We searched PubMed and Medline from Sept 1, 2013, to Jan 31, 2014, with search terms that included but were not restricted to “fatty kidney”, “obesity”, “metabolic syndrome”, “chronic kidney disease”, “ectopic lipid”, “lipotoxicity”, “renal adipogenesis”, “obesity-related glomerulopathy”, “mesangial cells” or “mesangium”, “foam cell transformation”, “podocytes”, “insulin resistance”, “mTOR”, “albuminuria”, “tubular cell”, “renal gluconeogenesis”, “metabolic imaging”, and “treatment” in various
ReviewFatty kidney: emerging role of ectopic lipid in obesity-related renal disease
Introduction
The global increase in chronic kidney disease (CKD) parallels the obesity epidemic.1 Obesity drives two leading causes of CKD worldwide: hypertensive glomerulosclerosis and type 2 diabetic nephropathy, which together account for almost three-quarters of end-stage renal disease.2 Obesity is the central feature of the metabolic syndrome, which further includes renovascular risk factors such as dyslipidaemia, hypertension, and glucose disturbances.3 The risk of CKD increases with the number of metabolic syndrome traits.4 The clustering of obesity-associated risk factors and diseases in so-called metabolically unhealthy obesity distinguishes these people from obese people who do not seem to suffer from their adiposity.5 In particular, a central or visceral body fat distribution has been linked to metabolically unhealthy obesity as well as renal function impairment.6, 7, 8 In this Review, we discuss the emerging role of ectopic lipid (the accumulation of lipid in non-adipose tissue) from metabolically unhealthy obesity as a novel pathway of obesity-related renal disease.
Section snippets
The effect of obesity on CKD
Obese people have an increased risk of progression of CKD that is gradually dependent on the amount of obesity, but independent of hypertension, diabetes, and dyslipidaemia in regression analyses. A longitudinal cohort study9 with more than 8 million person-years of follow-up showed that BMI was an independent risk factor for end-stage renal disease after adjustment for traditional risk factors, including (but not limited to) age, sex, blood pressure, diabetes, and dyslipidaemia. The increased
Glomerular hyperfiltration in obesity
Glomerular hyperfiltration has been hypothesised as a mechanism linking metabolically unhealthy obesity to renal injury.15 Tomaszewski and colleagues20 analysed 1572 healthy young men in a cross-sectional study and observed that those with glomerular hyperfiltration were more obese, hypertensive, and had higher glucose and triglyceride concentrations. The more traits of the metabolic syndrome that were present, the higher the insulin resistance (measured by homoeostatic model assessment) and
Obesity-related glomerulopathy: a hyperfiltration nephropathy
Pathologists increasingly recognise ORG as obesity's histological substrate when no other primary nephropathy is apparent. Alarmingly, a study27 led by D'Agati found a ten-fold increased incidence of ORG in a study of native kidney biopsies between 1986 and 2000. ORG constitutes a secondary form of focal segmental glomerulosclerosis that in addition to sclerosed glomeruli consists of glomerulomegaly (glomerular hypertrophy) with mesangial cell proliferation, matrix accumulation, and a decreased
Obesity beyond Moorhead's lipid nephrotoxicity hypothesis
In 1982, John Moorhead brought together several experimental findings in hyperlipidaemia and renal disease to postulate that concomitant hyperlipidaemia and albuminuria would cause self-perpetuating renal disease through accumulation of lipid in the injured kidney leading to glomerulosclerosis in analogy to atherosclerosis.36 Since Moorhead's seminal research, which focused predominantly on LDL and atheroma, the pathophysiological pathways through which obesity might cause disease have been
Mesangial foam-cell transformation giving way to glomerulomegaly
Mesangial cells are a specialised form of microvascular pericyte in the renal glomerulus that support capillary loops and regulate capillary flow.50 In preclinical models loss of normal pericyte function contributes to microaneurysm formation and glomerular capillary ballooning.51 Mesangial cells are in direct contact with lipoproteins, since there is no basal membrane between glomerular endothelium and mesangium. Much evidence exists linking obesity to endothelial dysfunction of the
