Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
Condition: Diabetic Nephropathy; Nephrotic Syndrome
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Proteinuria; Nephrotic Syndrome; Nephrosis
Study type: Interventional
Phase: Phase 4

Summary: 
      This is a prospective open labeled trial examining the efficacy of ACTHar Gel (porcine ACTH)
      on the level of proteinuria in patients with diabetic nephropathy and nephrotic range
      proteinuria.
    

Detailed description: 
      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.
    

Intervention name(s): ACTH; ACTH
Intervention type(s): Drug; Drug
Intervention description(s): Patients with nephrotic range proteinuria randomized to this group will receive 16 units ACTHargel sub-cutaneously every day.; Patients with nephrotic range proteinuria randomized to this group will receive 32 units ACTHargel sub-cutaneously every day.
Other intervention name(s): ACTHar Gel; ACTHar Gel
Intervention MeSH terms: Adrenocorticotropic Hormone; Melanocyte-Stimulating Hormones; beta-Endorphin
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diabetic Nephropathy; Nephrotic syndrome