Purpose:A synthetic adrenocorticotropin (ACTH) analog has shown efficacy in Europe as primary and secondary therapy for nephrotic syndrome, but there is no published experience using the natural, highly purified ACTH gel formulation, available in the United States, for nephrotic syndrome. We therefore investigated the use of ACTH gel for nephrotic syndrome in the United States.Patients and methods:Twenty-one patients with nephrotic syndrome treated with ACTH gel outside of research settings in the United States, with initiation of therapy by December 31, 2009, allowing a minimum 6 months follow-up. We defined complete remission as stable renal function with proteinuria falling to <500 mg/day, and partial remission as stable renal function with >50% reduction in proteinuria from 500 to 3500 mg/day.Results:Twenty-one patients with nephrotic syndrome were treated: 11 with idiopathic membranous nephropathy (iMN), 4 with membranoproliferative glomerulonephritis (MPGN), 1 with focal segmental glomerulosclerosis (FSGS), 1 with minimal change disease (MCD), 1 with immunoglobulin A (IgA) nephropathy, 1 with class V systemic lupus erythematosus (SLE) glomerulonephritis, 1 with monoclonal diffuse proliferative glomerulonephritis, and 1 with unbiopsied nephrotic syndrome. ACTH was used as primary therapy for 3 patients; the remaining patients had previously failed a mean 2.3 immunosuppressive regimens. Eleven patients achieved a complete or partial remission, with 4 (19%) in complete remission. Of the 11 patients who achieved remission, 9 had iMN, 1 had FSGS, and 1 had IgA nephropathy. Of the 11 patients with iMN, 3 (27%) achieved complete remission and 6 (55%) achieved partial remission despite having previously failed a mean 2.4 therapies. Five patients reported steroid-like adverse effects, but there were no severe infections. The limitations were retrospective data analysis with short-term follow-up.Conclusion:ACTH gel may be a viable treatment option for resistant nephrotic syndrome due to membranous nephropathy. Short-term data suggest that remission rates may approach 80%.

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Vitamin D-dependent calcium-binding protein (CaBP) was localized in tissue sections of kidneys from rabbits, rats, and chicks using antiserum specific for chick intestinal CaBP. In rabbit kidney, CaBP was present in all cells of the distal convoluted tubule and most cells of the connecting tubule. Fewer, but still a majority, of the cells of cortical collecting ducts contained CaBP. The intensity of immunochemical staining and the number of stained cells decreased markedly in medullary collecting ducts, and only a few collecting duct cells contained CaBP at the junction of the inner and outer medulla. In the rat kidney, CaBP was present in all distal convoluted tubule cells, but the immunochemical staining was less intense than in the rabbit. The protein also was found in most connecting tubule cells of the rat; however, only a few collecting duct cells in the superficial corte of the rat contained CaBP. CaBP was essentially absent from mid- to deep-cortical collecting duct cells, while a very few collecting duct cells always contained CaBP at the junction of the inner and outer stripes of the outer medulla. In the chick, CaBP was present in distal convoluted tubule cells as the distal convoluted tubule coursed adjacent to the central vein. CaBP was absent from chick collecting duct cells. In all three species CaBP was not detected in the other portions of the nephron.

Cortical thick ascending limbs of Henle's loop were dissected from rabbit kidneys and perfused in vitro. Unidirectional transepithelial calcium fluxes from lumen-to-bath and bath-to-lumen were measured with 45Ca. The tubules were bathed in 150 mM sodium and perfused with 60 mM sodium to simulate conditions in the cortical thick ascending limb in vivo. During the 20-30 min preceding the addition of parathyroid hormone (PTH), net calcium absorption decreased from 0.207 to 0.084 pmol x s-1 x cm-1. After addition of synthetic bovine PTH (60-64 nM) to the bath, there was an immediate increase in calcium absorption, and by 20 min the net flux increased to 0.415 pmol x s-1 x cm-1. The increase in calcium absorption was due to an increase in the lumen-to-bath flux. Dibutyryl-cAMP or 8-BrcAMP mimicked PTH; adrenocorticotropic hormone had no effect on the calcium flux. Transepithelial voltage was unchanged after addition of PTH. We conclude that PTH increases calcium absorption across the cortical thick ascending limb, probably by stimulation of adenylate cyclase.

Thick ascending limbs of Henle's loop were dissected from rabbit kidneys and perfused in vitro. Unidirectional transepithelial calcium fluxes from lumen-to-bath and bath-to-lumen were measured with 45Ca using different solutions that caused the transepithelial voltage to vary over a wide range. With lumen-positive voltages there was net calcium absorption from lumen to bath which varied directly with the voltage. With voltage near zero there was no measurable net flux. When the voltage was made negative, the direction of net calcium transport reversed (i.e., secretion from bath to lumen). The presence or absence of bicarbonate in the lumen did not affect the calcium fluxes. Calcium permeability, calculated from the dependence of net flux on voltage, was 7.7 x 10(-6) cm/s, which is approximately 25% of the sodium permeability previously determined in this segment. Analysis of the calcium flux ratios revealed interdependence of the bidirectional fluxes consistent with single-file diffusion but no evidence for active calcium transport. We conclude that there is an important component of passive net calcium transport driven by the voltage in this segment.