Everolimus in Patients with Autosomal Dominant Polycystic Kidney Disease

Renal Division, University Hospital Freiburg, Hugstetter St., 55 79106 Freiburg, Germany.
New England Journal of Medicine (Impact Factor: 55.87). 08/2010; 363(9):830-40. DOI: 10.1056/NEJMoa1003491
Source: PubMed


Autosomal dominant polycystic kidney disease (ADPKD) is a slowly progressive hereditary disorder that usually leads to end-stage renal disease. Although the underlying gene mutations were identified several years ago, efficacious therapy to curtail cyst growth and prevent renal failure is not available. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth.
In this 2-year, double-blind trial, we randomly assigned 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The primary outcome was the change in total kidney volume, as measured on magnetic resonance imaging, at 12 and 24 months.
Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P=0.02) and between baseline and 2 years by 230 ml and 301 ml, respectively (P=0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P=0.27) and by 181 ml and 215 ml, respectively, after 2 years (P=0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P=0.003) and by 56 ml and 93 ml, respectively, after 2 years (P=0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m2 of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P=0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups.
Within the 2-year study period,as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment [corrected]. (Funded by Novartis; EudraCT number, 2006-001485-16; number, NCT00414440.)

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    • "There was a high dropout rate in the rapamycin group. Surprisingly, the estimated glomerular filtration rate (eGFR) even decreased more rapidly in intervention group (60). Serra et al. found no significant difference in kidney volume or eGFR in 100 less progressed ADPKD patients after 18 months of treatment with sirolimus or placebo, but detected an increase in albuminuria in the sirolimus group (61). "
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    ABSTRACT: The evaluation and treatment of the heterogeneous group of kidney diseases poses a challenging field in pediatrics. Many of the pediatric disorders resulting in severe renal affection are exceedingly rare and therapeutic approaches have remained symptomatic for most of these disease entities. The insights obtained from cellular and molecular studies of rare disorders by recent genetic studies have now substantially changed our mechanistic understanding of various important pediatric renal diseases and positive examples of targeted treatment approaches are emerging. Three fields of recent breathtaking developments in pediatric nephrology are the pathophysiology of nephrotic syndrome and proteinuria, the molecular mechanisms underlying atypical hemolytic uremic syndrome, and the genetics and cellular biology of inherited cystic kidney diseases. In all three areas, the combined power of molecular basic science together with deeply characterizing clinical approaches has led to the establishment of novel pathophysiological principles and to the first clinical trials of targeted treatment approaches.
    Frontiers in Pediatrics 07/2014; 2:68. DOI:10.3389/fped.2014.00068
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    • "The mTOR signaling pathway has, in the past several years, gained much attention in the PKD research field. It was reported that mTOR is activated in cyst-lining cells in human ADPKD kidneys and inhibition of mTOR pathway reverses renal cystogenesis in animal models [20], although clinical trials with rapamycin in human ADPKD patients were disappointing [21]. The mTOR protein binds to other proteins to form a rapamycin-sensitive complex (mTORC1) or a rapamycin-insensitive complex (mTORC2) [19], [22]. "
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    ABSTRACT: FPC (fibrocystin or polyductin) is a single transmembrane receptor-like protein, responsible for the human autosomal recessive polycystic kidney disease (ARPKD). It was recently proposed that FPC undergoes a Notch-like cleavage and subsequently the cleaved carboxy(C)-terminal fragment translocates to the nucleus. To study the functions of the isolated C-tail, we expressed the intracellular domain of human FPC (hICD) in renal epithelial cells. By 3-dimensional (3D) tubulogenesis assay, we found that in contrast to tubule-like structures formed from control cells, hICD-expressing cells exclusively formed cyst-like structures. By western blotting, we showed that the Akt/mTOR pathway, indicated by increased phosphorylation of Akt at serine 473 and S6 kinase 1 at threonine 389, was constitutively activated in hICD-expressing cells, similar to that in FPC knockdown cells and ARPKD kidneys. Moreover, application of mTOR inhibitor rapamycin reduced the size of the cyst-like structures formed by hICD-expressing cells. Application of either LY294002 or wortmannin inhibited the activation of both S6K1 and Akt. Expression of full-length FPC inhibited the activation of S6 and S6 kinase whereas co-expression of hICD with full-length FPC antagonized the inhibitory effect of full-length FPC on mTOR. Taken together, we propose that FPC modulates the PI3K/Akt/mTOR pathway and the cleaved C-tail regulates the function of the full-length protein.
    PLoS ONE 05/2014; 9(5):e95630. DOI:10.1371/journal.pone.0095630 · 3.23 Impact Factor
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    • "This complex might regulate a series of biological features such as cell proliferation and apoptosis by modulating different signals including cAMP, mTOR and EGFR pathways [9] [10] [11] [12] [13]. Although several inhibitors of these ways are able to reduce kidney cysts in animal models for ADPKD, results from clinical trials are not completely satisfactory [14] [15] [16] [17] [18]. Moreover, there is also evidence of a reduced intracellular Ca 2+ activity which accelerates cell proliferation in ADPKD cystic cells, resulting in kidney cyst formation , which might be reverted by the treatment with calcium channel activators [19] [20]. "
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    ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 micrograms/ml) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 micrograms/ml, berberine reduces cell growth in ADPKD cystic cells only enhancing G0/G1 phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new opportunities for the therapy of ADPKD patients.
    Biochemical and Biophysical Research Communications 10/2013; 441(3). DOI:10.1016/j.bbrc.2013.10.076 · 2.30 Impact Factor
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