Obesity-related nephropathy (ORG): Pathophysiological mechanisms, clinical manifestations and prevention

I. Overview In 1974, Weisinger et al. first reported massive proteinuria in severely obese patients. Since then, obesity-related nephropathy (ORG) has come to the forefront of research. ORG typically has an insidious onset, with microalbuminuria or clinically overt proteinuria as the primary manifestation, with or without impaired renal function. Renal histology shows significant glomerular enlargement, which can manifest as simple glomerular hypertrophy or focal segmental glomerulosclerosis with glomerular hypertrophy. ORG progresses slowly; without treatment, proteinuria progresses slowly, and a small number of patients may develop renal insufficiency or even end-stage renal disease. Combined with existing domestic and international research, it has been found that the incidence of albuminuria in obese individuals varies by race. A British epidemiological study showed that 27.2% of obese individuals with a body mass index ≥30 kg/m² had albuminuria. A Portuguese study indicated that the prevalence of kidney disease in obese individuals was 33.7%, higher than in most European countries. A retrospective analysis by Chinese scholars of 10,093 renal biopsy cases from 2002 to 2006 showed that the incidence of ORG increased from 0.62% to 1.00% over the five years. Another study in China indicated a 9% incidence of microalbuminuria in individuals with abdominal obesity. It is important to note that studies diagnosing ORG through renal biopsy in obese individuals in China are limited; the actual proportion of kidney damage in obese individuals is likely much higher than the aforementioned figures. II. Pathophysiological Changes: Activation of the RAAS system and alterations in glomerular hemodynamics are the most significant mechanisms in the pathophysiological development of ORG. In obese individuals, the RAAS system is overactivated. Angiotensin II and aldosterone both have vasoconstrictive effects, with a greater effect on the efferent arteriole than the afferent arteriole, leading to efferent arteriole constriction. On the other hand, angiotensin II, sympathetic nerve excitation, insulin, and changes in peritubular colloid osmotic pressure can activate sodium transport proteins, increasing proximal tubular sodium reabsorption, thereby reducing solute transfer to the macula densa, leading to tubuloglomerular feedback inactivation and afferent arteriole dilation. Dilation of the afferent arteriole and constriction of the efferent arteriole lead to increased transmembrane pressure, thereby increasing the glomerular filtration rate (GFR). Activation of the renal arteriosclerosis system (RAAS) can also promote cell proliferation, extracellular matrix accumulation, and tissue fibrosis. In obese patients, increased renal fluid load creates a hyperperfused, high-pressure, and hyperfiltration environment in the glomeruli. This hemodynamic alteration further damages and activates endothelial and mesangial cells, producing and releasing vasoactive mediators, cytokines, and growth factors, thus exacerbating nephron hypertrophy and hemodynamic changes, creating a vicious cycle that ultimately leads to glomerular sclerosis. Furthermore, high-salt, high-protein diets and low nephron counts can also increase the GFR, exacerbating the hyperfiltration state and promoting glomerular sclerosis. Dietary protein load also increases urinary protein excretion, further aggravating the damaging effects of proteinuria. Obese individuals often exhibit insulin resistance. One study showed that among metabolic indicators such as blood lipids, blood glucose, and insulin levels, the insulin resistance index was significantly correlated with the prevalence of ORG (glomerular glomerulonephritis) and positively correlated with proteinuria. Insulin resistance can lead to compensatory insulin secretion, resulting in hyperinsulinemia. Hyperinsulinemia damages vascular endothelial cells and stimulates endothelial cell plasminogen activator inhibitor 1 (PAI-1), leading to renal vascular damage. Insulin can stimulate the excessive production of various cytokines, such as insulin-like growth factor (IGF-1 and IGF-2), further accelerating glomerular hypertrophy. Insulin can also act on podocytes; advanced glycation end products (AGEs) and impaired fatty acid metabolism have potential toxicity to podocytes. Insulin resistance can inhibit fatty acid oxidation in mitochondria, and the accumulated fatty acids cause kidney damage. In addition, insulin resistance can also trigger metabolic syndrome, adipokines dysregulation, and mild systemic inflammation. Obesity, especially central or abdominal obesity, easily leads to fatty acid metabolism disorders and lipid accumulation. Perivascular lipid accumulation can slow renal blood flow and increase sodium reabsorption. Intracellular lipid accumulation can affect the contractile function of glomerular mesangial cells, thereby causing glomerular structural damage and dysfunction. Adipose tissue not only stores and provides energy, but also secretes various adipokines that broadly influence and regulate the body's energy metabolism and various functions, including leptin, adiponectin, endothelin, resistin, type I plasminogen activator inhibitor, angiogenic factor, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and acylated stimulating protein. Leptin can activate the sympathetic nervous system, leading to hypertension and indirectly affecting the kidneys; it can also