sirolimus and Polycystic-Kidney--Autosomal-Dominant

The role of the mammalian target of rapamycin (mTOR) inhibition in the treatment of autosomal dominant polycystic kidney disease (ADPKD) remains unclear. This meta-analysis included all randomized controlled trials (RCTs) that used mTOR inhibitors (TORIs) to halt the progression of ADPKD.. Databases including MEDLINE, EMBASE, and the Cochrane Library were searched to find relevant trials. RCTs of TORI treatment in patients with ADPKD were included. Effects on the primary outcome [total kidney volume (TKV)] and secondary outcomes [changes in cyst volume (CV) and parenchymal volume (PV), glomerular filtration rate (GFR), proteinuria, and adverse events] were analyzed.. The results of 5 RCTs, which included 619 patients, were analyzed. TORIs did not significantly reduce TKV [mean difference (WMD) -90.01 ml, 95% CI -235.49 to 55.47, p = 0.23; I(2) = 0%; p for heterogeneity = 0.67]. CV decreased after TORI treatment (WMD -15.08 ml, 95% CI -17.82 to -12.34, p < 0.00001), and PV did not change (WMD -0.55 ml, 95% CI -64.55 to 63.45, p = 0.99). There was no significant difference in GFR between the TORI-treated and control groups (WMD 4.94 ml/min, 95% CI -0.81 to 10.68, p = 0.09). Proteinuria was significantly higher in the TORI-treated group than in the control group (standard mean difference 0.27, 95% CI 0.09-0.44, p = 0.002).. Long-term treatment with TORIs does not benefit patients with ADPKD.

Topics: Evidence-Based Medicine; Humans; Immunosuppressive Agents; Longitudinal Studies; Polycystic Kidney, Autosomal Dominant; Proteinuria; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

The review will examine clinically relevant advances in the area of polycystic kidney disease (PKD), mainly focusing on autosomal dominant polycystic kidney disease (ADPKD). Discussion will focus on predicting the course of ADPKD, clinical trials and new research endeavors.. During the past several years PKD research has been one of the most prolific areas in investigative nephrology. Research endeavors have focused on decreasing cyst proliferation and cyst fluid formation based on an understanding of the pathophysiology of these processes. If cysts can be prevented from growing, kidney function can be better preserved.. Progression of this most common inherited kidney disorder can be altered by understanding that cysts are the disease in ADPKD. Assessing total kidney volume and noting its relationship to glomerular filtration rate is key in predicting the course of the disease and will aid in the evaluation of the new research initiatives that are designed to stop cyst proliferation and fluid secretion into the kidney cysts. The role of biomarkers is an advancement in predicting PKD progression and can potentially be used in evaluation of treatments for this disease. Complications of PKD alter the course and prognosis; hence management approaches will be addressed.

Topics: Antineoplastic Agents; Benzazepines; Curcumin; Everolimus; Gastrointestinal Agents; Glomerular Filtration Rate; Humans; Hypertension; Hypoglycemic Agents; Immunosuppressive Agents; Indazoles; Kidney; Metformin; Octreotide; Organ Size; Polycystic Kidney, Autosomal Dominant; Sirolimus; Sodium; Tolvaptan

The objective of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) to present a profound review and an objective appraisal of the efficacy and safety of the mammalian target of rapamycin (mTOR) inhibitor therapy in patients with autosomal dominant polycystic kidney disease (ADPKD).. RCTs involving the mTOR inhibitor therapy in patients with ADPKD are included. The data of studies and major outcomes include changes in patients' glomerular filtration rate (GFR), urinary protein, total kidney volume (TKV), cyst volume, parenchymal volume, and lipid profile and the frequency of adverse events. Review Manager 5.0 for meta-analysis was used in this study.. Up to January 31, 2011, 4 RCTs (with a total of 564 patients) were included. The mTOR inhibitor therapy group had smaller TKV than the control group [weighted mean difference (WMD) of TKV after treatment: -318.45, P = 0.04]. The mTOR inhibitor treatment does not necessarily slow down the aggravation of renal function in patients with ADPKD (WMD of GFR after therapy: 5.55, P < 0.01; at 6-month analyses = -0.97, P = 0.56). Side effects could occur during the mTOR inhibitor therapy, but the severities can be controlled by the appropriate use of drug.. Based on the current limited clinical trials, this study suggests that short-duration mTOR inhibitor therapy is relatively safe to slow down the increase in kidney volume in patients with early-stage ADPKD, but it has limited impact on slowing down the decrease in GFR.

Topics: Everolimus; Glomerular Filtration Rate; Humans; Kidney; Lipids; Organ Size; Polycystic Kidney, Autosomal Dominant; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Animals; Biomarkers; Everolimus; Glomerular Filtration Rate; Glycopeptides; Humans; Immunosuppressive Agents; Octreotide; Polycystic Kidney, Autosomal Dominant; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

More frequent utilization and continuous improvement of imaging techniques has enhanced appreciation of the high phenotypic variability of autosomal dominant polycystic kidney disease, improved understanding of its natural history, and facilitated the observation of its structural progression. At the same time, identification of the PKD1 and PKD2 genes has provided clues to how the disease develops when they (genetic mechanisms) and their encoded proteins (molecular mechanisms) are disrupted. Interventions designed to rectify downstream effects of these disruptions have been examined in animal models, and some are currently tested in clinical trials. Efforts are underway to determine whether interventions capable to slow down, stop, or reverse structural progression of the disease will also prevent decline of renal function and improve clinically significant outcomes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Hormonal; Benzazepines; Clinical Trials as Topic; Genetic Therapy; Humans; Octreotide; Polycystic Kidney, Autosomal Dominant; Sirolimus; Tolvaptan

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of countless cysts in both kidneys, which compress the cyst-free renal parenchyma, leading to a loss of renal function and the need for renal replacement therapy and/or kidney transplantation in ∼50% of affected patients. In animal models of experimental polycystic kidney disease, the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus effectively reduce cyst growth and loss of renal function. Furthermore, an analysis of renal transplant patients with ADPKD has shown that cystic kidney and liver volumes regress more on a sirolimus-based regimen than on a calcineurin inhibitor-based immunosuppressive regimen. Several prospective controlled clinical trials have been initiated to investigate whether mTOR inhibitors retard cyst growth and slow renal functional deterioration in patients with ADPKD. Study results are expected in 2010.

Topics: Animals; Disease Models, Animal; Everolimus; Humans; Polycystic Kidney, Autosomal Dominant; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the massive enlargement of both kidneys caused by numerous cysts. The cyst formation begins in utero and the continuous growth of cysts leads to compression and destruction of non-cystic renal parenchyma, so that finally a kidney replacement in the 5th to 6th decade of life is necessary. So far there is no therapy that halts disease progression. Animal data show that pharmacological inhibition of a central regulator of cell proliferation, the so-called mammalian target of rapamycin (mTOR), slows disease progression. This overview provides an insight into the disease and the specific mTOR inhibitor sirolimus, which is currently tested in clinical trials.

