Age at onset of type 1 diabetes between puberty and 30 years old is associated with increased diabetic nephropathy risk

In this registry study, the prevalence of diabetic nephropathy in patients with type 1 diabetes in Taiwan was 16.7%, with a mean diabetes duration of 14.5 years. Longer duration, higher HbA1c, SBP, and plasma triglyceride level, diabetic retinopathy, hospitalization in the past 3 years were independently associated with the presence of diabetic nephropathy in patients with type 1 diabetes. Age at onset of type 1 diabetes between puberty and under 30 years old was also independently associated with higher presence rate of diabetic nephropathy after adjusting diabetes duration. To the best of our knowledge, this is the first Asian-Pacific multicenter diabetes registration study that demonstrated type 1 diabetes diagnosed between puberty and under 30 years old is associated with higher prevalence of diabetic nephropathy.

Compared with our cohort, one prospective study from the UK indicated that the cumulative incidence of microalbuminuria was 25.7% and 50.7% after 10 and 19 years of diabetes, respectively²⁴. This difference in incidence may be attributed to both genetic susceptibility and environmental triggers^25,26. In the recent Genome-Wide Association Study²⁷, Caucasian and Chinese populations have been shown to share different type 1 diabetes risk loci, and several environmental factors were identified to affect the incidence of type 1 DM²⁸. Another important factor affected diabetic nephropathy risk was the onset age of type 1 diabetes. Patients with type 1 diabetes diagnosed between puberty and under 30 years old had higher odds compared with pre-puberty onset group (OR 95% CI 1.61, 1.11–2.34; p = 0.012) in this study. In our following stepwise multivariate logistic regression model for diabetic nephropathy, patients who diagnosed type 1 diabetes between puberty and under 30 years old also have higher odds for diabetic nephropathy (OR 95% CI 1.56, 1.05–2.34, p = 0.029). Puberty has been considered as an important but controversial independent risk factor of type 1 diabetic nephropathy. Several studies demonstrated that albuminuria and variation in renal function during puberty changed more rapidly than those in pre-puberty group^29,30. Although previous studies showed that patients with type 1 diabetes with onset age during puberty would have higher risk of developing diabetic nephropathy than those with onset age during pre-puberty^15,31,32, these studies only included patients with type 1 diabetes diagnosed during childhood and adolescence, but the patients with type 1 diabetes between 18 and under 30 years old were not investigated. Recent cohort in Finland showed most type 1 diabetes diagnosed younger than 5 years had lower residual serum C-peptide level and progressed faster to absolute insulin deficiency, and was associated with higher HbA1c, higher percentage with nephropathy, retinopathy, and hypertension than older onset groups³³. However, in Finland diabetes registry, patients with type 1 diabetes diagnosed between 10 and 14 years old group have the highest relative risk of ESRD (compared to age of onset < 5 years old), suggesting pubertal onset of type 1 diabetes may have an accelerating role in kidney damage³⁴. In contrast, a Swedish diabetes registry showed that the risk of ESRD seemed different between gender. The age at onset 20–34 years conferred the highest risk of developing diabetic nephropathy in male, but the highest risk of onset age in female was 10–19 years³⁵. Another type 1 diabetes cohort in Korea demonstrated patients with type 1 diabetes diagnosed at childhood/adolescent (age < 20 years) had higher prevalence of diabetes nephropathy than in older onset groups, and the degree of eGFR decrease was more prominent in the childhood/adolescent-onset group than in the older onset group¹⁷. In contrast, a population-based retrospective cohort study of type 1 diabetes in Hong Kong showed that people with type 1 diabetes diagnosed aged older than 40 years had a higher hazards of end stage renal disease (ESRD) versus those diagnosed aged less than 20 years¹⁶. The above studies on type 1 diabetes cohort showed different onset age group of type 1 diabetes had different prevalence of diabetic nephropathy. Some reported patients diagnosed type 1 diabetes at younger age had higher prevalence of diabetic nephropathy^17,33, and one showed type 1 diabetes diagnosed older than 40 years had a higher risk to develop ESRD¹⁶. This discrepancy among the previous studies and our study may be due to the different genetic backgrounds of ethnic difference, the cohort including LADA with the mixture of type 1 and type 2 diabetes, and the grouping of onset age not according to the puberty. It needs further investigation to elucidate the impact of puberty on the development of diabetic nephropathy and decline rate of eGFR in patients with type 1 diabetes. In our study, we found that the onset of type 1 diabetes between puberty and 30 years old was associated with a higher prevalence of diabetic nephropathy, even after adjusting for disease duration, which supported the hypothesis that post-puberty related hormone disturbance would induce insulin resistance, resulting more contribution in diabetic complications than pre-puberty ones. From the treatment point of view, more stringent glycemic and blood pressure control, and early detection of microalbuminuria or deterioration of eGFR are especially important in patients with type 1 diabetes diagnosed between puberty and under 30 years old.

