European Journal of Cardiovascular Medicine

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from defects in insulin secretion, insulin action, or both (1,2). It is associated with long-term damage, dysfunction, and failure of various organs, particularly the eyes, kidneys, nerves, heart, and blood vessels. With an increasing global prevalence, diabetes has emerged as a major public health challenge, particularly in low- and middle-income countries. India, currently home to one of the largest populations of people with diabetes, faces an alarming increase in diabetes-related complications, notably chronic kidney disease (CKD) (3,4).

Diabetic nephropathy (DN), a microvascular complication of diabetes, is the leading cause of end-stage renal disease (ESRD) globally. It has traditionally been diagnosed through the detection of elevated urinary albumin excretion—first as microalbuminuria, and then progressing to overt proteinuria (5,6). However, recent studies have identified a subset of diabetic patients who experience progressive decline in glomerular filtration rate (GFR) despite the absence of albuminuria. This phenotype, known as non-albuminuric diabetic kidney disease (NA-DKD), is increasingly recognized but remains under-investigated, especially in the Indian context (7,8).

Albuminuria, although widely used as an early marker of DN, has several limitations. It can be influenced by various transient factors such as exercise, infection, and hyperglycemia, and may not accurately reflect early structural or functional renal changes in all diabetic patients (9,10). Furthermore, patients with non-albuminuric renal impairment are often overlooked during routine diabetes care, resulting in late diagnosis and missed opportunities for intervention. These individuals are at risk of cardiovascular events, progressive renal decline, and other microvascular complications similar to their albuminuric counterparts (11,12).

GFR estimation, particularly using equations such as the Modification of Diet in Renal Disease (MDRD) or the CKD-EPI formula, provides a more direct measure of renal function and may be useful for early detection of CKD, even in normoalbuminuric individuals (13). Decline in eGFR, independent of albuminuria, has been associated with adverse renal and cardiovascular outcomes, making it a critical marker in the comprehensive evaluation of diabetic kidney disease (14,15).

This study was conducted with the objective of evaluating GFR in normoalbuminuric individuals with Type 1 and Type 2 diabetes mellitus admitted to a tertiary care hospital in South India. By applying the MDRD formula to estimate GFR, the study aimed to identify early renal dysfunction in this subgroup, assess its correlation with clinical and demographic parameters, and advocate for incorporating GFR estimation into standard diabetes screening protocols. Such an approach could lead to improved early detection and management of CKD in the diabetic population, thereby reducing the long-term burden of ESRD.

Study Design and Setting

This was a hospital-based, cross-sectional observational study conducted at the Department of General Medicine, Maharajah Institute of Medical Sciences, Nellimarla, Vizianagaram, Andhra Pradesh. The study was carried out over a 24 month period from 2023 June to 2024 December.

Study Population

A total of 400 patients with diagnosed diabetes mellitus (Type 1 and Type 2) were initially screened. After applying inclusion and exclusion criteria, 185 normoalbuminuric patients were included in the final analysis, comprising 25 patients with Type 1 diabetes mellitus (T1DM) and 160 patients with Type 2 diabetes mellitus (T2DM).

Inclusion Criteria

·         Patients diagnosed with T1DM of ≥10 years’ duration or T2DM aged ≥40 years.

·         Normoalbuminuria

·         Serum creatinine <2.0 mg/dL.

·         Absence of clinical or laboratory evidence of other renal or systemic diseases.

Exclusion Criteria

·         Patients with microalbuminuria, macroalbuminuria, urinary tract infection, heart failure, menstruation, or any acute metabolic crisis (e.g., diabetic ketoacidosis, hyperosmolar state).

·         Patients currently on ACE inhibitors or angiotensin receptor blockers (ARBs).

·         Incomplete clinical or biochemical data.

Clinical Evaluation

Detailed history was obtained, including duration of diabetes, symptoms suggestive of diabetic complications (e.g., neuropathy, cardiovascular disease), and comorbid conditions (e.g., hypertension, coronary artery disease). A thorough physical examination included measurement of height, weight, BMI, blood pressure (average of six readings), and waist circumference. Fundus examination was done by direct ophthalmoscopy to assess for diabetic retinopathy.

Laboratory Investigations

·         Fasting and postprandial blood glucose, serum urea, creatinine, and albumin were measured using an ERB 300 autoanalyzer.

·         Hemoglobin was assessed using an automated coulter counter.

·         Urinalysis included spot urine protein-creatinine ratio and three 24-hour urine collections to confirm normoalbuminuria.

·         GFR was estimated using the Modification of Diet in Renal Disease (MDRD) equation

Statistical analysis:

Data were entered and analyzed using Microsoft excel 2019. Descriptive statistics were used to summarize demographic and clinical characteristics. Chi-square tests and cross-tabulations were applied to assess the relationship between GFR levels and variables such as duration of diabetes, presence of comorbidities, and type of diabetes. A p-value <0.05 was considered statistically significant.

Ethical Considerations

The study received approval from the Institutional Ethics Committee

A total of 185 normoalbuminuric diabetic patients were included in the final analysis. Of these, 25 patients (13.5%) had Type 1 diabetes mellitus (T1DM), and 160 patients (86.5%) had Type 2 diabetes mellitus (T2DM). The overall male-to-female ratio was approximately 1.5:1. The mean age of the study cohort was 52.6 ± 13 years. The average duration of diabetes was significantly longer in the T1DM group (15.5 ± 6 years) compared to the T2DM group (5.2 ± 6 years). Among T1DM patients, 62% had diabetes for 11–15 years, whereas 45% of T2DM patients were recently diagnosed.