Topics: Adult; Animals; Disease Models, Animal; Disease Progression; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Randomized Controlled Trials as Topic; Rats; Sirolimus

The mammalian target of rapamycin (mTOR) pathway has been shown to be central to cyst formation and growth in patients with autosomal dominant polycystic kidney disease (ADPKD). Drugs that suppress mTOR signaling are frequently used as antiproliferative agents for maintenance immunosuppression in patients who have undergone kidney transplantation. The aim of this study was to determine the effect of sirolimus, an mTOR inhibitor, on cyst volume regression in patients with ADPKD who have undergone renal transplantation.. In this single-center, prospective, open-label, parallel-group, randomized trial, 23 adult patients with ADPKD who successfully underwent renal transplantation from 2008 to 2012 were subsequently randomized (on a 1:1 basis) to a maintenance immunosuppression regimen with either sirolimus (sirolimus, tacrolimus, prednisone) or mycophenolate (mycophenolate, tacrolimus, prednisone). Total kidney volumes were measured by means of high-resolution magnetic resonance imaging within 2 weeks after transplantation and at 1 year. The primary end point was change in total kidney volume at 1 year.. Sixteen patients completed the 1-year study (8 patients in each group). There was a decrease in kidney volume in both the sirolimus group (percentage change from baseline, 20.5%; P < .001) and mycophenolate group (percentage change from baseline, 17%; P = .048), but there was no significant difference in percentage change of total kidney volume between the groups (P = .665).. In ADPKD patients at 1 year after kidney transplantation, there was a similar decrease in polycystic kidney volume in patients receiving an immunosuppression regimen containing sirolimus compared with patients receiving mycophenolate.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Polycystic Kidney, Autosomal Dominant; Prospective Studies; Research Design; Sirolimus; TOR Serine-Threonine Kinases

The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.. In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.. At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m(2) (P<0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P<0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8±81.8 versus 154.9±152.9 μg/min; P=0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P<0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P<0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrast-enhanced computed tomography imaging) increased by 9.0% from 2857.7±1447.3 to 3094.6±1519.5 ml on sirolimus and 4.3% from 3123.4±1695.3 to 3222.6±1651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.. Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.

Topics: Adult; Albuminuria; Disease Progression; Early Termination of Clinical Trials; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Sirolimus

Autosomal-dominant polycystic kidney disease (ADPKD) is a hereditary illness that causes renal tubular epithelial cells to form cysts that proliferate and destroy renal tissue. This usually leads to a decline in renal function, and often to terminal kidney failure, with need for renal replacement therapy. There is currently no causative therapy. The mammalian target of rapamycin (mTOR) inhibitor sirolimus (SIR) is an immunosuppressant with strong antiproliferative effects, and is potentially able to stop or reduce cyst growth and preserve renal function in ADPKD. Continuous mTOR exposure results in a loss of its antiproliferative effects on renal tubular cells. With a half-life of roughly 60 hours, pulsed (weekly) administration of SIR may be an effective way to reduce cyst growth and preserve excretory renal function in ADPKD.. The Vienna RAP Study is a randomized, double-blind, placebo-controlled trial, funded by the Anniversary Fund of the Oesterreichische Nationalbank. We will investigate the effects of a weekly dose of 3 mg SIR on kidney function in 34 patients with advanced ADPKD, compared to a placebo equivalent in 34 patients with advanced ADPKD, over 24 months. The primary endpoint is creatinine level (less or equal than 1.5-fold increase in serum creatinine without initiation of dialysis over two years) and dialysis, renal transplantation, or death. The secondary endpoints are safety, change in proteinuria (as indicated by albumin/creatinine- and protein/creatinine ratio, respectively), and creatinine clearance.. The Vienna RAP Study is, to the best of our knowledge, the first study to investigate the effects of a pulsed (weekly) dose of SIR on renal function in ADPKD.. This trial was registered with EudraCT (identifier: 2012-000550-60 (EU)) on 27 November 2013 and with ClinicalTrials.gov (identifier: NCT02055079 (USA)) on 3 February 2014.

Topics: Administration, Oral; Austria; Biomarkers; Clinical Protocols; Creatinine; Disease Progression; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Polycystic Kidney, Autosomal Dominant; Pulse Therapy, Drug; Renal Dialysis; Research Design; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome

The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in (125)I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily.. In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2-5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (>5-8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography.. Change in iGFR at 12 months was significantly higher in the LD group (7.7±12.5 ml/min per 1.73 m(2); n=9) than in the SC group (-11.2 ± 9.1 ml/min per 1.73 m(2); n=9) (LD versus SC: P<0.01). Change in iGFR at 12 months in the STD group (1.6 ± 12.1 ml/min per 1.73 m(2); n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P<0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range ± SD, 2.40 ± 0.64 to 2.90 ± 1.20 ng/ml) compared with those in the STD group (3.93 ± 2.27 to 5.77 ± 1.06 ng/ml) (P<0.01).. Patients with ADPKD receiving LD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.

Topics: Adult; Aged; Arterial Pressure; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Organ Size; Pilot Projects; Polycystic Kidney, Autosomal Dominant; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Young Adult

Polycystic liver disease (PLD) is associated with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PCLD). The resulting hepatomegaly compromises quality of life. Somatostatin analogues reduce PLD volume by approximately 5% when given for 6-12 months. A pilot trial in 16 ADPKD patients demonstrated that sirolimus, an mTOR inhibitor, reduced PLD volume by 26%. The aim of this study was to assess the PLD volume reducing effect of everolimus and octreotide relative to octreotide monotherapy.. We designed a randomized controlled trial that compared 48 weeks of everolimus 2.5 mg daily, combined with octreotide 40 mg intramuscularly every 4 weeks, to octreotide monotherapy. We included PCLD and ADPKD patients. Exclusion criteria were MDRD-GFR <60 ml/min/1.73 m(2) and liver volume <2500 ml. Primary outcome was change in liver volume measured with CT-volumetry.. We randomized 44 PLD patients (29 PCLD, 15 ADPKD, 89% female) to treatment with octreotide (n=23) or octreotide-everolimus (n=21). Liver volume decreased by 3.5% (p<0.01) in the monotherapy arm, compared to 3.8% with combination therapy (p<0.01). The difference between treatment arms was not significant (p=0.73).. Adding everolimus to octreotide in PLD does not increase the liver volume reducing effect of octreotide.

