Obesity is a well-established independent risk factor for chronic kidney disease. The rising prevalence of childhood obesity is likely to lead to an increase in obesity-related glomerulopathy (ORG). ORG is characterized histologically by glomerular hypertrophy and focal segmental glomerulosclerosis, which can be observed even in children and adolescents with obesity. A key feature of early ORG is an elevated whole-kidney glomerular filtration rate (GFR). While the exact mechanisms behind glomerular hyperfiltration are not fully understood, it is known that it can eventually lead to podocyte detachment, proteinuria, and progression to chronic kidney disease. Moreover, glomerular hyperfiltration has been identified as an independent risk factor for all-cause mortality in seemingly healthy individuals.
In obese adults with chronic kidney disease, weight loss has been shown to improve proteinuria and albuminuria and normalize GFR. However, there is limited research on the effects of weight loss on renal function in children with obesity. A prospective study was conducted to evaluate the impact of a one-year interdisciplinary lifestyle intervention on renal function in children with overweight, obesity, and morbid obesity, while also considering the mediating roles of anthropometric changes and cardiovascular risk markers.
Study Design and Baseline Characteristics
The study included 245 children with an average age of 12.4 years. The baseline characteristics of the participants revealed that 40% were boys, and the mean BMI z-score was 3.46. A significant portion of the children were classified as overweight (14.3%), obese (42.9%), and morbidly obese (42.9%). Glomerular hyperfiltration was observed in 2% to 18% of the participants, depending on the specific definition and equation used. Microalbuminuria was present in seven participants (2.9%).
Correlations at Baseline
At the beginning of the study, eGFR-FAS (estimated GFR using the FAS equation) showed a positive correlation with eGFR-Schwartz (estimated GFR using the Schwartz equation), waist-to-hip ratio, and triacylglyceride concentration. However, no significant correlation was found with fasting glucose concentration or HOMA-IR (Homeostatic Model Assessment for Insulin Resistance). De-indexed eGFR-FAS (eGFR not adjusted for body surface area) was positively correlated with de-indexed eGFR-Schwartz, age, BMI z-score, diastolic blood pressure z-score, fasting glucose concentration, fasting insulin concentration, HOMA-IR, and triacylglyceride concentration. Additionally, de-indexed eGFR-FAS was negatively correlated with HDL-cholesterol concentration. De-indexed eGFR-Schwartz exhibited similar correlations as de-indexed eGFR-FAS, with only slight differences in the correlation coefficients.
Longitudinal Study and Impact of Lifestyle Intervention
A follow-up examination was conducted on 144 participants (58.8%) after approximately one year. The reasons for study discontinuation were documented. Participants who dropped out were significantly older and had higher fasting glucose concentrations and lower total cholesterol concentrations compared to those who completed the study. However, eGFR-Schwartz and eGFR-FAS, as well as the serum creatinine/Q value ratio, did not differ significantly between the two groups. The percentage of participants with glomerular hyperfiltration was also similar, except when using the Schwartz equation with a cutoff of more than 135 ml/min/1.73 m2.
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After approximately one year of lifestyle intervention, significant decreases were observed in BMI-z score, waist-to-hip ratio, diastolic blood pressure z-score, HbA1c, and concentrations of total cholesterol, LDL-cholesterol, and triacylglyceride. Both eGFR-Schwartz and eGFR-FAS also decreased significantly. However, de-indexed eGFR-Schwartz and eGFR-FAS did not show a significant decrease. In fact, de-indexed eGFR-FAS even increased significantly after the intervention, along with BSA, serum creatinine/Q value, fasting glucose concentration, and HOMA-IR.
Subgroup Analysis: Participants with Glomerular Hyperfiltration
In the subgroup of participants who had glomerular hyperfiltration at baseline, de-indexed eGFR showed significant changes after the intervention, depending on the definition used for glomerular hyperfiltration and the eGFR equation.
Postpubertal Adolescents
A subgroup of participants who started the intervention as postpubertal adolescents showed a significant decrease in de-indexed eGFR-Schwartz. However, de-indexed eGFR-FAS did not decrease significantly in this group.
Correlations Post-Intervention
Analysis of post-treatment parameters revealed a correlation between eGFR-FAS and eGFR-Schwartz, fasting insulin concentration, and triacylglyceride concentration. De-indexed eGFR-FAS was positively correlated with de-indexed eGFR-Schwartz, age, BMI z-score, systolic blood pressure z-score, diastolic blood pressure z-score, fasting insulin concentration, HOMA-IR, and triacylglyceride concentration. De-indexed eGFR-FAS was negatively correlated with HDL-cholesterol concentration. De-indexed eGFR-Schwartz showed similar correlations as de-indexed eGFR-FAS, with only minor differences in the correlation coefficients. No associations were found between changes in de-indexed eGFR and changes in BMI z-score, blood pressure, or parameters of glucose and lipid metabolism.
