With rapid nutrition and lifestyle transitions over the past two decades, the global rate of obesity has been increasing at an alarming rate, including in China [19
]. The frequency of diabetes has risen in tandem, as obesity is a component of risk factors for diabetes [20
]. Today, China has the largest number of patients with obesity and diabetes mellitus in the world. Furthermore, increasing numbers of studies have investigated the relationship between obesity and DN in this ethnic group. This study shows for the first time that obesity and weight loss are common in Chinese patients with biopsy-confirmed DN.
Although all the patients were from a single unit, the profile of patients is representative of the characteristics of Chinese patients with renal disease, especially those in Eastern China. In our institute, there was an abrupt rise in the number of patients undergoing biopsy after 1985, reaching 500 cases per year in 1991, with a further increase to over 1,000 cases per year after 1998 [9
]. Recently, the number of renal biopsies performed each year has exceeded 2,000. The expanded pool of renal biopsies from kidney disease patients makes the epidemiologic investigation more reliable. However, the patients were not regularly interviewed in our institute because of concerns of economy and/or distance. The follow-up information, therefore, was relatively limited. Among all 757 patients with DN, follow-up information was available for only 264 subjects. The baseline characteristics were similar between the 757 patients and 264 patients (data not shown).
In Chinese patients with biopsy-confirmed DN, 22.3% presented with obesity and 53.7% with overweight/obesity. The prevalence of obesity was as high as 24.8% in patients with early stage DN. Compared with the prevalence in the general Chinese population [21
], obesity was more common in the patients with DN. High prevalence of obesity has been confirmed in other ethnic groups [22
]. The obese patients with DN in this study exhibited weight loss with diabetes during follow-up. On average, BMI decreased by 4.62% (2.28 kg/m2
) after 63-months in obese patients, while only moderate decreases were observed in patients at the early stage. This suggested that weight loss was a predictive marker of poor or declining health for diabetic patients, which was consistent with the findings of other studies [23
]. Accordingly, the patients with lean phenotype had a longer duration of diabetes than those with obesity. Compared with obese patients, lean patients exhibited more severe renal injury, including higher percentage of renal insufficiency and a higher score for tubular lesions. Taking the lean group as the reference, obesity and overweight significantly decreased the risk for ESRD. This confirmed that a proportion of lean patients suffer from both DN development and weight loss before renal biopsy, and indicates that weight loss is the major characteristics of the natural course of DN and shows a predictive effect on DN in China. Thus, the lean phenotype indicates disease progression. However, a protective role for obesity in renal disease progression was not identified in this retrospective study.
On the other hand, weight control was generally thought to decrease the risk for renal injury associated with obesity and diabetes. Our previous study also proved that weight loss decreased urinary protein by 51% after 24 months in subjects with obesity-related glomerulopathy (ORG) [24
]. Saiki et al. reported the protective effect of weight loss using a formula diet on renal function in obese patients with DN [25
]. These results contrast with our findings. In fact, more studies have suggested the “obesity paradox” in diabetes and renal diseases [26
]. In the present study, a lean phenotype and weight loss were associated with a “deterioration phenomenon” and progression of renal injury in DN patients in China. On the other hand, obesity contributed to increased proteinuria at the early stage of DN. Among patients at CKD stage I, obese patients showed greater hyperfiltration than lean patients. Obesity further increased the risk for increased proteinuria by 2.872 compared with the lean patients. Similar results were found in the subjects with normal renal function or at the early stage of disease. Thus, the present study using one population of DN patients showed a varied effect of obesity and weight loss on the progression of DN.
Much evidence has shown that the different effect of weight loss resulted from two different mechanisms of weight loss: intentional and unintentional. In brief, diet control and extra exercise leads to intentional weight loss, mainly from the fat mass, thus improving insulin resistance, inflammation, and subsequent renal injury. However, with the progression of diabetes, high sugar levels lead to dehydration, muscle breakdown and an unintentional weight loss, which predicted clinical deterioration. Zoccali [27
] suggested that maintenance of the current weight was the best way to protect against DN. Unfortunately, BMI was the only marker used to evaluate obesity in the present study, and it was difficult to classify the source of weight loss. As a retrospective study, the different effect of weight loss on DN was suggested by the “obesity paradox” with no direct evidence in support of this phenomenon. Further studies, especially prospective cohort studies, are required to compare the effect of intentional and unintentional weight loss on DN, which might help to explain the “obesity paradox” and “weight loss paradox” in China.
It should be pointed out that there are several additional limitations associated with this retrospective study. Serum creatinine levels were used in the present study to define ESRD, although this is not a sufficient measure of the loss of renal function, as it can be influenced by muscle mass, nutritional status and gender. In our institute, patients are usually diagnosed with ESRD, when serum creatinine levels exceed 6 mg/dL for more than 1 month, and other causes of renal disease are excluded. The value of “6 mg/dL” was adopted as a “cut-off” based on the value commonly used in Chinese medical schools [28
]. Although insufficient, serum creatinine is a conveniently tested measure in clinical practice, and was therefore used as a marker of the loss of renal function.
Because of the limitations of this study in terms of population number and follow-up information, the development of ESRD does not reflect the progression of renal injury in all patients with DN. According to the different features of DN at different stages, two end-points were used to assess the progression of DN in the present study. The development of ESRD was used as the first endpoint, and increased proteinuria was used as the second endpoint only for those patients at the early stage. It is well known that early stage patients exhibit micro-albuminuria or moderate proteinuria, with normal levels of serum creatinine [10
]. The levels of albuminuria/proteinuria were shown to be associated with the severity and out-come of renal injury. At a later stage, most patients had gross proteinuria and increased serum creatinine. High levels of serum creatinine are linked with ESRD, while the levels of proteinuria fluctuate with diet and other factors. Using diverse end-points, our study shows that obesity is significantly associated with increased proteinuria in early stage patients, and the lean phenotype is linked with ESRD in all DN patients.
It should also be noted that a direct effect of obesity has been shown on renal function contributing to proteinuria and renal lesions [29
]. Some obese patients probably suffered from ORG prior to the diagnosis of type 2 diabetes or DN. It is difficult to distinguish between these two diseases based on natural history, or from histological features. ORG is characterized by glomerulomegaly and focal segmental glomerulosclerosis, which can also be observed in DN. Patients with DN, especially obese subjects, might present with ORG simultaneously. Previous ORG and/simultaneous ORG partly added to the difference in progression of CKD between lean and overweight/obese patients.