News & Research
Adler, Sharon G., MD
Minocycline: Safe and antiproteinuric treatment for diabetic nephropathy?
Focus: Complications, Complications Nephropathy
Type of Grant: Clinical Translational Research
Project Start Date: January 1, 2009
Project End Date: December 31, 2011
Research Description
Diabetic kidney disease increases cardiovascular mortality and morbidity in patients with Type 2 diabetes (T2DM). ACEi/ARBs slow progression to ESRD, but dosing is limited by side effects. A safe and inexpensive medication that doesn't lower kidney function or blood pressure or raise serum potassium would be a useful adjunct.
Minocycline is a tetracycline with recently appreciated protective properties. Isermann et al showed that minocycline inhibited death of specialized kidney cells in mice, with virtually complete microscopic normalization and prevention of urinary protein loss. Minocycline also lessened kidney injury in a model of non-diabetic kidney disease. A related tetracycline lowered urine protein in diabetic patients. These data support a rationale for testing minocycline in diabetic kidney disease.
Hypothesis: Minocycline will be a safe and and effective anti-proteinuric additional treatment in T2DM patients with proteinuria and normal to low kidney function. Specific Aims: Primary: 1) Assess minocycline safety; and 2) Determine whether minocycline (100 mg po bid for 24 weeks (vs placebo)) when added to a stable regimen of anti-proteinuric medications decreases proteinuria. Specific Aims: Secondary: 1) Compare the variability of different timed urinary collections in minocycline vs placebo patients; and 2) Assess the change in serum cystatin C (a blood test) and creatinine clearance (a urine and blood test) in minocycline vs placebo-treated patients at 24 weeks. These studies test a role for minocycline, a reasonably priced agent with a side-effect profile that differs from current treatments, in lowering proteinuria in diabetes.
Reseacher Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes? The antibiotic minocycline has been shown to have beneficial effects on a mouse model of diabetic kidney disease. This project seeks to test whether minocycline also diminishes proteinuria in patients with diabetic kidney disease, when added to maximal dosing of ACE inhibitors or angiotensin blockers, over a period of 6 months. If this medication is proven to be safe and also to lower proteinuria in patients with diabetic kidney disease, it could be a helpful adjunct to ACE inhibitors and angiotensin receptor blockers, particularly because it does not lower blood pressure or raise serum potassium. If this agent is shown to lower proteinuria, however, additional studies would then be required to test whether it also preserves kidney function over the long-term.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond? ACE inhibitors and angiotensin receptor blockers are the main therapies for slowing progression of kidney disease in patients with nephropathy from diabetes. However, in many patients, maximal dosing of these medications is limited by high serum potassium and low blood pressure. Even under the best of circumstances, in patients with Type 2 diabetes and nephropathy, the relative risk reduction of death, dialysis and kidney disease progression is only about 20%. Diabetes remains the number one cause of kidney failure in patients who need dialysis. Clearly, additional treatment are needed. Minocycline is an inexpensive medication with a reasonable side effect profile that is used in patients with acne. It has not been tested in people to see if it can lower proteinuria. However, in mice with diabetic kidney disease, minocycline prevented proteinuria and improved kidney histology. This study will test whether minocycline is safe in people with diabetic kidney disease, and will also test whether minocycline improves protein losses in patients with diabetic kidney disease. If this study shows that minocycline is safe and effective, in the future it may become a cost-effective adjunct to blockers of the renin-angiotensin-aldosterone pathway for the treatment of diabetic kidney disease.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts? I am a nephrologist and have cared for thousands of patients in whom diabetes has destroyed kidneys, hearts, blood vessels, and nerves. While the USRDS database clearly shows that in the decade since ACE inhibitors and angiotensin receptor blockers have become the standard of care for diabetic kidney disease, the epidemic of diabetic kidney disease is attenuated, diabetes nevertheless remains the number one cause of end stage kidney disease in the US and around the world. It would be personally gratifying if I could contribute to lessening the suffering of people with diabetes by helping to develop a treatment that is cost-effective, has an acceptable side-effect profile, and is additive to the currently available treatments.
In what direction do you see the future of diabetes research going? This clinical trial is limited to determining if the antibiotic minocycline is safe and if it lowers urinary protein excretion. These goals can be accomplished with a relatively small number of participating subjects. Our goal was to enter 120 subjects over the course of 3 years. In most circumstances, lowering proteinuria is associated with preservation of kidney function. However, that is not always the case. The ultimate test of the value of a treatment regimen is its ability to maintain kidney function. Much larger clinical trials are required to answer the latter question. Thus, if this trail shows that minocycline is safe and effective at lowering proteinuria, a larger clinical trial to test its ability to slow the loss of renal function would be indicated.
