Slowing or halting renal disease takes multidisciplinary diabetes management, treatment programs.
Kidney disease linked to diabetes, hypertension, and obesity is increasing throughout the world. It is estimated that diabetes leading to end-stage renal disease (ESRD) accounts for 40% of the patients who require kidney transplants in the United States, Europe, Japan, Australia, and New Zealand. An estimated 20% of all patients with ESRD in India and Pakistan have diabetes. The cost is staggering. In the United States, $23 billion was spent in 2001 treating patients with ESRD, and every year and costs are increasing rapidly. Patients with impaired renal function who have not yet developed ESRD are at high risk of hospitalization, cardiovascular complications, and all-cause mortality. So it is surprising that few treatments are available to delay or halt the progression of kidney disease. Innovative and aggressive therapeutic approaches are desperately needed if we are to address this serious public health issue.
BP control is key
Studies over the past two decades have demonstrated that the most effective treatment to date for diabetic nephropathy is tight BP control. However, the likelihood of reaching target BP goals in the private physician office and clinical settings is extremely low due to a variety of reasons including compliance, lack of aggressive treatment by physicians, cost of medications, and side effects. In the UK, for example, it has been estimated that only 5% of CKD patients achieve established BP goals.
Numerous studies have evaluated the effectiveness of various classes of BP medications. Although some controversy still surrounds the preferential renoprotective benefit of the blockers of the renin-angiotensin system (RAS), most investigators and clinicians agree that these drugs are the most efficacious. It is also widely accepted that if optimal control of BP is difficult to achieve, it is advisable to prescribe an ACE inhibitor or angiotensin receptor blocker (ARB), rather than other classes of blood pressure medications as primary treatment.
Although recent studies have clearly demonstrated the efficacy of interrupting the RAS in patients with type 1 and 2 diabetes, the intensive use of ACE inhibitors and ARBs is often limited by severe hyperkalemia and decreased renal function. The goal should always be optimal BP control with RAS inhibitors as long as possible in patients with diabetes and impaired renal function.
The benefit of a multi-pronged approach to clinical management of the diabetic patient has been well established by Denmark’s StenoDiabetesCenter, as well as several smaller centers. By monitoring and controlling BP, glycemic index, lipids, and smoking, the Steno investigators achieved a reduction in all diabetic complications of 50%. There is no reason to think this strategy would not be equally successful elsewhere, but the nature of health-care systems in other countries may prevent this approach from being cost-effective. Even in the United States, where more than $100 billion is spent per year on diabetes treatment, few multidisciplinary programs are dedicated to preventing diabetic nephropathy.
Another important issue affecting diabetes management is the marked discrepancy between levels of glycemic control achieved by endocrinologists compared with internists. Many countries, as well as many states in the United States, have a limited number of practicing endocrinologists. Therefore, the bulk of diabetes management falls to internists and family practitioners, physicians who may be less stringent and comprehensive in their overall approach.
Clearly, multidisciplinary diabetes management and treatment programs are needed. Changes in Medicare reimbursement based on pay for performance may be an appropriate first step to stimulate the medical establishment and private providers to develop models that will focus on reaching target goals rather than emphasizing service and testing. Currently insurance coverage is based purely on the number of medical visits and lab tests, not on outcome measurements such as BP and glycemic control.
Online disease management systems may be a cost-effective and efficient way to make available to larger segments of the diabetic population the expertise of nephrologists and endocrinologists. Innovative approaches based upon various models that address the problem of diabetic nephropathy and other types of CKD should be developed and piloted across different regions. What works for one city or state may not be appropriate for another.
Novel drug therapies
Meanwhile, research has provided a wealth of data regarding the potential pathways by which elevated glucose levels may lead to vascular complications. The translation of basic science to preclinical studies already has been established for many of these pathways. It is encouraging that several academic groups and pharmaceutical companies now view diabetic kidney disease as a very important market.
The new approaches that appear to be closest to reaching the clinic in the next five years are inhibitors of protein kinase C (PKC), a key intracellular signaling pathway, and regulators of renal fibrosis, primarily TGF-b. PKC is stimulated in response to acute and chronic elevations of glucose in a variety of cell types and target tissues. Animal studies have suggested that PKC activation plays a critical role in diabetic retinopathy, neuropathy, cardiomyopathy, and nephropathy. Thus far, one inhibitor against the PKC-b isoform has been studied in clinical trials. PKC-b inhibition reduced vision loss in patients with diabetic retinopathy. Studies with diabetic nephropathy would be of interest and, if successful, would provide a new and potentially low- risk additional disease-modifying agent for nephropathy.