Topics: Adult; Cysts; Delayed-Action Preparations; Drug Therapy, Combination; Everolimus; Female; Humans; Kidney; Liver; Liver Diseases; Male; Middle Aged; Octreotide; Organ Size; Polycystic Kidney, Autosomal Dominant; Sirolimus; Treatment Outcome

Topics: Adult; Female; Humans; Immunosuppressive Agents; Menstrual Cycle; Ovarian Cysts; Ovary; Polycystic Kidney, Autosomal Dominant; Sirolimus

Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of cystic kidney disease. An inappropriate stimulation of mammalian target of rapamycin may represent the converging point in the molecular pathways leading to renal cyst growth.. The primary objectives of this prospective, open-label, randomized clinical trial were to assess whether rapamycin may reduce the progressive increase in single cyst and total kidney volume in type I ADPKD and the decline in renal function and to identify the optimal rapamycin dose. Fifty-five patients with type I ADPKD were enrolled and randomized to receive ramipril (Group A), ramipril + high-dose rapamycin (Group B, trough level 6-8 ng/mL) and ramipril + low-dose rapamycin (Group C, trough levels 2-4 ng/mL). Rapamycin efficacy was monitored measuring p70 phosphorylation in peripheral blood mononuclear cells.. Both rapamycin doses significantly reduced p70 phosphorylation. Nevertheless, total kidney volume increased in all groups after 24 months, although only in Groups A and B, was the final volume significantly higher compared with the baseline. Single cyst final volume was not significantly different in the three groups, although it was increased in Group A compared with the baseline, whereas in Groups B and C, it was significantly reduced. We did not observe any difference in renal function at 24 months among the three study groups. Group A presented a significant worsening of renal function that remained stable in both Groups B and C.. Our study would suggest that rapamycin does not influence the progression of type I ADPKD, although the higher drug dose tested prevented both the increase in kidney volume and the worsening of renal function (RAPYD-study, EUDRACT No. 2007-006557-25).

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases, Cystic; Male; Middle Aged; Phosphorylation; Polycystic Kidney, Autosomal Dominant; Prognosis; Prospective Studies; Ramipril; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Young Adult

Sirolimus has been approved for clinical use in non proliferative and proliferative disorders. It inhibits the mammalian target of rapamycin (mTOR) signaling pathway which is also known to regulate ovarian morphology and function. Preliminary observational data suggest the potential for ovarian toxicity but this issue has not been studied in randomized controlled trials. We reviewed the self-reported occurrence of menstrual cycle disturbances and the appearance of ovarian cysts post hoc in an open label randomized controlled phase II trial conducted at the University Hospital Zürich between March 2006 and March 2010. Adult females with autosomal dominant polycystic kidney disease, an inherited kidney disease not known to affect ovarian morphology and function, were treated with 1.3 to 1.5 mg sirolimus per day for a median of 19 months (N = 21) or standard care (N = 18). Sirolimus increased the risk of both oligoamenorrhea (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.1 to 29) and ovarian cysts (HR 4.4, CI 1.1 to 26); one patient was cystectomized five months after starting treatment with sirolimus. We also studied mechanisms of sirolimus-associated ovarian toxicity in rats. Sirolimus amplified signaling in rat ovarian follicles through the pro-proliferative phosphatidylinositol 3-kinase pathway. Low dose oral sirolimus increases the risk of menstrual cycle disturbances and ovarian cysts and monitoring of sirolimus-associated ovarian toxicity is warranted and might guide clinical practice with mammalian target of rapamycin inhibitors.. ClinicalTrials.gov NCT00346918.

Topics: Adult; Animals; Female; Humans; Immunosuppressive Agents; Oligomenorrhea; Ovarian Cysts; Ovarian Follicle; Polycystic Kidney, Autosomal Dominant; Prevalence; Rats; Rats, Wistar; Sirolimus

This double-blind trial followed 16 patients with autosomal dominant polycystic kidney disease (ADPKD) who received telmisartan or sirolimus plus telmisartan for 24 months. The 6-month pilot study showed a promising effect of sirolimus. The primary metric of this 2-year study was the change in total kidney volume at 12 and 24 months, as measured on magnetic resonance imaging. Secondary outcome was changes in renal function from the baseline at months 12 and 24. Among patients receiving sirolimus, the mean total kidney volume increased from 2845 mL to 3381 mL at 1 year and to 3901 mL at 2 years versus placebo values increasing from 2667 mL to 3680 mL and 3776 mL, respectively. The posttreatment mean total kidney volume increased less on sirolimus (P = .07) versus control therapy (P = .05) after 1 year, but there was no difference at 24 months. Kidney volume was stable on sirolimus to 12 months, increasing steadily to 24 months. In contrast, kidney volume increased steadily among patients on telmisartan alone both at 12 and 24 months. In conclusion, sirolimus appeared to retard kidney growth among patients with ADPKD during the first 6 months of therapy but not to halt growth thereafter, thus eliciting S-shaped effect. The dose of sirolimus (1 mg per day) was associated with a low rate of side effects similar those observed in kidney transplantation.

Topics: Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Egypt; Glomerular Filtration Rate; Humans; Kidney; Magnetic Resonance Imaging; Organ Size; Polycystic Kidney, Autosomal Dominant; Protein Kinase Inhibitors; Sirolimus; Telmisartan; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Topics: Adult; Cell Proliferation; Cross-Over Studies; Disease Progression; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Protein Serine-Threonine Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

In autosomal dominant polycystic kidney disease (ADPKD), aberrant activation of the mammalian target of rapamycin (mTOR) pathway is associated with progressive kidney enlargement. The drug sirolimus suppresses mTOR signaling.. In this 18-month, open-label, randomized, controlled trial, we sought to determine whether sirolimus halts the growth in kidney volume among patients with ADPKD. We randomly assigned 100 patients between the ages of 18 and 40 years to receive either sirolimus (target dose, 2 mg daily) or standard care. All patients had an estimated creatinine clearance of at least 70 ml per minute. Serial magnetic resonance imaging was performed to measure the volume of polycystic kidneys. The primary outcome was total kidney volume at 18 months on blinded assessment. Secondary outcomes were the glomerular filtration rate and urinary albumin excretion rate at 18 months.. At randomization, the median total kidney volume was 907 cm3 (interquartile range, 577 to 1330) in the sirolimus group and 1003 cm3 (interquartile range, 574 to 1422) in the control group. The median increase over the 18-month period was 99 cm3 (interquartile range, 43 to 173) in the sirolimus group and 97 cm3 (interquartile range, 37 to 181) in the control group. At 18 months, the median total kidney volume in the sirolimus group was 102% of that in the control group (95% confidence interval, 99 to 105; P=0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group.. In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth. (Funded by Wyeth and others; ClinicalTrials.gov number, NCT00346918.)

Topics: Adult; Albuminuria; Creatinine; Disease Progression; Female; Glomerular Filtration Rate; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Failure, Chronic; Male; Organ Size; Polycystic Kidney, Autosomal Dominant; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

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; ClinicalTrials.gov number, NCT00414440.)

