The impact of microalbuminuria and insulin resistance as prognostic biomarker for nephropathy in obese persons: a systematic review

Introduction

The prevalence of chronic vascular dysfunctions, such as diabetes mellitus, and kidney anomaly, is an important and expanding public health issue.¹ The public health issues related to obesity are the result of an epidemiological shift that is taking place in developing countries. The progression and complications of these conditions are linked to vascular damage. In addition, they share many risk factors.² They contribute to the global burden of mortality and disease.³ A significant number of these obesity related complications are not properly diagnosed and treated.³ This has led to the failure of treatment, and the lack of effective primary prevention has contributed to the spread of the obesity epidemic.³ Also, it is known that being overweight is associated with a higher chance of developing kidney anomalies.⁴ Research carried out on a large population at the University of California in 2013 revealed that the baseline body mass index was linked to the likelihood of developing nephropathy.⁴

The initial stages of kidney disease in obese individuals are usually asymptomatic.⁵ The first stages in kidney disease necessitates the use of reliable biomarkers to detect and prevent the progression of this disease.⁵ These should be easy to measure and stay stable in blood or urine for a long time without affecting the chemical composition of the fluid. They should also be high in validity and reliability and examples are albumin, NGAL, N-acetyl-beta-glucosaminidase, cystatin C, interleukin 18, and so on.⁶ Studies have shown that metabolic irregularities characterized by insulin resistance are linked to obesity and can intensify the development and advancement of nephropathy.⁷ Thus, it is suggested that screening for this condition could help predict the likelihood of developing renal damage.⁷ One of the earliest known findings of diabetes nephropathy is microalbuminuria, which is can indicate damage to the filtration action of the kidney.⁸

Studies have shown that elevated microalbuminuria levels can increase the risk of cardiovascular and renal problems in both non- and diabetic patients.^8,9 In addition to microalbuminuria being used as a marker for diabetic patients, this condition is also commonly evaluated for other metabolic disorders.⁹ There has been a strong link between metabolic syndrome and microalbuminuria.¹⁰ Various pathways have been suggested as possible causes of this link, such as the development of adverse effects of inflammatory substances, insulin resistance, and obesity-related kidney disease.¹⁰ Several studies revealed that insulin resistance (IR) is associated with microalbuminuria.^11–15 Compared to individuals without microalbuminuria, those with this condition had a higher insulin resistance rate. The risk of microalbuminuria also increased with IR. There are studies that looked into the effects of insulin resistance on this condition in diabetic individuals which have observed microalbuminuria and kidney related disorders.^16,17

Central obesity is also linked with the development of other conditions, such as insulin resistance, kidney disease, and metabolic disturbances.¹⁸ Research have also suggested that microalbuminuria is linked with central obesity.^18,19 Therefore, the goal of this study is to analyze the impact that microalbuminuria, as well as insulin resistance, play in predicting the severity of nephropathy among obese individuals and also look into these markers in identifying patients with this condition.

Methods

Literature search approach

We did a scientific search using Google Scholar and PubMed until November 2022. All published studies on the impact of Predictive Markers (Microalbuminuria & Insulin Resistance) for Nephropathy in Obese individuals published up to November 2022 were evaluated and the most relevant outcomes were included.

This search was carried out using these particular keywords: Nephropathy, Insulin Resistance, Obesity, Microalbuminuria, Renal insufficiency, and Glomerular Filtration rate.

The PubMed search string used:

((((((((((obesity (Title/Abstract) OR “microalbuminuria*” (Title/Abstract) OR “albuminuria*” (Title/Abstract) OR “insulin resistance*” (Title/Abstract) OR “proteinuria*” (Title/Abstract) OR “WHO*” (Title/Abstract). OR “chronic kidney disease*” (Title/Abstract) OR “ckd*” OR (Title/Abstract) OR “ESRD*” (Title/Abstract) OR “glomerular filtration rate*” (Title/Abstract) OR “nephropathy*” (Title/Abstract) OR “nephritis*” (Title/Abstract) OR “urine albumin*” (Title/Abstract) OR “urine creatinine*” (Title/Abstract) OR “albumin to creatinine ratio*”(Title/Abstract) OR “body mass index*”(Title/Abstract). OR “full text” (Title/Abstract). OR “free full text (sub)” AND “last 10 years (Pat).” AND Humans (mesh).

