The burden of diabetic nephropathy in India: Need for prevention

1 Introduction

Globally, chronic kidney disease and end-stage renal disease (ESRD) are emerging health problems in people with diabetes. In 2017, there were 697.5 million cases of chronic kidney disease (CKD) worldwide; India is the second most afected country, with 115.1 million cases [1]. India’s total magnitude and pattern of CKD have been reported sporadically. Diabetic nephropathy (DN) refers to the definite pathological, functional, and structural changes in the kidneys of patients with diabetes (types 1 and 2). Clinically, a continuous decline in kidney function and persistent albuminuria are characteristics of DN [2]. Diabetic kidney disease (DKD) is a unique cohort of patients with diabetes and CKD, characteristics can be diagnosed by a decline in glomerular filtration rate/elevated urine albumin excretion, or both. Unlike DN, DKD does not have a definite pathology and may have various other causes. Approximately 30% to 40% of patients with type 1 or type 2 diabetes mellitus (DM) develop DKD [3].

2 Epidemiology of DN

The worldwide prevalence of DN can be attributed to the substantial increase in the incidence of diabetes worldwide. According to the IDF 2021, the number of people afected worldwide has increased by 46.0% to approximately 783 million [4], placing a great socioeconomic burden on patients, healthcare professionals, and the nation. In India, the prevalence of DN ranges from 0.9% to 62.3% [5]. The magnitude of the problem is expected to increase by 170.0% in developing countries [6]. Type 2 DM emerged as the second leading cause of CKD and CKD-related death and was also the third leading cause of CKD-related daily adjusted life-years in 2019. There was an incidence of 2.62 million cases related to CKD and DM globally [1].

In the United Kingdom, the incidence of microalbuminuria in patients with type 2 DM is 2.0% per year, with a prevalence of 25.0% 10 years after diagnosis [7,8]. The prevalence of overt nephropathy and microalbuminuria was 26.9% and 2.2%, respectively, in the Chennai Urban Rural Epidemiology Study (CURES). People with a history of diabetes had higher prevalence rates of both microalbuminuria, retinopathy, and overt nephropathy than newly diagnosed patients [9]. In a 12-year observational study in India, Viswanathan et al. reported that 44.1% of people with type 2 DM developed proteinuria at follow-up [10].

The prevalence of microalbuminuria in patients with a duration of diabetes < 1 year was 24.7% and that of proteinuria was 6.2% [11]. Mir et al. showed that the overall prevalence of nephropathy in newly diagnosed type 2 DM was 32.9% [12]. Dash et al. conducted a prospective observational study to find the frequency of DM as a cause of CKD and the association between diabetic CKD, hypertension (HT), and obesity. Of the 6175 patients, 62.3% had diabetic CKD and 75.4% with primary hypertension developed diabetes and CKD [13]. The association between diabetic CKD and HT and diabetic-CKD and obesity was 55.5% and 78.7%, respectively [13]. All patients with proteinuria had associated diabetic retinopathy compared to those without proteinuria [14]. In a population-based study from Bhopal, ESRD’s crude and age-adjusted incidences were 151 and 232 per million population (p.m.p), respectively [15]. In India, approximately 170,000–250,000 new patients may need renal replacement therapy yearly. The prevalence is estimated to be approximately 55,000 and grows by approximately 10% annually. Approximately 10%–15% of all patients with ESRD receive renal transplant therapy. A high turnover rate has been observed among the dialysis population, as many patients abandon after initiation of dialysis for economic reasons [16].

3 Burden of DN

DN imposes a great economic burden, significantly affecting the patient’s quality of life. The cost of DN increases exponentially as the disease progresses to the advanced stages of CKD. The risk of disease progression is high among people with type 2 DM. A retrospective cohort study showed that patients with stage 4 CKD spent approximately USD 33,162 annually on treatment. In low-and middle-income countries, resources are limited, and proper healthcare coverage is unaffordable to patients. Knowledge of CKD among patients with type 2 DM is of utmost importance as it is a step forward in prevention. One study showed that one-third of the patients identified hypertension and diabetes as risk factors for CKD [17].

Most specialty care, such as dialysis, is provided in the urban sector; therefore, patients must travel with their families, increasing indirect costs. An earlier study from India reported that the monthly average price of dialysis was Rs.12,000, and the annual cost was found to be Rs. 14,000. The average cost of a kidney transplant varies from Rs. 50,000 in a government hospital to Rs. 300,000 INR in an average private hospital [18]. The average annual treatment costs for patients with medication alone and hemodialysis plus medicine were Rs. 25,836 (US $386) and Rs. 213,144 (US $3181), respectively [19]. Patients with ESRD spent more per hospitalization, as most patients have multiple complications and need admission and emergency dialysis.