Topics: Adult; Cholesterol; Creatinine; Disease Progression; Double-Blind Method; Everolimus; Female; Glomerular Filtration Rate; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Failure, Chronic; Male; Organ Size; Polycystic Kidney, Autosomal Dominant; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

We initiated a randomized controlled clinical trial to assess the effect of sirolimus on disease progression in patients affected by autosomal dominant polycystic kidney disease (ADPKD). Here we report the preliminary safety results of the first 6 months of treatment.. A total of 25 patients were randomized to sirolimus 2 mg/day and 25 patients to no treatment except standard care. Treatment adherence was monitored electronically. At baseline and at Month 6, laboratory parameters were analysed and the urinary protein profile in 24-h urine collections was determined.. Both treatment groups were well balanced for age, sex and renal function. In 94.1 +/- 11.4% of the study days, patients in the sirolimus group were exposed to the drug when assuming a therapeutic efficacy duration of 30 h. At Month 6, the mean sirolimus dose and trough level were 1.28 +/- 0.71 mg/day and 3.8 +/- 1.9 microg/l, respectively. Glomerular (albumin, transferrin, IgG) and tubular (retinol-binding protein, alpha(1)-microglobulin) protein excretion remained unchanged. Glomerular filtration rate also did not change significantly. Haematological parameters were similar in both groups, except for a mild reduction of the mean corpuscular volume of erythrocytes in patients receiving sirolimus. Lipid levels were similar in both groups. Adverse events were transient and mild, and no grade 3 or 4 events occurred. The incidence of infections was similar in the sirolimus group (80%) and the standard group (88%). The most common gastrointestinal adverse events were mucositis (72% in the sirolimus group versus 16% in the standard group, P = 0.0001) and diarrhoea (36% in the sirolimus versus 20% in the standard group, P = 0.345).. Treatment of ADPKD patients with sirolimus with a dose of 1-2 mg/day is safe and does not cause proteinuria or impairment of GFR. Treatment adherence was excellent. (ClinicalTrials.gov number, NCT00346918.).

Topics: Adult; Erythrocyte Indices; Female; Humans; Immunosuppressive Agents; Kidney; Lipids; Male; Medication Adherence; Polycystic Kidney, Autosomal Dominant; Sirolimus

The immunosuppressive agent sirolimus exerts an antiproliferative effect by inhibiting mammalian target of rapamycin (mTOR). Because excessive proliferation of the biliary epithelium is a prominent feature of the polycystic liver that accompanies autosomal dominant polycystic kidney disease (ADPKD), we hypothesized that sirolimus may benefit patients with this disorder. We retrospectively measured the volumes of polycystic livers and kidneys in ADPKD patients who had received kidney transplants and had participated in a prospective randomized trial that compared a sirolimus-containing immunosuppression regimen to a tacrolimus-containing regimen. Sixteen subjects (seven with sirolimus, nine with tacrolimus) had received abdominal imaging studies within 11 mo before and at least 7 mo after transplantation, making them suitable for our analysis. Treatment with the sirolimus regimen for an average of 19.4 mo was associated with an 11.9 +/- 0.03% reduction in polycystic liver volume, whereas treatment with tacrolimus for a comparable duration was associated with a 14.1 +/- 0.09% increase. A trend toward a greater reduction in native kidney volume was also noted in the sirolimus group compared with the nonsirolimus group. Regarding mechanism, the epithelium that lines hepatic cysts exhibited markedly higher levels of phospho-AKT, phospho-ERK, phospho-mTOR, and the downstream effector phospho-S6rp compared with control biliary epithelium. In summary, treatment with sirolimus was associated with decreased polycystic liver volume, perhaps by preventing aberrant activation of mTOR in epithelial cells lining the cysts.

Topics: Aged; Epithelium; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Liver; Liver Diseases; Magnetic Resonance Imaging; Male; Middle Aged; Organ Size; Polycystic Kidney, Autosomal Dominant; Protein Kinases; Retrospective Studies; Ribosomal Protein S6; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Currently there is no effective treatment available to retard cyst growth and to prevent the progression to end-stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD). Evidence has recently been obtained from animal experiments that activation of the mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cyst growth and renal volume expansion, and that the inhibition of mTOR with rapamycin (sirolimus) markedly slows cyst development and renal functional deterioration. Based on these promising results in animals we have designed and initiated the first randomized controlled trial (RCT) to examine the effectiveness, safety and tolerability of sirolimus to retard disease progression in ADPKD.. This single center, randomised controlled, open label trial assesses the therapeutic effect, safety and tolerability of the mTOR inhibitor sirolimus (Rapamune) in patients with autosomal dominant polycystic kidney disease and preserved renal function. The primary outcome will be the inhibition of kidney volume growth measured by magnetic resonance imaging (MRI) volumetry. Secondary outcome parameters will be preservation of renal function, safety and tolerability of sirolimus.. The results from this proof-of-concept RCT will for the first time show whether treatment with sirolimus effectively retards cyst growth in patients with ADPKD.

Topics: Adolescent; Adult; Feasibility Studies; Female; Humans; Immunosuppressive Agents; Male; Pilot Projects; Polycystic Kidney, Autosomal Dominant; Sirolimus; Treatment Outcome

Autosomal dominant polycystic kidney disease (ADPKD) is characterised by progressive cysts formation and renal enlargement that in most of cases leads to end stage of renal disease (ESRD). This pathology is caused by mutations of either PKD1 or PKD2 genes that encode for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. These proteins function as receptor-channel complex able to regulate calcium homeostasis. PKD1/2 loss of function impairs different signalling pathways including cAMP and mTOR that are considered therapeutic targets for this disease. In fact, Tolvaptan, a vasopressin-2 antagonist that reduces cAMP levels, is the only drug approved for ADPKD treatment. Nevertheless, some ADPKD patients developed side effects in response to Tolvaptan including liver damage. Conversely, mTOR inhibitors that induced disease regression in ADPKD animal models failed the clinical trials.. Here, we show that the inhibition of mTOR causes the activation of autophagy in ADPKD cells that could reduce therapy effectiveness by drug degradation through the autophagic vesicles. Consistently, the combined treatment with rapamycin and chloroquine, an autophagy inhibitor, potentiates the decrease of cell proliferation induced by rapamycin. To overcome the dangerous activation of autophagy by mTOR inhibition, we targeted MDM2 (a downstream effector of mTOR signalling) that is involved in TP53 degradation by using RG7112, a small-molecule MDM2 inhibitor used for the treatment of haematologic malignancies. The inhibition of MDM2 by RG7112 prevents TP53 degradation and increases p21 expression leading to the decrease of cell proliferation and the activation of apoptosis.. The targeting of MDM2 by RG7112 might represent a new therapeutic option for the treatment of ADPKD.

