Advanced diabetic nephropathy with nephrotic range proteinuria: a pilot study of the long-term efficacy of subcutaneous ACTH gel on proteinuria, progression of CKD, and urinary levels of VEGF and MCP-1

Abstract

Background and objective: Adrenocorticotropic hormone (ACTH) is able to reduce proteinuria in nondiabetic glomerulopathies through activation of melanocortin receptors (MCR) expressed in the podocyte. To determine the efficacy of ACTH, we conducted a randomized, open-label pilot trial of ACTH gel in patients with advanced diabetic nephropathy.

Study design: Twenty-three (23) patients with diabetic nephropathy were randomized to daily subcutaneous (SQ) injections of 16 or 32 units of ACTH gel for six months. Outcome. The primary endpoint was the percentage of patients achieving a complete remission (<300 mg/24 hours) within 6 months. Exploratory endpoints included the percentage of partial (50% reduction) remissions, changes in Cr, and urinary cytokine markers.

Results: After 6 months of ACTH gel therapy, 8 of 14 (57%) patients achieved a complete (n = 1) or partial (n = 7) remission. In the low-dose ACTH gel group (16 units), urinary protein fell from 6709 + 953 to 2224 + 489 mg/24 hrs (P < 0.001). In contrast, 2 of 6 patients in the 32-unit group achieved partial remission, but aggregate proteinuria (5324 + 751 to 5154 + 853 mg/24 hours) did not change. Urinary VEGF increased from 388 to 1346 pg/mg urinary creatinine (P < 0.02) in the low-dose group but remained unchanged in the high-dose group.

Conclusion: ACTH gel stabilizes renal function and reduces urinary protein for up to 6 months after treatment. The ClinTrials.gov identifier is NCT01028287.

Figures

Figure 1

Figure 2

(a) 24-hour urinary protein (grams/24 hrs) is shown for each patient randomized to receive 16 units of ACTH gel SQ daily. Mean proteinuria decreased significantly after six months of therapy. Proteinuria tended to fall for 6 months after stopping ACTH therapy but did not reach statistical significance. (b) 24-hour urinary protein (grams/24 hrs) is shown for each patient randomized to receive 32 units of ACTH gel SQ daily. Mean proteinuria did not decrease after six months of therapy. Proteinuria tended to increase during the six months after stopping ACTH therapy but did not reach statistical significance. Two patients, including one with a late response, achieved a sustained partial remission.

Figure 3

Whisker box plots of 24-hour urinary protein (grams/24 hrs) response for the 16- and 32-unit ACTH groups. A significant reduction in proteinuria is noted for the 16-unit dose at 6 months with a trend toward additional reduction in proteinuria 6 months after withdrawing ACTH. No effect is seen with the 32-unit ACTH dose.

Figure 4

(a) The change in serum creatinine for patients randomized to the 16-unit dose from baseline to 12 months of completion of ACTH therapy. There was no significant change in average serum Cr. A single patient from this group developed ESRD within 17 months. (b) The change in serum creatinine for patients randomized to the 32-unit dose from baseline to 12 months of completion of ACTH therapy. There was a trend toward increased Cr at 12 months, but this difference did not reach statistical significance. Three of six patients in this group developed ESRD within 14.3 months. (c) The change in serum creatinine for age-matched diabetic controls not receiving ACTH therapy. Serum Cr significantly increased (P = 0.001) over 18 months. Of the 23 patients, 12 reached ESRD within 18 months.

Figure 5

The change in urinary VEGF levels among the total group, complete and partial responders, and nonresponders. Urinary VEGF was significantly increased in patients demonstrating complete or partial reduction in urinary protein. (b) The change in urinary MCP-1 levels among the total group, complete and partial responders, and nonresponders. Urinary MCP-1 was unchanged by ACTH therapy.