Discussion
This prospective study is the first to evaluate the effect of a multidisciplinary lifestyle intervention on renal function in children and adolescents with overweight, obesity, and morbid obesity without a history of renal disease. Glomerular hyperfiltration was present in 2% to 18% of the participants, depending on the definition and equation used. In the entire group of children, one year of lifestyle intervention did not significantly change eGFR after de-indexing for BSA. However, a significant decrease in eGFR was observed in children with glomerular hyperfiltration at the start of the intervention, even after de-indexing eGFR. This decrease was dependent on the eGFR equation and definition used for glomerular hyperfiltration.
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Since measured GFR was not available in this study, two different equations were used to estimate GFR. Although eGFR-Schwartz and eGFR-FAS correlated well, eGFR according to the Schwartz equation was approximately 5 ml/min/1.73 m2 higher compared to eGFR according to the FAS equation. After the intervention, de-indexed eGFR-Schwartz did not change significantly in the total group of children. However, de-indexed eGFR-FAS increased significantly after the intervention, with a mean increase of 3.5 ml/min. This post-intervention increase in de-indexed eGFR-FAS can be explained by an increase in BSA, as the serum creatinine/Q value increased.
All current eGFR equations have been designed for GFR indexed with BSA. Indexing GFR for BSA is a common practice because it allows direct comparison of GFR values between patients with different body sizes and helps define normal values. While indexation of GFR is theoretically questionable, its consequences are more significant in patients with unusual anthropometry. In obesity, indexing GFR results in a substantially lower GFR than un- or de-indexed GFR. Another argument against indexing GFR in obesity is that the number of nephrons does not increase with increased body fat. By indexing GFR for BSA, one can mask the hyperfiltrative state. Using de-indexed eGFR in the longitudinal study helped avoid bias due to possible changes in weight, length, or BSA.
The pathogenesis of glomerular hyperfiltration in obesity is complex and not completely understood. It involves hormonal factors, including adipokines, overactivity of the renin-angiotensin system, and the renal sympathetic nervous system. Insulin resistance has also been independently associated with glomerular hyperfiltration. More specifically, insulin resistance of podocytes is associated with lipid accumulation in the kidney, known as "fatty kidneys." In diabetes, glomerular hyperfiltration is mediated by the hyperglycaemic period over time. In youth-onset type 2 diabetes, insulin resistance is the most important risk factor for glomerular hyperfiltration.
In this study, de-indexed eGFR was positively correlated with the BMI-z score and HOMA-IR. High glucose levels over time increase the glucose concentration in the ultrafiltrate in the proximal tubule. This induces the expression of the sodium-glucose co-transporter 2 (SGLT2), which enhances the reabsorption of glucose and sodium. The increased sodium reabsorption reduces the sodium concentration in the macula densa lining the distal tubule, leading to dilatation of the afferent arteriole and renin production. Therefore, glucose might indirectly induce glomerular hyperfiltration. Previous research has shown that hyperglycaemic glucose excursions are frequently observed in children with overweight and obesity. Future studies should investigate the association between insulin resistance, the amount of time in a hyperglycaemic state, and glomerular hyperfiltration in children and adolescents with overweight and obesity.
Almost 3% of the children in this study presented with microalbuminuria at baseline, which aligns with other studies in children with obesity. After lifestyle intervention, no difference was observed in the percentages of children with microalbuminuria, which contrasts with findings in obese adults where the urinary albumin to creatinine ratio decreased significantly as a result of weight loss. This discrepancy may be due to an earlier, non-albuminuric phase of obesity-related renal damage present in children compared to adults.
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There are some limitations to this study. First, GFR was estimated using the Schwartz and FAS equations instead of being directly measured. Alternative methods, such as 24-hour urinary creatinine clearance, inulin, or iohexol clearance, were considered too invasive. Second, a random urine spot (RUS) was used for estimating the albumin excretion rate, whereas a 24-hour urine collection is considered the gold standard for determining albuminuria.
Strengths of this study include the large study population and the prospective design. Additionally, the outpatient lifestyle intervention program caused modifications in anthropometric, cardiovascular, and metabolic parameters, making it possible to correlate these alterations with changes in renal function.
Weight Loss, Muscle Mass, and GFR Estimation
Accurate assessment of GFR is essential for evaluating the progression of renal disease, monitoring the effect of interventions on kidney function, and informing drug dosing and patient counseling. However, the optimal methods for measuring kidney function in obese individuals or longitudinally during weight change are uncertain.