Topics: Animals; Apoptosis; Cell Line; Cell Proliferation; Polycystic Kidney, Autosomal Dominant; Sirolimus; Tolvaptan; TOR Serine-Threonine Kinases; TRPP Cation Channels

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and is characterized by the formation of renal cysts and the eventual development of end-stage kidney disease. One approach to treating ADPKD is through inhibition of the mammalian target of rapamycin (mTOR) pathway, which has been implicated in cell overproliferation, contributing to renal cyst expansion. However, mTOR inhibitors, including rapamycin, everolimus, and RapaLink-1, have off-target side effects including immunosuppression. Thus, we hypothesized that the encapsulation of mTOR inhibitors in drug delivery carriers that target the kidneys would provide a strategy that would enable therapeutic efficacy while minimizing off-target accumulation and associated toxicity. Toward eventual in vivo application, we synthesized cortical collecting duct (CCD) targeted peptide amphiphile micelle (PAM) nanoparticles and show high drug encapsulation efficiency (>92.6%). In vitro analysis indicated that drug encapsulation into PAMs enhanced the anti-proliferative effect of all three drugs in human CCD cells. Analysis of in vitro biomarkers of the mTOR pathway via western blotting confirmed that PAM encapsulation of mTOR inhibitors did not reduce their efficacy. These results indicate that PAM encapsulation is a promising way to deliver mTOR inhibitors to CCD cells and potentially treat ADPKD. Future studies will evaluate the therapeutic effect of PAM-drug formulations and ability to prevent off-target side effects associated with mTOR inhibitors in mouse models of ADPKD.

Topics: Animals; Humans; Kidney; Mammals; Mice; Micelles; MTOR Inhibitors; Polycystic Kidney, Autosomal Dominant; Sirolimus; TOR Serine-Threonine Kinases

Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst formation and growth, which are partially driven by abnormal proliferation of tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. Sirolimus indirectly inhibits mTORC1. Novel mTOR kinase inhibitors directly inhibit mTOR kinase, resulting in the inhibition of mTORC1 and mTORC2. The aim of the present study was to determine the effects of sirolimus versus the mTOR kinase inhibitor torin2 on cyst growth and kidney function in the

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Cell Cycle Proteins; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Kidney Tubules; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Naphthyridines; Phosphorylation; Polycystic Kidney, Autosomal Dominant; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels

Cell proliferation and apoptosis are typical hallmarks of autosomal dominant polycystic kidney disease (ADPKD) and cause the development of kidney cysts that lead to end-stage renal disease (ESRD). Many factors, impaired by polycystin complex loss of function, may promote these biological processes, including cAMP, mTOR, and EGFR signaling pathways. In addition, microRNAs (miRs) may also regulate the ADPKD related signaling network and their dysregulation contributes to disease progression. However, the role of miRs in ADPKD pathogenesis has not been fully understood, but also the function of p53 is quite obscure, especially its regulatory contribution on cell proliferation and apoptosis. Here, we describe for the first time that miR501-5p, upregulated in ADPKD cells and tissues, induces the activation of mTOR kinase by PTEN and TSC1 gene repression. The increased activity of mTOR kinase enhances the expression of E3 ubiquitin ligase MDM2 that in turn promotes p53 ubiquitination, leading to its degradation by proteasome machinery in a network involving p70S6K. Moreover, the overexpression of miR501-5p stimulates cell proliferation in kidney cells by the inhibition of p53 function in a mechanism driven by mTOR signaling. In fact, the downregulation of this miR as well as the pharmacological treatment with proteasome and mTOR inhibitors in ADPKD cells reduces cell growth by the activation of apoptosis. Consequently, the stimulation of cell death in ADPKD cells may occur through the inhibition of mTOR/MDM2 signaling and the restoring of p53 function. The data presented here confirm that the impaired mTOR signaling plays an important role in ADPKD.

Topics: Apoptosis; Cell Proliferation; Down-Regulation; Gene Silencing; Humans; MicroRNAs; Phosphorylation; Polycystic Kidney, Autosomal Dominant; Proteasome Endopeptidase Complex; Protein Stability; Proteolysis; Proto-Oncogene Proteins c-mdm2; PTEN Phosphohydrolase; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Protein p53; Ubiquitination; Up-Regulation

Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, many small-molecule drugs against such targets have proven effective in reducing renal cyst growth. For example, mammalian target of rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic disease in several rodent models. However, clinical trials with mTOR inhibitors were disappointing largely due to the intolerable extrarenal side effects during long-term treatment with these drugs. Most other potential drug targets in ADPKD are also widely expressed in extrarenal tissues, which makes it likely that untargeted therapies with small-molecule inhibitors against such targets will lead to systemic adverse effects during the necessary long-term treatment of years and decades in ADPKD patients. To overcome this problem, we previously demonstrated that folate-conjugated rapamycin (FC-rapa) targets polycystic kidneys due to the high expression of the folate receptor (FRα) and that treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst growth. Here we show, in a head-to-head comparison with unconjugated rapamycin, that FCrapa inhibits renal cyst growth, mTOR activation, cell cycling, and fibrosis in an orthologous Pkd1 mouse model. Both unconjugated rapamycin and FC-rapa are similarly effective on polycystic kidneys in this model. However, FC-rapa lacks the extrarenal effects of unconjugated rapamycin, in particular immunosuppressive effects. We conclude that folate-conjugation is a promising avenue for increasing the tissue specificity of small-molecule compounds to facilitate very long-term treatment in ADPKD.

Topics: A549 Cells; Animals; Disease Models, Animal; Drug Compounding; Folate Receptor 1; Folic Acid; Humans; Integrases; Kidney; Mice, Knockout; Polycystic Kidney, Autosomal Dominant; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Tissue Distribution; TOR Serine-Threonine Kinases; TRPP Cation Channels

Topics: Animals; Drug Delivery Systems; Folic Acid; Kidney; Mice; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Sirolimus

Attributing to their antiproliferative effect, both rapamycin and peroxisome proliferator-activated receptor-γ (PPARγ) can halt the progression of autosomal dominant polycystic kidney disease (ADPKD). Whether combined use could enhance this effect is unknown. The present study used rapamycin and the PPARγ agonist rosiglitazone concomitantly to observe their combined effects on the proliferation of ADPKD cyst-lining epithelial cells and the progression of ADPKD in Han:SPRD rats. Concomitant use of the two drugs inhibited the proliferation of WT9-12 cells significantly through a superimposition effect. Rosiglitazone inhibited the phosphorylation of mammalian target of rapamycin p70S6K. Concomitant use of rosiglitazone and rapamycin further downregulated the p-p70S6K level. Rosiglitazone also inhibited the phosphorylation of Akt and antagonized the activation of Akt induced by rapamycin. Concomitant use of rosiglitazone and rapamycin significantly retarded the deterioration of renal function, decreased cyst cell proliferation and interstitial fibrosis in Han:SPRD rats. Rapamycin significantly increased cholesterol levels in the blood, whereas rosiglitazone mitigated rapamycin-induced hyperlipidemia. These results indicate that the effects of concomitant use of rosiglitazone and rapamycin in inhibiting the proliferation of WT9-12 cells and delaying the progression of ADPKD in Han:SPRD rats are stronger than those of either drug alone. The present study may provide a new strategy for the long-term treatment of ADPKD.