4 Pathogenesis of DN

The key factors that can be attributed to the pathogenesis of DN are metabolic, hemodynamic, growth, and proinflammatory or profibrotic factors (Figure 1) [20]. Hyperglycemia can induce the aggregation of advanced glycation end products and activate receptor- and non-receptor-mediated pathways. This can lead to tissue injury and organ dysfunction. The by-products of glucose metabolism can activate the hexosamine, polyol, and protein kinase C pathways, which can induce tissue fibrosis and vascular dysfunction. When the pressure within the glomeruli increases, it alters the tone of both the afferent and eferent arterioles. The glucose transport mechanism and insulin by themselves can cause the reabsorption of sodium and glucose in the proximal tubule, activating tubuloglomerular feedback and contributing to hyperfiltration. Growth factors, such as vascular endothelial growth factor, can cause vascular proliferation and hypertensive alterations in the kidneys. Fibrosis and inflammation are both considered significant factors that contribute to the etiology of DN. Chemokines are produced due to trauma or activation of kidney cells, which can stimulate macrophages. These macrophages release cytokines that result in cellular proliferation and eventually cause tissue fibrosis [20].

Figure 1

The pathogenesis of diabetic nephropathy.

The flowchart below illustrates the pathogenesis of diabetic nephropathy, which is characterized by four factors: metabolic, growth, hemodynamic, and proinflammatory or pro-fibrotic [20].

5 Risk factors associated with DN

According to the CURES study, HbA1c, smoking, duration of diabetes, systolic blood pressure, and diastolic blood pressure were associated with microalbuminuria, while HbA1c, duration of diabetes, and systolic blood pressure were associated with overt nephropathy [9].

The risk factors associated with DN can be grouped into two categories: modifiable and non-modifiable (Figure 2) [21].

Figure 2

The various risk factors which are associated with diabetic nephropathy.

The hereditary component of DKD cannot be ignored, as some genetic predispositions and polymorphisms in specific genes have been associated with DKD. In a study by Vijay et al., a strong familial clustering of DKD was observed among siblings in South India [22].

6 Efforts and future solutions

Several longitudinal and cross-sectional studies have reported limited knowledge about CKD among people with diabetes. Only 6% of the public knew that CKD was reported in a cross-sectional study conducted in six parts of the world, including Eastern Asia, Southern Asia, the Middle East, Africa, Eastern Europe, and Latin America. A similar report was observed in the National Health and Nutrition Examination Survey (NHANES) and the Kidney Early Evaluation Program (KEEP); only 9% of patients with DKD were aware of their CKD status [23]. Therefore, the burden of DKD is usually intense in regions with a lower socio- economic status, as the chance of prevention is always neglected.

Due to limited knowledge, most CKD cases are not identi- fied early in disease progression. Therefore, CKD screening is essential; ADA recommends screening for microalbumin- uria 5 years after the diagnosis of type 1 and at the stage of diagnosis of type 2 [24]. It is imperative to understand that increased awareness and education about CKD are neces- sary for people with diabetes and healthcare providers. It is important to develop an effective and affordable early detec- tion tool for CKD and manage risk factors such as hyper- tension, diabetes, obesity, and cardiovascular disease. An integrated approach is essential to promote cost-effective home dialysis modalities, such as peritoneal dialysis, develop affordable dialysis techniques, and increase the resources of the workforce (nephrologists, nephrology nurses, dialysis technicians, and general practitioners). This is due to the alarming fact that 1,850 nephrologists serve 1.3 billion people, of whom are unequally distributed but mainly concentrated in urban centers [25]. Therefore, CKD can be either prevented or its progression can be delayed by cultivating the appropriate support of the government, private sector, non-governmental, and professional organizations in treatment modalities such as kidney replacement therapy delivery along with equity and justice.

7 Conclusion

Over the last decade, CKD has been recognized as a significant global public health problem. Data from different parts of the world confirm the contribution of CKD to the development of CVD and mortality. With increasing urbanization, the number of patients with diabetes is likely to increase in India. In low- and middle-income countries, most patients become aware of their CKD status when they reach the end stage of kidney failure and require dialysis, which is usually unaffordable. Prevention of CKD or a decrease in the progression of CKD will reduce the burden of DN in both patients and the nation. Therefore, early identification and treatment of DN have been shown to slow, stop, or even reverse disease progression and decrease kidney function.