Sustained renal function in a person is a fundamental issue affecting not only the quality of life, but also the quantity of life, in point of life span. DM, a chronic disease that is already the leading cause of CKD in many developed and developing countries, is increasing in its prevalence faster than predicted 15–17. Understanding the mechanism of developing CKD in DM patients is crucial for its management and prevention of DKD.
Since the progression of DKD by the pathway of glomerular hyperfiltration followed by albuminuria and proteinuria is a known important mechanism of renal function loss, treatment focusing on this mechanism has been studied and medications that could ameliorate glomerular hyperfiltration like RAS inhibitors and SGLT2 inhibitors are recommended as first-line therapy for this population 18,19. Mineralocorticoid receptor antagonists including finerenone recently developed with beneficial effect on risk of DKD can also reduce urinary albumin-to-creatinine ratio compared to a placebo 20.
There are rising evidence showing that DM patients can develop CKD without the known classic pathway 21. Some studies have investigated the nature of non-albuminuric DKD. A cross-sectional study by MacIsaac et al. in 2004 showed that those with non-albuminuric DM were more likely to be older and females. Decline rates of GFR were not significantly different from albuminuric DM 22. The Japan Diabetes Clinical Data Management study (JDDM15) in 2009 reported those with normoalbuminuric DM and low eGFR were more likely to be older, females, and fewer smokers than those with normoalbuminuric DM and preserved eGFR 23. A study published in 2012 based on The National Health and Nutrition Examination Survey (NHANES) enrolling 2,798 DM and 15,743 non-DM patients demonstrated that DM and women were more common in those with normoalbuminuric CKD 24. On the other hand, a nationally representative cohort study in Australia in 2009 posted that non-albuminuric renal impairment was less common in DM than in the general population independent of sex or DM duration 25. These inconsistent results of previous studies on characteristics of non-albuminuric DKD are probably due to different study populations and designs. This suggests that more studies are needed to confirm the nature of non-albuminuric DKD and the impact of DM itself on renal outcome without the classic pathway of glomerular hyperfiltration or concomitant albuminuria.
The current study tried to figure out the impact of T2D itself on renal outcome by comparing a non-albuminuric T2D population to a non-albuminuric non-T2D population. In this national health examination cohort study, the non-albuminuric T2D group showed a steeper decline of eGFR slope than the non-albuminuric non-T2D group. This result was consistent after adjusting for possible variables. The hazard risk of non-albuminuric T2D on composite renal outcome was 1.57 times higher. This implies that T2D itself without albuminuria is also a risk factor of renal impairment, which strengths the concept of non-albuminuric DKD.
In a mixed linear model to find out risk factors for rapid renal impairment in non-albuminuric DKD, longer T2D duration, older age, higher baseline eGFR, higher BMI, higher CCI, hypertension, and use of RAS inhibitors or statins showed a tendency of a steeper eGFR slope. Duration of T2D showed controversial results in previous studies based on renal biopsies remaking non-diabetic renal disease, with some studies showing shorter duration of T2D as a risk factor of renal impairment 26. Since our study enrolled a large amount of data accounting for relatively healthy people with baseline eGFR higher than 60 ml/min/1.73 m2, it could be more focused on the decline of renal function of general non-albuminuric T2D patients. Some variables showed unexpected results. For example, the usage of RAS inhibitors and statins was related to a steeper decline in annual eGFR. Considering that the current study was based on national health data, it could be interpreted that the usage of those medications known to give beneficial effects of renal protection 27,28 might be expressed as each disease condition of hypertension and dyslipidemia respectively. On the other hand, current smoking and heavy alcohol consumption showed a relatively less steep decline in annual eGFR. Some previous studies have reported similar results on smoking and preserved renal function 23,29. However, results are still uncertain to confirm the relationship between smoking and renal function of those with non-albuminuric T2D since causality is not revealed. One possible hypothesis for this is that healthier, younger people might be more likely to be smokers and alcohol drinkers.
According to our study findings, individuals with T2D without albuminuria might experience declining renal function due to glomerular hyperfiltration even in the absence of albuminuria, as well as longer duration of T2D. The possible mechanism behind our results is that hyperfiltration itself, even without albuminuria, is a risk factor for the decline of renal function considering sequential progression steps of classic DKD 30,31. A longer duration of T2D might also contribute to the worsening of renal function through chronic exposure to hyperglycemic inflammation and oxidative stress as well as endothelial dysfunction 32,33.
In this current study, we demonstrated effects of non-albuminuric T2D on renal outcome. Our study had a strength of being based on a reliable national health cohort that enrolled a large number of subjects with objective health data compared to previous studies regarding non-albuminuric T2D. Since we compared patients with non-albuminuric T2D to those with non-albuminuric non-T2D, we could compare and analyze a relatively pure effect of non-albuminuric T2D on renal outcome.
However, this study also has some limitations. Due to the study design, we could not establish the exact mechanism of causality between non-albuminuric T2D and renal outcome. We reached the conclusion that non-albuminuric T2D could worsen the annual decline of renal function. However, a future study is needed to reveal the exact mechanism for the worsening renal function in T2D besides the classic hyperfiltration-albuminuria pathway. Although our study used relatively long-term data of six years from 2009 to 2015, more reliable results might have been obtained if the study had been conducted for an additional period considering the long course of continuous renal function decline in DM. Lastly, our study excluded T1D. Therefore, we could not evaluate the effect of non-albuminuric T1D on renal outcome.
In conclusion, this nationwide cohort study demonstrated that subjects with non-albuminuric T2D experience a greater annual decline in renal function and a 1.5-fold increased risk of adverse renal outcomes, compared to those with non-albuminuric none-T2D.