Topics: Animals; Cell Line; Cell Proliferation; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Epithelial Cells; Fibrosis; G1 Phase Cell Cycle Checkpoints; Humans; Kidney; Lipids; Male; Phosphorylation; Polycystic Kidney, Autosomal Dominant; PPAR gamma; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Renal Agents; Ribosomal Protein S6 Kinases, 70-kDa; Rosiglitazone; Signal Transduction; Sirolimus

ADPKD is a renal pathology caused by mutations of PKD1 and PKD2 genes, which encode for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 plays an important role regulating several signal transducers, including cAMP and mTOR, which are involved in abnormal cell proliferation of ADPKD cells leading to the development and expansion of kidney cysts that are a typical hallmark of this disease. Therefore, the inhibition of both pathways could potentiate the reduction of cell proliferation enhancing benefits for ADPKD patients.. The inhibition of cAMP- and mTOR-related signalling was performed by Cl-IB-MECA, an agonist of A3 receptors, and rapamycin, respectively. Protein kinase activity was evaluated by immunoblot and cell growth was analyzed by direct cell counting.. The activation of A. The double treatment with rapamycin and Cl-IB-MECA may have synergistic effects on the inhibition of cell proliferation in ADPKD cells suggesting that combined therapies could improve renal function in ADPKD patients.

Topics: Adenosine; Adenosine A3 Receptor Agonists; Animals; Cell Line; Cell Proliferation; CREB-Binding Protein; Cyclic AMP; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Genetic Predisposition to Disease; Humans; Kidney; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Phosphorylation; Polycystic Kidney, Autosomal Dominant; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; TRPP Cation Channels

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. It is one of the most common heritable human diseases with eventual development of renal failure; however, effective treatment is lacking. While inhibition of mechanistic target of rapamycin (mTOR) effectively slows cyst expansions in animal models, results from clinical studies are controversial, prompting further mechanistic studies of mTOR-based therapy. Here, we aim to establish autophagy, a downstream pathway of mTOR, as a new therapeutic target for PKD. We generated zebrafish mutants for pkd1 and noted cystic kidney and mTOR activation in pkd1a mutants, suggesting a conserved ADPKD model. Further assessment of the mutants revealed impaired autophagic flux, which was conserved in kidney epithelial cells derived from both Pkd1-null mice and ADPKD patients. We found that inhibition of autophagy by knocking down the core autophagy protein Atg5 promotes cystogenesis, while activation of autophagy using a specific inducer Beclin-1 peptide ameliorates cysts in the pkd1a model. Treatment with compound autophagy activators, including mTOR-dependent rapamycin as well as mTOR-independent carbamazepine and minoxidil, markedly attenuated cyst formation and restored kidney function. Finally, we showed that combination treatment with low doses of rapamycin and carbamazepine was able to attenuate cyst formation as effectively as a single treatment with a high dose of rapamycin alone. In summary, our results suggested a modifying effect of autophagy on ADPKD, established autophagy activation as a novel therapy for ADPKD, and presented zebrafish as an efficient vertebrate model for developing PKD therapeutic strategies.

Topics: Animals; Autophagy; Autophagy-Related Protein 5; Carbamazepine; Cells, Cultured; Disease Models, Animal; Embryo, Nonmammalian; Epithelial Cells; Mice; Mice, Knockout; Polycystic Kidney, Autosomal Dominant; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels; Zebrafish

Bronchiectasis is characterized by abnormal, permanent and irreversible dilatation of the bronchi, usually responsible for daily symptoms and frequent respiratory complications. Many causes have been identified, but only limited data are available concerning the association between bronchiectasis and renal transplantation.. We conducted a retrospective multicenter study of cases of bronchiectasis diagnosed after renal transplantation in 14 renal transplantation departments (French SPIESSER group). Demographic, clinical, laboratory and CT scan data were collected.. Forty-six patients were included (mean age 58.2 years, 52.2 % men). Autosomal dominant polycystic kidney disease (32.6 %) was the main underlying renal disease. Chronic cough and sputum (50.0 %) were the major symptoms leading to chest CT scan. Mean duration of symptoms before diagnosis was 1.5 years [0-12.1 years]. Microorganisms were identified in 22 patients, predominantly Haemophilus influenzae. Hypogammaglobulinemia was observed in 46.9 % patients. Bronchiectasis was usually extensive (84.8 %). The total bronchiectasis score was 7.4 ± 5.5 with a significant gradient from apex to bases. Many patients remained symptomatic (43.5 %) and/or presented recurrent respiratory tract infections (37.0 %) during follow-up. Six deaths (13 %) occurred during follow-up, but none were attributable to bronchiectasis.. These results highlight that the diagnosis of bronchiectasis should be considered in patients with de novo respiratory symptoms after renal transplantation. Further studies are needed to more clearly understand the mechanisms underlying bronchiectasis in this setting.

Topics: Adult; Agammaglobulinemia; Aged; Aged, 80 and over; Azathioprine; Bronchiectasis; Chronic Disease; Cough; Cyclosporine; Everolimus; Female; Forced Expiratory Volume; Graft Rejection; Haemophilus Infections; Haemophilus influenzae; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polycystic Kidney, Autosomal Dominant; Respiratory Tract Infections; Retrospective Studies; Risk Factors; Rituximab; Sirolimus; Tacrolimus; Tomography, X-Ray Computed; Vital Capacity; Young Adult

Autosomal dominant polycystic kidney disease (ADPKD) is caused by loss-of-function mutations in either PKD1 or PKD2 genes, which encode polycystin-1 (TRPP1) and polycystin-2 (TRPP2), respectively. Increased activity of the mammalian target of rapamycin (mTOR) pathway has been shown in PKD1 mutants but is less documented for PKD2 mutants. Clinical trials using mTOR inhibitors were disappointing, while the AMP-activated kinase (AMPK) activator, metformin is not yet tested in patients. Here, we studied the mTOR activity and its upstream pathways in several human and mouse renal cell models with either siRNA or stable knockdown and with overexpression of TRPP2. Our data reveal for the first time differences between TRPP1 and TRPP2 deficiency. In contrast to TRPP1 deficiency, TRPP2-deficient cells did neither display excessive activation of the mTOR-kinase complex nor inhibition of AMPK activity, while ERK1/2 and Akt activity were similarly affected among TRPP1- and TRPP2-deficient cells. Furthermore, cell proliferation was more pronounced in TRPP1 than in TRPP2-deficient cells. Interestingly, combining low concentrations of rapamycin and metformin was more effective for inhibiting mTOR complex 1 activity in TRPP1-deficient cells than either drug alone. Our results demonstrate a synergistic effect of a combination of low concentrations of drugs suppressing the increased mTOR activity in TRPP1-deficient cells. This novel insight can be exploited in future clinical trials to optimize the efficiency and avoiding side effects of drugs in the treatment of ADPKD patients with PKD1 mutations. Furthermore, as TRPP2 deficiency by itself did not affect mTOR signaling, this may underlie the differences in phenotype, and genetic testing has to be considered for selecting patients for the ongoing trials.

