We found that approximately half of the diabetic patients visiting the endocrinology clinic had DKD. The prevalence of DKD was related to age, ranging from 46% in patients aged <60 to 52.8% in those aged >60 years. The following factors were significantly correlated with DKD: older age (>60 years), diabetic microvascular and macrovascular complications, and dyslipidemia. Metformin and RAAS blockers were associated with a lower degree of albuminuria and less advanced CKD.
Our results were in line with the reported prevalence of DKD in the Middle East (33–54.1%) [10, 11]. These studies relied on albuminuria to define DKD and this potentially underestimated the prevalence of DKD in some reports [12,13,14]. The reported overall prevalence in our study was also in line with that reported in the US (54%) [15]. Nevertheless, the prevalence of DKD in younger patients in the US were found to be approximately 25%, as compared with 46% in our population [15]. The higher prevalence of DKD in younger patients is alarming and might result in a public health crisis in the coming years if active intervention is not performed.
The prevalence of DKD increases with age and is more evident by a low eGFR than by albuminuria. This can be explained by the physiological decline in renal function with age, which is associated with a gradual decline in eGFR [16]. This observation was confirmed in our study, wherein the impairment of eGFR with age was more marked than the occurrence of albuminuria.
Our results showed that patients who reported using metformin or RAAS blocker had a lower risk of developing DKD and proteinuria. Metformin is the preferred treatment option for DM type 2 and we found that metformin was negatively associated with DKD, albuminuria, and advanced CKD, consistent with most of the observational studies reporting that metformin is associated with reduced progression to ESKD in type 2 diabetes patients with DKD. However, the reason for these observations remains unknown [17]. In most animal model studies, metformin has shown prominent inhibitory effects on tubulointerstitial fibrosis in both diabetic and non-diabetic models [18]. Further, the long-term benefits of metformin regarding ESKD and cardiovascular disease in patients with moderate CKD have been demonstrated. To achieve the maximal renoprotective benefits of metformin, it may be necessary to use metformin in combination with SGLT2 (Sodium-Glucose co-transporter-2) inhibitors or incretin-based therapies at an early stage of DKD [19]. Unfortunately, metformin should be discontinued in cases of advanced CKD despite this favorable early effect.
Clinical trials have also demonstrated the beneficial effects of RAAS blockers in delaying the progression of DKD. Two large randomized long-term trials, the Angiotensin Antagonist Losartan study [20] and the Irbesartan Diabetic Nephropathy Trial [21] indicated that ARBs are effective in slowing the progression of diabetic nephropathy. These studies have shown that nephroprotection with ACE inhibitors and ARBs was greater than what might be expected due to a reduction in blood pressure. Our study found that RAAS blockers were negatively associated with a lower degree of albuminuria and advanced CKD stage. Many studies have shown that ACEIs and ARBs have beneficial renoprotective effects concerning the progression of DKD in hypertensive diabetic patients and can delay or prevent the development of diabetic nephropathy independently of the beneficial blood pressure-lowering effect in patients with DM type 2 and microalbuminuria [22, 23]. Subsequently, the National Kidney Foundation has recommended using that either ARBs or ACEIs in patients with diabetes regardless of the presence of hypertension.
Albuminuria is considered the first clinical symptom of DKD and is traditionally used as a screening test for DKD. However, mounting evidence suggests that the traditional concept of the natural history of DKD has changed, and a considerable proportion of adult diabetics are normoalbuminuric despite having a low eGFR [24]. The prevalence of normoalbuminuric DKD varies from 14.29 to 56.6% among diabetic patients of different ethnicities [25, 26]. These findings have led the American Diabetes Association to recommend screening DKD based on albuminuria and eGFR to avoid missing cases. In our population, only 5.4% of patients had an eGFR of <60 mL/min/1.73 m2 without evidence of albuminuria.
The association between hypertension and albuminuria is well established but the mechanism is still controversial. It is thought to be an endothelial dysfunction, which is strongly associated with increased cardiovascular risk, and causes renal manifestation. Hypertension is reported in approximately 70–80% of DM type 2 at the time of diagnosis and known to exacerbate diabetic nephropathy [27]. Our study also showed that hypertension was associated with higher degree of albuminuria and DKD in patients with DM type 2.
The association between dyslipidemia and the development of DKD was investigated in several studies, and many epidemiological studies demonstrated an association between diabetic dyslipidemia and DKD [28]. Post-hoc analysis of large interventional studies of high-risk patients with diabetes [29, 30] revealed that high triglyceride and low HDL concentrations were associated with DKD. The ADVANCE study demonstrated that lower baseline HDL levels were a significant and independent predictor of DKD. In contrast, no association was found with the risk of diabetic retinopathy, suggesting that differences may exist in the pathophysiology of these microvascular complications [29]. The FELD study showed that the hypotriglyceridemic drug fenofibrate slowed the decline of renal function and reduced the degree of albuminuria in patients with DM type 2 [30]. Our study also showed that low HDL cholesterol levels and high triglyceride levels were associated with DKD.
There were several limitations to this study. First, the retrospective and the cross-sectional study design introduced recall bias and precluded temporal evaluation of risk factors and outcomes of interest. Therefore, a cause-effect relationship cannot be concluded. However, the data obtained by personal interviews and referring to medical charts minimized the recall bias and improved the data quality.
Second, our study was performed in a tertiary medical center and might not reflect the status-quo of diabetes in Jordan. Nevertheless, this tertiary center provides service to a wide range of patients with different socio-economic backgrounds all over Jordan. Additionally, given the Jordanian population’s unique composition, our findings can be generalized to the middle East. Third, this study had a small sample size for a common disease and did not examine the onset and the course of DKD in the population as the baseline readings of albuminuria and renal function at the time of diagnosis were not available.