Plasma creatinine is commonly used to estimate GFR because it is an inexpensive and reliable index of kidney function. Skeletal muscle mass is the primary determinant of creatinine generation/production, as creatinine is the final catabolite of muscular energetic metabolism. Therefore, changes in body weight, particularly muscle mass, can affect plasma creatinine levels and, consequently, estimates of kidney function, even without actual changes in accurately measured GFR. The impact of these factors on eGFR may depend on the equations used, as the MDRD and CKD-EPI equations include plasma creatinine.
Cystatin C is a filtration marker that is less influenced by changes in muscle mass and may be a more suitable marker of renal function in individuals experiencing rapid and significant weight loss.
A study investigated the effect of substantial weight loss (after Roux-en-Y gastric bypass surgery (RYGB)) on measured GFR (mGFR) (51Cr-EDTA plasma clearance) and estimated GFR (using both plasma creatinine and cystatin C). Dual-energy X-ray absorptiometry (DXA) scans were performed before and after RYGB to estimate changes in skeletal muscle mass.
The study hypothesized that significant weight loss would reduce muscle mass (lean limb mass) and plasma creatinine, leading to increases in eGFR (creatinine-based equations), whereas mGFR and cystatin C-based eGFR would remain unaffected when adjusted for body surface area (BSA).
The results showed that absolute mGFR was reduced, while BSA-corrected mGFR was unchanged. Plasma creatinine was reduced, causing increases in creatinine-based eGFR (MDRD and CKD-EPI), while cystatin C-based eGFR was unchanged (all adjusted for BSA). Lean limb mass, a surrogate measure of skeletal muscle mass, was reduced, which might explain the reduction in plasma creatinine, as a significant correlation was found between these changes.
These findings suggest that for monitoring changes in renal function over time in patients experiencing significant weight loss, cystatin C-based estimates of GFR may be more useful.
Impact of Weight-Reduction Therapies on GFR in Obese Patients with CKD
Weight-reduction therapies, including bariatric surgery (BS), are standard treatments for severely obese patients with type 2 diabetes. However, the outcomes of these therapies for obese patients with chronic kidney disease (CKD) have been inconclusive.
A study used data from the weight Reduction Intervention on GFR in Obese Patients with Renal Impairment-Taipei Medical University (TMU) study, a large, long-term, propensity score-matched cohort study. Patients were stratified based on whether they had undergone BS and into mild, moderate, and high CKD risk groups using the Kidney Disease: Improving Global Outcomes guidelines. The primary outcome was the eGFR calculated using the Taiwan Chronic Kidney Disease-Epidemiology Collaboration equation.
The study included 4332 obese patients. After propensity score matching, 1620 patients were divided into BS or non-surgery groups. The overall mean eGFRs increased in the BS group and decreased in the non-surgery group. In the moderate/high CKD risk BS group, a significant correlation was found between increased eGFR and reduced BMI. Cox regression analysis showed that the BS group had a significantly lower risk of an eGFR decline â¥25% at 12 months.
These findings indicate that bariatric surgery was associated with eGFR preservation in all obese patients, particularly those with moderate-to-high CKD risks.
Severe Obesity and Medical Weight Loss: Impact on Estimated Glomerular Filtration Rate
Numerous studies have demonstrated an association between obesity and chronic kidney disease (CKD). Higher body mass index (BMI) has been linked to lower estimated glomerular filtration rate (eGFR), loss of eGFR over time, and incident end-stage renal disease (ESRD).
A study assessed the association between severe obesity, serum creatinine, and cystatin C, and to assess the impact of substantial medical weight loss on eGFR in individuals with normal fasting glucose (NFG), impaired fasting glucose (IFG), and type 2 diabetes (T2DM) in the short-term (3-to-6 months) and long-term (2-years).
The study included 146 patients enrolled in the University of Michigan Weight Management Program (WMP). The WMP is an intensive, behavioral weight management program that employs a very low energy diet for three-to-six months to achieve a 15% reduction in body weight, followed by reintroduction of regular food stuffs to maintain weight loss for a total of 2 years.
The results showed that eGFR was consistently lower when creatinine-based rather than cystatin C-based estimating equations were used. eGFR was lower when creatinine-based or cystatin C-based equations were indexed to 1.73m2 BSA than when they were indexed to actual BSA. eGFR indexed to actual BSA was more likely to demonstrate hyperfiltration (eGFR â¥135 ml/min) than eGFR indexed to 1.73m2 BSA and decreased into the normal range with weight loss.
These findings suggest that with severe obesity, high fat-free mass and BSA result in low estimates of eGFR indexed to 1.73m2 BSA, especially when creatinine-based estimating equations are used. GFR indexed to actual BSA is approximately 50% higher. When eGFR is indexed to actual BSA, many subjects display evidence of renal hyperfiltration which improves with weight loss.
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