Topics: Animals; Drug Synergism; Gene Knockdown Techniques; Humans; Metformin; Mice; Mutation; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels; Up-Regulation

Topics: Female; Humans; Immunosuppressive Agents; Kidney Diseases, Cystic; Male; Polycystic Kidney, Autosomal Dominant; Sirolimus

Polycystic kidney disease (PKD) in humans involves kidney cyst expansion beginning in utero. Recessive PKD can result in end-stage renal disease (ESRD) within the first decade, whereas autosomal dominant PKD (ADPKD), caused by mutations in the PKD1 or PKD2 gene, typically leads to ESRD by the fifth decade of life. Inhibition of mTOR signalling was recently found to halt cyst formation in adult ADPKD mice. In contrast, no studies have investigated potential treatments to prevent cyst formation in utero in recessive PKD. Given that homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in foetal Pkd1 homozygous mutant mice.. Pregnant Pkd1(+/-) female mice (mated with Pkd1(+/-) male mice) were treated with rapamycin from E14.5 to E17.5. Foetal kidneys were dissected, genotyped and evaluated by cyst size as well as expression of the developmental marker, Pax2.. Numerous cysts were present in Pkd1(-/-) kidneys, which were twice the weight of wild-type kidneys. Cyst size was reduced by a third in rapamycin-treated Pkd1(-/-) kidney sections and kidney mass was reduced to near wild-type levels. However, total cyst number was not reduced compared with control embryos. Pax2 expression and kidney development were unaltered in rapamycin-treated mice but some lethality was observed in Pkd1(-/-) null embryos.. Rapamycin treatment reduces cyst formation in Pkd1(-/-) mutant mice; therefore, the prevention of kidney cyst expansion in utero by mTOR inhibition is feasible. However, selective rapamycin-associated lethality limits its usefulness as a treatment in utero.

Topics: Animals; Embryo, Mammalian; Feasibility Studies; Female; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Gestational Age; Homozygote; Kidney; Male; Mice; Mice, Inbred C3H; Mice, Knockout; PAX2 Transcription Factor; Phenotype; Polycystic Kidney, Autosomal Dominant; Protein Kinase Inhibitors; Sequence Deletion; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels

Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomal-dominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in rodent models, but clinical trials have not shown benefit, possibly as a result of low tissue concentrations of rapamycin at clinically tolerable doses. To overcome this limitation, we synthesized a folate-conjugated form of rapamycin (FC-rapa) that is taken up by folate receptor-mediated endocytosis and cleaved intracellularly to reconstitute the active drug. We found that renal cyst-lining cells highly express the folate receptor in ADPKD and mouse models. In vitro, FC-rapa inhibited mTOR activity in a dose- and folate receptor-dependent manner. Treatment of a PKD mouse model with FC-rapa inhibited mTOR in the target tissue, strongly attenuated proliferation and growth of renal cysts and preserved renal function. Furthermore, FC-rapa inhibited mTOR activity in the kidney but not in other organs. In summary, these results suggest that targeting the kidney using FC-rapa may overcome the significant side effects and lack of renal efficacy observed in clinical trials with mTOR inhibitors in ADPKD.

Topics: Animals; Cell Line; Disease Models, Animal; Endocytosis; Folate Receptors, GPI-Anchored; Folic Acid; Humans; Kidney; Mice; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser473) Akt (p-Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser657) PKCα, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser473) was decreased by rapamcyin. PKCα (Ser657) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser473) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats.

Topics: Animals; Apoptosis; Caspase 3; Female; Polycystic Kidney, Autosomal Dominant; Protein Kinase C-alpha; Proto-Oncogene Proteins c-akt; Rats; Ribosomal Protein S6; Sex Characteristics; Sirolimus; TOR Serine-Threonine Kinases

The human condition autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of cysts in the kidneys that increase renal volume and lead to kidney failure. Mice studies are performed for treatment development monitored with imaging. The analysis of the imaging data is typically manual, which is costly and potentially biased. This paper presents a reliable and reproducible method for the automated segmentation of polycystic mouse kidneys.. Treated and untreated mice have been imaged longitudinally with high field anatomic MRI. The region of interest (ROI) of the kidneys in the images is identified and restored for artifacts. It is then analyzed statistically and geometric models are estimated for each kidney. The statistical and geometric information are provided to the graph cuts algorithm that delineates the kidneys.. The accuracy of the analysis has been demonstrated by showing consistency with results obtained with previous methods as well as by comparing with manual segmentations.. The method developed can accelerate and improve the accuracy of kidney volumetry in preclinical treatment trials for ADPKD.

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Immunosuppressive Agents; Magnetic Resonance Imaging; Mice; Morpholines; Organ Size; Polycystic Kidney, Autosomal Dominant; Reproducibility of Results; Sirolimus; Spiro Compounds; Treatment Outcome

Topics: Everolimus; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Organ Size; Polycystic Kidney, Autosomal Dominant; Sirolimus; TOR Serine-Threonine Kinases

Topics: Disease Progression; Everolimus; Glomerular Filtration Rate; Humans; Kidney; Organ Size; Polycystic Kidney, Autosomal Dominant; Sirolimus; TOR Serine-Threonine Kinases

Topics: Disease Progression; Everolimus; Glomerular Filtration Rate; Humans; Kidney; Organ Size; Polycystic Kidney, Autosomal Dominant; Sirolimus; TOR Serine-Threonine Kinases

In autosomal dominant polycystic kidney disease, cysts arise focally and disrupt normal renal tissue leading to renal failure. In the present study, we show that cyst-lining cells express the stem cell marker CD133. CD133+ progenitor cells isolated from polycystic kidney, carrying mutations of PKD genes, showed a dedifferentiated phenotype similar to CD133+ progenitor cells from normal kidney. However, these cells were more proliferative and presented a defective epithelial differentiation phenotype with respect to normal renal CD133+ cells as they were not able to express all tubular epithelial cell markers when cultured in epithelial differentiation medium. Polycystic CD133+ cells, in contrast to normal renal CD133+ cells, formed cysts in vitro in a three-dimensional culture system and in vivo when injected subcutaneously within Matrigel in SCID mice. Rapamycin treatment reduced in vitro proliferation of polycystic CD133+ cells and decreased cystogenesis both in vitro and in vivo. The in vitro epithelial differentiation was only partially improved by rapamycin. These results indicate that polycystic CD133+ cells retain a dedifferentiated phenotype and the ability to generate cysts.