Regarding diabetic nephropathy risk factors, our findings were consistent with Diabetes Control and Complications Trial (DCCT) cohort, which increased mean HbA1c, SBP, increased mean triglyceride level and longer diabetes duration were associated with presenting microalbuminuria¹⁰. According to Taiwan’s NHI medical claims (1995–2017), in type 1 diabetes patients with a family history of type 2 diabetes, the adjusted hazard ratio for nephropathy was also higher (HR 95% CI 1.44, 1.27–1.64) compared with those without a family history of type 2 DM³⁶. Similarly, type 1 DM patients in this study who had a family history of diabetes had higher odds of having diabetic nephropathy (OR 95% CI 1.91, 1.34–2.72; p < 0.001). In this study, a higher percentage of diabetic nephropathy patients had coexisting CAD and heart failure, which may have contributed to a higher percentage of hospitalization in the past 3 years in the diabetic nephropathy group than in the non-diabetic nephropathy group. Diabetic retinopathy, especially in the proliferative retinopathy group, was also more prevalent in type 1 diabetes patients with diabetic nephropathy in our study. According to the literature, the presence of a pre-existing microvascular complication (retinopathy or nephropathy) may contribute to the development of another complication, especially in patients with type 1 diabetes³⁷. In the Steno study, which observed 220 patients with type 1 diabetes with and without nephropathy in a 15 year-follow-up study, those developed gross proteinuria were found to have a higher risk of progression to proliferative retinopathy (12% annually) as compared with those without nephropathy (1–2% annually)³⁸. In the EURODIAB Complications Study, retinopathy at baseline in type 1 DM patients was positively associated with new-onset microalbuminuria (53.2%) after 15 years, and it was more frequent among proliferative retinopathy group (67.2%)³⁹. Chronic hyperglycemia, which is measured by mean blood glucose or HbA1c levels, has been linked to the development and progression of microvascular complications⁴⁰. In this study, we also found that a higher HbA1c level was positively associated with the presence of diabetic nephropathy. In this study, patients with type 1 DM who were taking ACEI or ARB had higher odds for the diagnosis of diabetic nephropathy. Because this registration cohort was a cross-sectional study, only association could be found, but no causal relationship could be determined. This finding may be due to the higher SBP and DBP found in patients with diabetic nephropathy, which led to more patients with diabetic nephropathy receiving ACEI/ARB compared to non-diabetic nephropathy. ACEI and ARB was preferred as first-line therapy to patient with UACR ≥ 30 mg/g to slow down the progression⁴¹. It is well documented that higher triglyceride and cholesterol levels are associated with a more rapid decline in kidney function⁴². Dyslipidemia may directly affect the kidney by disturbing the renal lipid homeostasis. Further, it indirectly affects the kidneys through systemic inflammation, oxidative stress, and vascular injury^43,44. A population-based prospective cohort study in Hong Kong showed smoking, increased HbA1c level, hypertension, albuminuria, and dyslipidemia were associated with greater risk of ESRD in patients with youth-onset type 1 diabetes (age at onset of type 1 DM < 20 years old)⁴⁵. The identified risk factors associated with ESRD are similar with the risk factors associated with diabetic nephropathy in patients with type 1 diabetes in our study. However, our study emphasized on the onset age of type 1 diabetes after puberty, instead of only diabetes duration, is associated with higher prevalence of diabetic nephropathy, which was not emphasized in the above study⁴⁵.