directly act on the kidneys, causing renal cell fibrosis. The above cytokines can work together to cause oxidative stress and inflammatory responses, creating a low-inflammatory internal environment in obese patients, leading to kidney damage. III. Clinical Manifestations The clinical manifestations of ORG are not specific. It usually occurs in young and middle-aged people, with an insidious onset, mild to moderate proteinuria with or without renal function impairment, and rarely hematuria. Proteinuria progresses slowly, but it can also progress to end-stage renal disease. Early renal changes in obese patients under light microscopy include glomerular hypertrophy, glomerular capsule dilation, increased mesangial matrix, and thickening of the tubular basement membrane. Some patients show glomerular sclerosis or segmental sclerosis, and the interstitium may show fibrosis or localized sclerotic lesions. Mild to moderate sclerosis of small arteries can be seen in the renal vessels. Under fluoroscopic electron microscopy, the nuclei of glomerular endothelial cells appear pyknotous with periphery aggregation of chromatin, the basement membrane shows a double-track sign, podocytes are enlarged with irregular nuclei, mitochondria are swollen, and the foot processes show mild microvilliformization. Some patients also show dilation of the renal papillary ducts and collecting ducts. Immunofluorescence detection shows IgM and complement C3 deposition. Currently, there is no unified diagnostic standard. Clinically, it is mainly based on clinical manifestations and pathological features. The following conditions can be used to diagnose ORG: ① Obesity. The diagnostic criteria for obesity in my country are BMI ≥ 28.0 kg/m², or waist circumference ≥ 85 cm (male) or ≥ 80 cm (female). ② The presence of small to moderate amounts of proteinuria, mainly composed of medium-molecular-weight proteins, or large amounts of proteinuria without obvious edema, hypoalbuminemia, hyperlipidemia, or other nephrotic syndrome manifestations. ③ Enlarged kidney volume and increased glomerular filtration rate. ④ Kidney biopsy showing glomerular hypertrophy or obesity-related focal segmental glomerulosclerosis. ⑤ Exclusion of other related diseases. IV. Treatment and Prognosis 1. Treatment of ORG is based on weight loss, supplemented by measures such as lowering blood pressure, improving insulin resistance, and lowering lipids, thereby reducing proteinuria (controlled to within 1g/day) and delaying the progression of kidney damage. 2. Weight loss is the most economical, effective, and safe treatment method. Weight loss helps improve systemic circulatory pressure and intraglomerular pressure, reducing glomerular hyperfiltration; weight loss can also increase insulin sensitivity. Controlling diet and increasing exercise are effective ways to lose weight. SHEN et al. reported that proteinuria decreased by more than 50% in 63 ORG patients through diet and exercise intervention. For severely obese patients, bariatric surgery has remarkable effects. Hou et al. found that glomerular filtration rate (GFR) significantly improved in severely obese patients after bariatric surgery. 3. The clinical efficacy of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in treating ORG patients is controversial. Some studies have shown that the use of ARBs and ACEIs can significantly improve proteinuria, but long-term follow-up studies have demonstrated that the effect of RAAS blockers in reducing proteinuria can be exhausted over time, especially during periods of further weight gain or cessation of weight loss. 4. Enhancing insulin sensitivity is also an important aspect of ORG treatment. Studies have found that insulin sensitizers such as thiazolidinediones can improve insulin resistance, reduce renal dysfunction, and prevent further deterioration of renal function. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown in animal experiments to improve glucose metabolism while reducing glomerular endothelial damage, lipid oxidation, podocyte damage, and mesangial inflammation, thereby achieving a renal protective effect. 5. Statins, while lowering lipids, also provide endothelial protection and inhibit inflammatory responses. Recent studies have shown that the renal mitochondrial protectant SS-31 can overcome renal cell lipotoxicity by inhibiting the Wnt/nt-linked protein pathway in podocytes, thus providing renal protection. Other studies have also shown that certain drugs may provide specific renal protection by acting on various metabolic, inflammatory pathways, or target organelles. However, these targeted therapies are still in the animal testing phase. International studies have found that the 5-year and 10-year cumulative renal survival rates for ORG patients are 77% and 51%, respectively. However, there are currently few studies on the long-term prognosis of ORG patients in China. A domestic study involving 227 patients showed that the 5-year and 10-year cumulative renal survival rates for ORG patients were 93.6% and 89.9%, respectively. Ultimately, 6.Two percent of patients with ORG progress to ESRD. Early diagnosis and treatment of ORG are crucial factors in delaying the deterioration of renal function. In summary, with obesity becoming a global epidemic, the incidence of ORG is gradually increasing. The clinical manifestations of ORG are nonspecific, and there is currently a lack of unified diagnostic criteria. ORG treatment mainly includes weight loss, improvement of insulin resistance, and inhibition of RAAS activity.