Review
Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease

https://doi.org/10.1016/S2213-8587(14)70065-8Get rights and content

Summary

The global increase in chronic kidney disease (CKD) parallels the obesity epidemic. Obesity conveys a gradual but independent risk of progression of CKD that seems irrespective of the underlying nephropathy. Obesity has been associated with a secondary focal segmental glomerulosclerosis coined obesity-related glomerulopathy (ORG). Pathways through which obesity might cause renal disease are not well understood, and early clinical biomarkers for incipient ORG or renal relevant obesity are currently lacking. Recent human and experimental studies have associated ectopic lipid accumulation in the kidney (fatty kidney) with obesity-related renal disease. There is enough growing insight that ectopic lipid—the accumulation of lipid in non-adipose tissue—is associated with structural and functional changes of mesangial cells, podocytes, and proximal tubular cells to propose the development of ORG as a maladaptive response to hyperfiltration and albuminuria. Recent advances in metabolic imaging might validate ectopic lipid as a biomarker and research aid, to help translate novel therapeutics from experimental models to patients.

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

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

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