Slowing or halting renal disease takes multidisciplinary diabetes management, treatment programs

 

BY KUMAR SHARMA, MD

 

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.

 

Multi-pronged approach

 

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.

 

TGF- β

 

Accumulation of matrix molecules in the glomerulus is a characteristic of established and progressive diabetic nephropathy. Several growth factors and cytokines produced in the kidney appear to contribute to the matrix accumulation and scarring in progressive diabetic nephropathy. Foremost among these is transforming growth factor-β (TGF-β) Our investigative group and many others have found that the TGF-b system is activated and plays a pathogenic role in diabetic kidney disease in both animal and human diabetes models. Approaches that block TGF-βaction and do not rely on glycemic control, BP control, or blocking the RAS axis will provide important additional therapies to prevent progressive diabetic nephropathy and renal failure.

The significant role of TGF-β in mediating mesangial matrix accumulation has now been established in cell culture and animal models of diabetic kidney disease. The use of neutralizing anti-TGF-β have demonstrated that patients with diabetes have increased renal production of TGF-b. This is evidenced not only by increased renal vein blood levels of TGF-b but also increased urinary levels of TGF-β. Urine TGF-β levels may provide insight into the activity of the renal TGF-β system and reflect disease activity.

 

Methods to inhibit TGF-β production or activity may be divided into indirect and direct approaches. Indirect means of inhibiting TGF-β include blocking known stimulators of the TGF-β system, such as ele-vated glucose, RAS, advanced glycated proteins, PKC, hemodynamic stress, and reactive oxygen species generation. There are multiple pathways by which TGF-β may be stimulated, thus complicating the treatment approach to block TGF-β. Direct blockade with antibodies to TGF-β remains a possibility and awaits further clinical developments.

 

Pirfenidone

 

Another anti-fibrotic strategy involves pirfenidone, a low molecular weight synthetic molecule that exerts dramatic anti-fibrotic as well as anti-inflammatory and anti-oxidant activity. Although, the mechanism of action of pirfenidone as an anti-fibrotic agent is not fully understood, data from cell culture and various animal models suggest that pirfenidone is a selective regulator of gene expressions triggered by signals from a variety of cytokine factors, including TGF-β, PDGF, and TNF-α.

 

In addition, pirfenidone reduces the production of other fibrogenic factors such as connective tissue growth factor that are induced by TGF-β. As similar pathologic pathways contribute to the eventual scarring of ESRD from diabetes, it is likely that the combined inhibitory actions of pirfenidone on inflam-mation, growth factor production, fibroblast proliferation and matrix accumulation would be very effective in progressive fibrotic disorders. The combined experience with pirfenidone in limited patient studies and in animal models of progressive kidney disease suggests that the compound is safe and may provide stabilization of renal function, even when administered for a relatively short period.

 

We are conducting an NIH-sponsored study to determine if pirfenidone is beneficial in patients

with progressive diabetic nephropathy. This is the first randomized double-blind study to evaluate the role of this novel anti-fibrotic agent in diabetic nephropathy. Other anti-fibrotic approaches will likely be coming to the clinic in the near future, thus heralding a new wave of therapies aimed at arresting progressive kidney disease.

 

Conclusions

 

The prevalence of CKD, and its associated risk to the cardiovascular system, presents an opportune time for identifying innovative approaches to the treatment of diabetic nephropathy. Disease management approaches similar to the multidisciplinary clinical teams used to treat patients with cancer and heart failure should become the standard of care. Patients with diabetic nephropathy can benefit from early intervention by nephrologists, endocrinologists, and cardiologists. Efficient, cost-effective models that meet target goals should be strongly supported by insurers.

 

Novel therapies are clearly needed for this growing population before complications of CKD and

the need for dialysis overwhelm the health-care system. With recent insights gained from translational studies in diabetic kidney disease, it is likely that within the next 5-10 years, several innovative therapies based on PKC inhibition and anti-fibrotic strategies will become available. Consequently, for a large segment of the at-risk population, there is renewed optimism that diabetic nephropathy may be stopped in its early stages. Such strategies will have major repercussions for our patients and the health-care system.

 

Dr. Sharma is an endowed professor of medicine at JeffersonMedicalCollege and director of

the Center for Novel Therapies for Kidney Disease at ThomasJeffersonUniversityHospital in Philadelphia. Dr. Sharma is also a translational researcher and clinician focused on diabetic kidney disease. His work is funded by grants from the NIH, ADA, and JDRF.