration theory to humans remain controversial. Remnant kidney in humans by extensive surgical removal of renal parenchyma has been associated with proteinuria, progressive renal insufficiency and biopsy-proven glomerulomegaly with FSGS [35, 36]. However, subsequent analyses of similar population results showed contradictory data [37]. Unilateral renal agenesis is another case in which glomerular injury can be induced in a similar fashion [38], although a significant number of patients with such congenital abnormality can maintain normal renal function without any proteinuria throughout their lifetime.
Gonzalez et al. [39] described the factors affecting the progression of renal damage in patients with unilateral renal agenesis and remnant kidney. Thirty-four of 54 patients displayed a diverse degree of proteinuria and renal insufficiency; the remaining 20 patients had normal kidney function without proteinuria. The most striking difference between the groups was BMI (29 ± 7.4 kg/m2 in the renal dysfunction group versus 24 ± 4.1 kg/m2 in the normal renal function group) [39]. A long-term follow-up study (100 ± 72 months) in the same population demonstrated that 45% of the cohort developed proteinuria or renal insufficiency and that renal dysfunction in this cohort exhibited higher BMI (27 ± 3.6 kg/m2) compared with that of the kidney without any sign of such damage (21.6 ± 2.6 kg/m2) [39]. These results indicate that overweight/obesity is an essential factor associated with the deterioration of renal function and a significant reduction in renal mass. Therefore, a synergistic interaction between reduced renal mass and obesity-induced haemodynamic changes could be relevant in the progression of renal damage in such a population with reduced renal mass.
Such renal mass reduction is not restricted in surgical resection of the kidney or renal agenesis. This theory could be relevant in all of the patients with some of chronic kidney disease patients [11]. The nephron number has been shown to be significantly associated with birthweight, and the low-birthweight population has been shown to develop metabolic syndrome and obesity in adulthood [11]. The offspring of malnourished pregnant rats displayed low birthweight with small kidney, pancreas and liver, although these small pups experienced an accelerated growth with hyperphagia, hyperinsulinemia, abdominal obesity and hypertension later in life [40]. Researchers have described similar observations in children with low birthweight who often display an exaggerated growth in weight and BMI compared with their height during childhood and adolescence [41]; these observations suggest compensatory growth in such a population as well as associated health problems, such as obesity, diabetes, hypertension and kidney deficiency. The prevalence of such low birthweight and future obesity in adults is common in developing countries with poor socioeconomic status [42]. Therefore, it is critical to devise strategies for managing ORG patients and combating ORG, gestational intervention with appropriate education and guidance for nutritional support.
CONCLUSIONS
Recent epidemiological studies have shown that obesity poses a significant risk for the new-onset kidney diseases [43]. To treat current ORG patients, we realize that the therapeutic options can be limited and that the best option is body-weight reduction. To avoid epidemic obesity-associated health problems, we must think about our next generation, who will need sufficient medical access, proper nutritional support, appropriate education and a better environment without exposure to potentially poisonous or toxic molecules.
FUNDING
Author's laboratory is supported by grants from the Japan Society for the Promotion of Science and by several other foundation grants.
- © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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