In addition, the references from retrieved publications were evaluated to identify any qualified research that was missed by the search. Figure 1 shows the search mechanism using PRISMA 2020 guidelines.

Figure 1. The flowchart illustrates the various steps in the selection process for articles.

Results

The PubMed research portal searched the keyword “Microalbuminuria and Nephropathy” and retrieved 5,167 articles, ‘Microalbuminuria and Obesity’ yielded 913, ‘Insulin resistance and Nephropathy’ found 5,589 articles, and ‘Microalbuminuria and Insulin resistance’ yielded 847 articles. Similarly, we searched for all articles on the impact of microalbuminuria and IR as a prognostic biomarker for nephropathy in obese persons. This showed 89 results. After the screening of all articles with the required conditions for eligibility, a total number of 15 studies were analyzed for this review.⁵⁶

Overall, six studies showed positive association between Nephropathy and microalbuminuria, as stated in Table 1. Table 2 shows studies conducted by different country region, showing association between obesity and microalbuminuria, and Table 3 shows association between insulin resistance and nephropathy; all study showed positive association while study conducted by Mamily et al. showed no positive association between insulin resistance and nephropathy.

Figures 2-4 show the link between microalbuminuria and nephropathy, microalbuminuria and obesity, and insulin resistance and nephropathy, respectively.

Figure 2. Forest plot showing the link between microalbuminuria and nephropathy.^22,39–43

Figure 3. Forest plot showing the link between microalbuminuria and obesity.^{19,40,43–48}

Figure 4. Forest plot showing the link between insulin resistance and nephropathy.^{14,16,40,42,43,47,49}

Discussion

The existence of microalbuminuria can be regarded as an early indicator of kidney disease, and persistent cases can also be a reliable indicator of its progression. In this way, early intervention can help prevent kidney disease.^50,51 Also, the progression of diabetic nephropathy can be insidious and lead to major complications for obese individuals.⁵¹ A study from Portugal by Lobato et al. (2003) identified that patients with the presence of microalbuminuria at the early stage are more susceptible to developing nephropathy. Therefore, they concluded that the measurement of microalbuminuria could be a prognostic indicator for renal diseases.³⁹

In cross-sectional research conducted by Kiconco et al. (2019), the appearance of microalbuminuria was assessed among diabetic individuals alongside its impact against other known biomarkers for renal stability during nephropathy.⁴⁰ There were several factors that affected the prevalence of microalbuminuria however, they attributed their variations to population differences, the method of urine collection, measurement of microalbuminuria, and the meaning of microalbuminuria by various laboratories.⁵² They observed a significant relationship among the levels of microalbumin in urine, uric, creatinine, and glucose levels in the serum. There was no association with chloride, sodium, and potassium levels. In synchrony with other studies, they recorded a correlation between microalbuminuria and high level of glucose. Therefore, they conclude that even while other markers are involved, microalbuminuria should be included for better evaluation of nephropathy.⁴⁰

Similarly, a study by Mamilly et al. (2021) highlighted the negative impacts of nephropathy on the prognosis and quality of life.⁴² They concluded that microalbuminuria can serve as an early predictor for nephropathy, however, their results didn’t show any significant correlation between high glucose levels and nephropathy. This raises the notion that the progression of nephropathy may or may not be affected by the variability in glucose levels or the mean of the blood glucose levels. Therefore, more study has to be carried out to understand this process and develop new treatment options.⁴²

In 2014, Yoon et al., carried out a study in Korea on microalbuminuria as an early biological indicator for kidney dysfunction.²² They found out there is still a significant relationship between these two even after some modifications to obesity, age, physical activities, hypertension, high consumption of alcohol, diabetes mellitus, and smoking history.²² Also, Jiang et al. used clinical markers in a multivariable assessment resulting in microalbuminuria having the highest odd ratio for increased estimated glomerular filtration rate.⁴¹ Therefore, not only is this a biomarker for picking on kidney diseases but also an indicator of the deteriorative functions of the kidneys. Diabetes is an established disease that affects the kidneys hence this can also lead to total damage to the kidney if appropriate measures are not put into place. Hence, understanding the influence of insulin resistance and microalbuminuria can help improve insights into the pathogenesis of renal dysfunctions.⁴¹