A majority of patients—147 out of 185 (79.5%)—exhibited a reduced eGFR (<90 mL/min/1.73m²) despite normoalbuminuria.

• In the T1DM group, 15 patients (60%) had reduced GFR: 12 (48%) were in Stage 2 CKD (GFR 60–89 mL/min) and 3 (12%) in Stage 3 CKD (GFR 30–59 mL/min).
• In the T2DM group, 132 patients (82.5%) had reduced GFR: 37 (23.1%) in Stage 2 and 95 (59.4%) in Stage 3 CKD.

Among males with T2DM, 76 out of 96 had GFR <90 mL/min. Among females with T2DM, 56 out of 64 were similarly affected. No significant sex-based difference in GFR distribution was noted in the T1DM group.

Cardiovascular and Neurological Comorbidities

• Cardiovascular symptoms such as chest pain and past myocardial infarction were reported in 93% of males and 88% of females with T2DM. No cardiovascular events were recorded in T1DM patients.
• Hypertension was present in 52.5% of T2DM males and 47.5% of females; none in the T1DM group had hypertension.
• Diabetic peripheral neuropathy symptoms were reported in 65% of T2DM males and 34% of females. In the T1DM group, 50% of both males and females reported similar symptoms.

Peripheral Vascular Disease and Foot Complications

• Peripheral vascular disease was observed exclusively in the T2DM group—77% of affected males and 23% of females had diminished or absent peripheral pulses.
• Non-healing foot ulcers were also limited to T2DM patients, with 78% of males and 22% of females affected.
• No patient in the T1DM group had signs of vascular insufficiency or foot ulcers.

This study aimed to explore the utility of glomerular filtration rate (GFR) estimation in detecting early renal dysfunction among normoalbuminuric patients with diabetes mellitus, using the MDRD formula. Our findings underscore a significant prevalence of reduced GFR in the absence of albuminuria, particularly among patients with Type 2 diabetes mellitus (T2DM).

Among the 185 diabetic patients studied, 79.5% had GFR values below 90 mL/min/1.73 m², despite no clinical evidence of proteinuria. This challenges the classical model of diabetic nephropathy (DN) progression, which assumes a linear sequence from microalbuminuria to overt proteinuria and finally to declining GFR. Notably, 60% of patients with Type 1 diabetes mellitus (T1DM) and 82.5% of those with T2DM had decreased GFR, demonstrating that non-albuminuric renal impairment is not uncommon in either group.

This finding is in line with recent studies that describe a distinct subset of diabetic kidney disease (DKD) termed “non-albuminuric DKD” (NA-DKD). These patients may progress to advanced stages of CKD without exhibiting micro- or macroalbuminuria, which has long been considered the earliest marker of renal involvement in diabetes. Pathophysiologically, NA-DKD may involve more tubulointerstitial fibrosis, ischemia, or vascular changes rather than glomerular injury, as reflected in lower GFR without albuminuria.

In our cohort, T2DM patients had a higher prevalence of cardiovascular comorbidities—including hypertension (50.6%), coronary artery disease (43.8%), and peripheral vascular disease—compared to T1DM patients. This aligns with prior evidence that cardiovascular disease risk is significantly elevated in patients with declining renal function, independent of albuminuria status. These comorbidities also likely contribute to the observed GFR decline.

The study population's mean age (53 years) and shorter average diabetes duration in T2DM (5 ± 6 years) suggest that reduced GFR can occur early in the disease course, emphasizing the need for routine GFR monitoring in newly diagnosed diabetic individuals. Interestingly, 41% of T2DM patients were recently diagnosed, yet 82.5% already showed signs of renal compromise, suggesting that subclinical kidney damage may precede clinical diagnosis or albuminuria detection.

GFR estimation using equations like MDRD or CKD-EPI provides a valuable non-invasive and cost-effective tool for assessing renal function in diabetes. While serum creatinine alone may appear normal, eGFR can uncover hidden impairment, allowing clinicians to initiate nephroprotective interventions such as tight glycemic and blood pressure control, and use of renin-angiotensin system inhibitors.

This study also supports the emerging clinical paradigm that albuminuria should not be the sole marker of diabetic nephropathy. Comprehensive kidney assessment in diabetes must include both urinary and filtration markers to capture the full spectrum of renal involvement.

Limitations:

This study was cross-sectional and hospital-based, potentially limiting generalizability to the broader community. The MDRD formula, while widely used, has limitations in accuracy among those with near-normal GFR, and may be influenced by nutritional and racial factors. Additionally, lack of cystatin C measurement or renal biopsy restricts deeper phenotypic classification

This study demonstrates that a significant proportion of normoalbuminuric diabetic patients—particularly those with Type 2 diabetes—exhibit reduced glomerular filtration rate (GFR), indicating early renal dysfunction even in the absence of detectable proteinuria. These findings challenge the conventional reliance on albuminuria alone for the early diagnosis of diabetic nephropathy and emphasize the emerging clinical importance of non-albuminuric diabetic kidney disease (NA-DKD). Routine estimation of GFR using formulas such as MDRD can reveal subclinical kidney impairment and should be integrated into standard diabetes care protocols to enable timely intervention, reduce progression to end-stage renal disease, and mitigate cardiovascular risks. A combined assessment of albuminuria and GFR is therefore essential for comprehensive evaluation and early management of diabetic kidney disease.

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