From podocyte failure to glomerulopathy
Patients with ORG showed a 45% diminished density of podocytes.28 Podocyte loss is thought to cause further podocyte loss,59 because podocytes are terminally differentiated cells, which are not thought to undergo renewal or division.60 Glomerulomegaly and loss of podocytes consequently place increased mechanical strain on remaining podocytes, which hypertrophy to cover the enlarged and denuded sections of the tuft, but eventually seem to fall short causing a secondary or adaptive focal
Tubular uptake of NEFA-coated albumin driving renal gluconeogenesis
Tobar and colleagues75 also found hypertrophy of proximal tubular epithelial cells in ORG. Proximal tubular cells probably match haemodynamic and metabolic load with growth also via mTOR pathways to compensate for increased sodium and albumin absorption in obesity. Endocytic uptake of albumin is regulated by phosphatidyl inositide 3-kinase, which is upstream of the mTOR pathway.76 Yamahara and colleagues77 showed that obese patients with proteinuria have upregulated mTORC1 in proximal tubular
Lack of early-onset clinical biomarkers
Although initial case reports in the 1970s described a nephrotic syndrome that remitted with weight loss in massive obesity,89 such clinical presentation is rare and a gradual (adaptive) course is seen in most cases.90 In fact, the parallel burden of obesity and CKD at a population level notwithstanding, most people who are overweight or obese will never develop significant CKD. Moreover, around 10–25% of obese patients are deemed to be metabolically healthy.5 Concepts such as metabolic
Non-invasive metabolic imaging of fatty kidney
Proton magnetic resonance spectroscopy (1H-MRS) has evolved in past years in the clinic as a valid non-invasive in-vivo technique95 to study lipid content in tissue such as liver, muscle, and heart.95, 96 Recently, in-vivo proton spectroscopy of human kidney was shown to be feasible (figure 4).97 Total cortical triglyceride content in healthy young volunteers was around 0·44% (SD 0·10).97 Although glomerular versus tubular accumulation was unknown and probably dependent on factors such as
Therapeutic avenues for ORG
A meta-analysis102 of intentional weight loss in obese patients showed normalisation of renal function and reversal of albuminuria, independent of blood pressure. Weight loss prevented further decline in renal function, suggesting reversibility when intervention is made early, closely resembling early diabetic nephropathy. Unfortunately, most weight loss attempts show only temporary results, underscoring the need to explore other therapeutic avenues. Inhibition of the RAAS has long been the
Conclusion
Ectopic lipid accumulation in the kidney (fatty kidney) has emerged in recent years as a novel pathway in obesity-related kidney disease (including type 2 diabetic nephropathy). Fatty kidney not only epitomises metabolically unhealthy obesity from a renal perspective, but also has been associated with obesity-related glomerulopathy, hyperfiltration, renal cell maladaptation, albuminuria, and tubular interstitial injury and fibrosis in various experimental and human biopsy studies. Recent
Search strategy and selection criteria
References (107)
- et al.
Evolving importance of kidney disease: from subspecialty to global health burden
Lancet
(2013) - et al.
Waist-to-hip ratio, body mass index, and subsequent kidney disease and death
Am J Kidney Dis
(2008) - et al.
Prehypertension, obesity, and risk of kidney disease: 20-year follow-up of the HUNT I study in Norway
Am J Kidney Dis
(2009) - et al.
Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis
Am J Kidney Dis
(2001) - et al.
Influence of obesity on the appearance of proteinuria and renal insufficiency after unilateral nephrectomy
Kidney Int
(2000) - et al.
Glomerular hyperfiltration: a new marker of metabolic risk
Kidney Int
(2007) - et al.
The role of the renin-angiotensin-aldosterone system in obesity-related renal diseases
Semin Nephrol
(2013) - et al.
Obesity-related glomerulopathy: an emerging epidemic
Kidney Int
(2001) - et al.