Some of the strengths of this study are as follows: first, this was the first nationwide registration cohort of type 1 diabetes which emphasized on the impact of onset age of type 1 diabetes on diabetic nephropathy, especially between puberty to under 30 years old. As we excluded LADA (age of onset ≥ 30 years old) group in our statical analysis, the interference of diabetic nephropathy risk factors (more related to type 2 diabetes) was mitigated. Second, detailed information about anthropometric characteristics, family history, comorbidity, diabetes-related complications, medications, and laboratory data were collected, which greatly decreased the bias of making inappropriate inference.

However, our study also had some limitations. First, since this is a cross-sectional study, the efficacy of causal association may be weaker than that of longitudinal cohort studies. Since we lacked exposure period of drugs and baseline kidney function before recruitment, it is difficult to answer the use of ACEi/ARB was before or after diabetic nephropathy noticed, as well as excluding any systemic factors such as systemic lupus erythematosus which may also lead to proteinuria. However, since type 1 diabetes is a relatively young onset disease, we could only assume that the proteinuria was mostly associated with diabetes. Second, 274 (30.5%) of the total patients lacked urine albumin-to-creatinine ratio (UACR), which may strongly influence our diabetic nephropathy classification. Therefore, we applied a conversion equation from urine dipstick protein to UACR for the missing data, which was validated in a meta-analysis²³. Third, the mean age of menarche could be estimated with a shift of 0.43 years per decade in previous Taiwan study²⁰. However, studies referred to puberty onset shift among male are scarce, which the exact cutoff was difficult to be confirmed. Lastly, the total number of participants in the study was approximately 900, which may not be sufficient for extrapolation of our findings to other type 1 diabetes populations with a higher incidence of type 1 diabetes as well as to populations of other ethnicities. Additional limitation of questionnaire including not specifying type 1 or type 2 diabetes in diabetes family history and hospitalization reason were also noted.

In conclusion, we identified several modifiable risk factors of diabetic nephropathy in patients with type 1 diabetes from the nationwide registration of the type 1 diabetes cohort in Taiwan. These included poor glycemic control, high SBP, and high serum triglyceride levels. In addition, we identified that patients with type 1 diabetes diagnosed between puberty and under 30 years old was associated with higher prevalence of diabetic nephropathy in patients with type 1 diabetes. Finally, we found a lower rate of ACEI or ARB use in type 1 DM patients with diabetic nephropathy, which could be a room for improvement to our daily practice.

Since ACEI or ARB prescription is recommended in patient with diabetic nephropathy in both American Diabetes Association (ADA)⁴¹ and Diabetes Association of the Republic of China (DAROC) type 1 diabetes guideline⁴⁶, our government has implemented the policy for screening all diabetic patients at least annually for UACR, and strongly suggest further semi-annually follow-up if the result was abnormal. As there were only 20% of prescription rate of ACEI or ARB and short consultation time for doctors spending on patients in Taiwan (less than 5 min)⁴⁷, enhancing the awareness of the clinicians to regular check proteinuria and a pop-up reminder implemented in electronic medical record (EMR) system would be an applicable solution in raising ACEI/ARB prescription rate. All the above findings are informative and will be helpful to emphasize the screening for proteinuria in daily clinical practice and diabetes self-management education to improve the quality of care for patients with type 1 diabetes.