Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)

Diabetes Mellitus is a significant and growing health problem in the United States and other
developed countries. Despite improving public awareness, end-organ complications including
diabetic nephropathy and coronary atherosclerotic heart disease continues to grow by 5-10%
per year. While improvements in the control of blood pressure and the wide-spread use of
antagonists of the renin-angiotensin-aldosterone system have significantly improved renal
outcomes, therapies designed to disrupt the more central pathogenic mechanisms of diabetic
nephropathy are still needed. Recent observations have shown that effacement of podocyte
foot-plate processes and accelerated apoptosis, are central to the pathogenesis of diabetic
nephropathy. The resulting increase in glomerular permeability leads to nephrotic range
proteinuria and interstitial fibrosis from local synthesis of transforming growth factor b
(TGF-b) and direct toxicity to the renal epithelium. Recent studies have shown that synthetic
forms of adrenocorticotropic hormone (ACTH) are able to achieve sustained reductions in
proteinuria in non-diabetic glomerulopathies. Moreover, while the numbers of patients are
quite limited, preliminary studies also suggest that pharmacologic administration of ACTH can
reduce proteinuria in patients with diabetic nephropathy. The observation that ACTH can
reduce proteinuria in a variety of glomerulopathies suggests that ACTH may be important for
podocyte function and viability independent of the primary disease. Interestingly, recent
studies confirm that melanocortin receptors are expressed in non-adrenal tissues including
the circulating T and B cells and most recently the glomerular podocyte. Previous studies
investigating the effect of diabetes and insulin therapy on ACTH levels have given mixed
results. It is therefore unclear how podocytes in patients with diabetic nephropathy could
become functionally deficient in ACTH. However, studies in adrenal cortical cells finds that
TGF-b is able to down regulate the expression of ACTH receptors. Moreover, TGF-b is able
block an ACTH-induced stimulation of melanocortin receptors. This intriguing link between
TGF-b and ACTH signaling raises the question of whether impaired signaling of ACTH in the
glomerulus leads to podocyte dysfunction, accelerated detachment and ultimately podocyte
apoptosis. Moreover, we postulate that a complex interaction between TGF-b and ACTH
expression exists within the glomerulus such that restoration of ACTH function will lead to a
reduction in renal TGF-b expression. We therefore propose to study the effect of increasing
doses of exogenous ACTH on rates of albuminuria and urinary TGF-b expression in diabetics
with nephrotic range proteinuria. In addition to TGF-b we will examine whether a similar
effect occurs on the 3 major isoforms of vascular endothelial growth factor, VEGF120, 164,
and 180. We will also determine the duration of the effect and whether it is additive with
ACE/ARB therapy inhibition.

Inclusion Criteria:

1. Age > 18 and < 80

2. Type I or Type II Diabetes Mellitus

3. Stable ACE or ARB therapy for 4 weeks prior to study enrollment

4. Urinary protein > 3000 mg/24 hrs

5. Patients with more than one protein lowering agent (e.g. ACE or ARB, or MR antagonist
or Tekturna require two consecutive 24 hour urinary protein of 2000 mg/24 hrs.

Exclusion Criteria:

1. Age <18 or >80

2. HgbA1c > 9.0% or 11% if using the (DCCT / NGSP) method.

3. eGFR < 20 mls/min by MDRD formula or eGFR by (Cockoff-Gault 20 mls/min)

4. Dilated cardiomyopathy with known EF < 40%

5. Pregnant or nursing mothers

6. Patients with an admission for diabetic ketoacidosis, or non-ketotic hyperosmolar coma
within 6 months of study enrollment.

7. Patients with known mixed glomerulonephritis and diabetic glomerulopathy

8. Patients within 3 mths of operative procedures or chronic non-healing wounds

9. Patients with glucocorticoid-induced diabetes mellitus

10. Patients with known sensitivity to porcine protein products

11. Patients with bleeding gastric or duodenal ulcers requiring hospitalization six months
prior to study enrollment