Podocyte lesions in patients with obesity-related glomerulopathy
Am J Kidney Dis
(2006) Obesity-associated focal segmental glomerulosclerosis: pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia
Am J Kidney Dis
(1992)
Renal injury in the extremely obese patients with normal renal function
Kidney Int
Absence of glomerular injury or nephron loss in a normotensive rat remnant kidney model
Kidney Int
Lipid homeostasis, lipotoxicity and the metabolic syndrome
Biochim Biophys Acta
Leukocyte lipid bodies—biogenesis and functions in inflammation
Biochim Biophys Acta
Lipid redistribution in renal dysfunction
Kidney Int
Human mesangial cells express inducible macrophage scavenger receptor
Kidney Int
Apolipoproteins and lipoprotein receptors in glomeruli in human kidney diseases
Kidney Int
IGF-1-induced lipid accumulation impairs mesangial cell migration and contractile function
Kidney Int
Dysregulation of LDL receptor under the influence of inflammatory cytokines: a new pathway for foam cell formation
Kidney Int
mTOR signaling in growth control and disease
Cell
Insulin signaling to the glomerular podocyte is critical for normal kidney function
Cell Metab
Alterations in fatty acid utilization and an impaired antioxidant defense mechanism are early events in podocyte injury: a proteomic analysis
Am J Pathol
CXCL16 is expressed in podocytes and acts as a scavenger receptor for oxidized low-density lipoprotein
Am J Pathol
Glucose control by the kidney: an emerging target in diabetes
Am J Kidney Dis
Absence of hypoalbuminemia despite massive proteinuria in focal segmental glomerulosclerosis secondary to hyperfiltration
Am J Kidney Dis
Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease?
Am J Cardiol
Nephrectomy elicits impact of age and BMI on renal hemodynamics: lower postdonation reserve capacity in older or overweight kidney donors
Am J Transplant
Glomerular volume and renal histology in obese and non-obese living kidney donors
Kidney Int
The GFR and GFR decline cannot be accurately estimated in type 2 diabetics
Kidney Int
Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus
J Am Coll Cardiol
USRDS 2012 annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States
Metabolic syndrome—a new world-wide definition. A consensus statement from the International Diabetes Federation
Diabet Med
Metabolic syndrome and kidney disease: a systematic review and meta-analysis
Clin J Am Soc Nephrol
The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals
Curr Opin Lipidol
Central body fat distribution associates with unfavorable renal hemodynamics independent of body mass index
J Am Soc Nephrol
Banting lecture 1988. Role of insulin resistance in human disease
Diabetes
Body mass index and risk for end-stage renal disease
Ann Intern Med
Waist circumference and waist-hip ratio: report of a WHO expert consultation
Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians?
Diabetes Care
Waist circumference as a measure for indicating need for weight management
BMJ
Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic kidney disease
Clin J Am Soc Nephrol
Adverse renal consequences of obesity
Am J Physiol Renal Physiol
Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults
J Am Soc Nephrol
Fasting insulin modifies the relation between age and renal function
Nephrol Dial Transplant
Glomerular hyperfiltration: definitions, mechanisms and clinical implications
Nat Rev Nephrol
Body mass index and body fat distribution as renal risk factors: a focus on the role of renal haemodynamics
Nephrol Dial Transplant
Insulin's acute effects on glomerular filtration rate correlate with insulin sensitivity whereas insulin's acute effects on proximal tubular sodium reabsorption correlation with salt sensitivity in normal subjects
Nephrol Dial Transplant
Hemodynamically mediated glomerular injury and the progressive nature of kidney disease
Kidney Int
Glomerular hyperfiltration and renal disease progression in type 2 diabetes
Diabetes Care
Pathological influence of obesity on renal structural changes in chronic kidney disease
Clin Exp Nephrol
Cited by (334)
Red ginseng ameliorates lipotoxicity-induced renal fibrosis in hyperuricemia mice
2024, Journal of EthnopharmacologyRole of TFEB-autophagy lysosomal pathway in palmitic acid induced renal tubular epithelial cell injury
2024, Biochemical and Biophysical Research CommunicationsAnti-obesity pharmacotherapy in adults with chronic kidney disease
2024, Kidney InternationalCCDC92 deficiency ameliorates podocyte lipotoxicity in diabetic kidney disease
2024, Metabolism: Clinical and Experimental