A population-based study by Bello et al. (2008) revealed that the occurence of microalbuminuria was higher in the relatives of people with chronic kidney disease than in a group matched with age and sex from the general population without the history.⁴³ Similar to this is a study by Tsai et al. (2010) which linked obesity, microalbuminuria, and nephropathy together.⁴⁷ Interestingly, they found out that in the presence of chronic kidney disease, microalbuminuria is higher in women than in males and people with low educational achievements. This is in conjunction with some other papers from the United States that concluded that socioeconomic factors can affect the distribution of microalbuminuria in the general population.^53,54

Furthermore, Ferris et al. (2007) evaluated the association of microalbuminuria as an early renal dysfunction marker among young obese adults.⁴⁴ In this study, they found out that this association has to be a matter of great concern and suggested that obesity may be used as a target for palliative interception for related kidney disturbances. They found out that the highest level of BMI is linked with microalbuminuria, especially in men both black and white. This is also in line with other studies on these aspects.^5,55 Similarly, Hao et al. (2019) and a study from the Peruvian Society of Nephrology support the suggestion that microalbuminuria can serve as an early indication for renal dysfunction in obsess individuals.^45,46

A study by Kim et al., has linked the section of visceral adipose tissue with the increase in microalbuminuria.¹⁹ In their study, the highest value of visceral obesity was significantly linked with the highest degree of microalbuminuria even in the absence of diabetes. It was also potentially associated with overexpressed levels of insulin resistance. Similar to other studies, this association was found to be more prevalent in men than women and this implies that obesity may be expressed differently in both genders.¹⁹

A common type of metabolic abnormality that increases the risk of developing kidney problems is insulin resistance.¹⁵ Research from Lucove et al. (2008) and Chen et al. (2011) supports this statement.^48,49 Chen et al., evaluated the association between metabolic elements and glomerulopathy. They implied that the assessment of the homeostasis model assessment of insulin resistance expresses values that may indicate renal damage in obese individuals. Studies have also suggested that insulin resistance might increase the chances of glomerulosclerosis and proteinuria which will ultimately lead to renal disturbances.⁴⁹ Thus, screening for markers for insulin resistance can help indicate the possibility of early renal damage.

An increasing body of evidence has shown that insulin resistance is linked to hemodynamic changes in the kidneys. It can raise the hydrostatic pressure in the glomerular membrane, increase vascular permeability, and enhance the kidney’s sodium reabsorption.^14,16,17 Hsu et al. (2011) stated that the hemodynamic harmonization and the renal endothelium’s steady state can be affected by the reactions triggered by insulin resistance and that this could shed light on the link between microalbuminuria and insulin resistance. In this prospective study, they concluded that there is a significant correlation between microalbuminuria and insulin resistance in obese persons.¹⁶

Moreso, that obtained from an Iranian study by Esteghamati et al. (2009) revealed that there is a significant association between insulin resistance and urinary albumin excretion in both males and females.¹⁴ Some other studies have reported this association in both sexes^11,12 however, some have had contradictory reports.^36,37 Most of all these associations have been reported in diabetic patients and there a little research on obese persons without a clinical diagnosis of diabetes.

Conclusions

The elevated levels of microalbuminuria in an obese person imply the leakage of albumin from the blood vessels in the kidneys and alongside insulin resistance can result in renal damage and other vascular diseases. Both microalbuminuria and insulin resistance can be biomarkers for vascular dysfunction which can be a part of the early stages of kidney dysfunctions. Although they cannot always predict the progression of this disease, they could help spot individuals at risk of experiencing renal dysfunction symptoms. Understanding the importance of the role these biomarkers play in the health of obese individuals may be very important to prevent nephropathy progression and premature death in both diagnosed and undiagnosed situations.