Topics: AC133 Antigen; Animals; Antigens, CD; Apoptosis; Cell Differentiation; Cell Proliferation; Cells, Cultured; Glycoproteins; Humans; Kidney; Mice; Mice, SCID; Mutation, Missense; Peptides; Polycystic Kidney, Autosomal Dominant; Sirolimus; Stem Cells; TOR Serine-Threonine Kinases; Transplantation, Heterologous; TRPP Cation Channels

Polycystic liver disease may complicate autosomal dominant polycystic kidney disease (ADPKD), a disease caused by mutations in polycystins, which are proteins that regulate signaling, morphogenesis, and differentiation in epithelial cells. The cystic biliary epithelium [liver cystic epithelium (LCE)] secretes vascular endothelial growth factor (VEGF), which promotes liver cyst growth via autocrine and paracrine mechanisms. The expression of insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor (IGF1R), and phosphorylated mammalian target of rapamycin (p-mTOR) and the protein kinase A (PKA)-dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) are also up-regulated in LCE. We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha (HIF1alpha)-dependent VEGF secretion by IGF1 and ERK1/2. Conditional polycystin-2-knockout (Pkd2KO) mice were used for in vivo studies and to isolate cystic cholangiocytes [liver cystic epithelial cells (LCECs)]. The expression of p-mTOR, VEGF, cleaved caspase 3 (CC3), proliferating cell nuclear antigen (PCNA), IGF1, IGF1R, phosphorylated extracellular signal-regulated kinase, p-P70S6K, HIF1alpha, and VEGF in LCE, LCECs, and wild-type cholangiocytes was studied with immunohistochemistry, western blotting, or enzyme-linked immunosorbent assays. The cystic area was measured by computer-assisted morphometry of pancytokeratin-stained sections. Cell proliferation in vitro was studied with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and bromodeoxyuridine assays. The treatment of Pkd2KO mice with the mTOR inhibitor rapamycin significantly reduced the liver cyst area, liver/body weight ratio, pericystic microvascular density, and PCNA expression while increasing expression of CC3. Rapamycin inhibited IGF1-stimulated HIF1alpha accumulation and VEGF secretion in LCECs. IGF1-stimulated LCEC proliferation was inhibited by rapamycin and SU5416 (a vascular endothelial growth factor receptor 2 inhibitor). Phosphorylation of the mTOR-dependent kinase P70S6K was significantly reduced by PKA inhibitor 14-22 amide and by the mitogen signal-regulated kinase inhibitor U1026.. These data demonstrate that PKA-dependent up-regulation of mTOR has a central role in the proliferative, antiapoptotic, and pro-angiogenic effects of IGF1 and VEGF in polycystin-2-defective mice. This study also highlights a mechanistic link between PKA, ERK, mTOR, and HIF1alpha-mediated VEGF secretion and provides a proof of concept for the potential use of mTOR inhibitors in ADPKD and conditions with aberrant cholangiocyte proliferation.

Topics: Animals; Cysts; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Liver Diseases; Mice; Polycystic Kidney, Autosomal Dominant; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels; Vascular Endothelial Growth Factor A

Topics: Disease Progression; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Liver; Liver Diseases; Octreotide; Polycystic Kidney, Autosomal Dominant; Sirolimus; Somatostatin; Treatment Outcome

Topics: Everolimus; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Organ Size; Polycystic Kidney, Autosomal Dominant; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, and sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to significantly retard cyst expansion in animal models. The optimal therapeutic dose of sirolimus is not yet defined. Here, we report the history of a previously unknown ADPKD deceased donor whose kidneys were engrafted in two different recipients. One of the two received an immunosuppressive regimen based on sirolimus for 5 years while the other did not. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a new hypomorphic mutation in PKD1. The rate of cyst growth was identical in the two patients regardless of the treatment. While sirolimus treatment reduced the activation of mTOR in peripheral blood mononuclear cells, it failed to prevent mTOR activation in kidney tubular cells, this could account for the inefficiency of treatment on cyst growth. Together, our results suggest that the dose of sirolimus required to inhibit mTOR varies according to the tissue.

Topics: Adult; Blotting, Western; Creatinine; Exons; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Introns; Kidney Transplantation; Liver Transplantation; Magnetic Resonance Imaging; Male; Polycystic Kidney, Autosomal Dominant; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels

In autosomal dominant polycystic kidney disease (ADPKD), abnormal proliferation of tubular cells drives cyst development and growth. Sirolimus, an inhibitor of the protein kinase mammalian target of rapamycin (mTOR) and a potent anti-proliferative agent, decreases cyst growth in several genetically distinct rodent models of polycystic kidney disease (PKD). We determined here the effect of sirolimus on renal cyst growth in Pkd2WS25/- mice; an ortholog of human ADPKD involving mutation of the Pkd2 gene. In Pkd2WS25/- mice treated with sirolimus, both the two kidney/total body weight (2K/TBW) ratio and the cyst volume density (CVD) were significantly decreased by over half compared with untreated mice suffering with PKD. However, there was no effect on the increased blood urea nitrogen (BUN) levels as an index of kidney function. There are two distinct complexes containing mTOR depending on its binding partners: mTORC1 and mTORC2. Western blot analysis of whole kidney lysates and immunohistochemistry of the cysts found that phospho-S6 ribosomal protein, a marker of mTORC1 activity, was increased in Pkd2WS25/- mice and its phosphorylation was decreased by sirolimus treatment. Phospho-Akt at serine 473, a marker associated with mTORC2 activity, was not different between Pkd2WS25/- mice and normal littermate controls. Hence, our study found that inhibition of mTORC1 by sirolimus correlated with decreased renal cyst growth in this model of human ADPKD but had no effect on the decline in renal function.

Topics: Animals; Body Weight; Cysts; Disease Models, Animal; Disease Progression; Humans; Immunosuppressive Agents; Kidney; Kidney Function Tests; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Mutant Strains; Multiprotein Complexes; Organ Size; Polycystic Kidney, Autosomal Dominant; Proteins; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels

Topics: Animals; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Everolimus; Glomerular Filtration Rate; Humans; Mutation; Phosphatidylinositol 3-Kinases; Polycystic Kidney, Autosomal Dominant; Rats; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels

Topics: Angiotensin-Converting Enzyme Inhibitors; Dioxanes; Everolimus; Glomerular Filtration Rate; Glucosyltransferases; Humans; Polycystic Kidney, Autosomal Dominant; Pyrrolidines; Sirolimus

Topics: Disease Progression; Everolimus; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Polycystic Kidney, Autosomal Dominant; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome in which severe renal cystic disease can occur. Many renal cystic diseases, including autosomal dominant polycystic kidney disease (ADPKD), are associated with absence or dysfunction of the primary cilium. We report here that hamartin (TSC1) localizes to the basal body of the primary cilium, and that Tsc1(-/-) and Tsc2(-/-) mouse embryonic fibroblasts (MEFs) are significantly more likely to contain a primary cilium than wild-type controls. In addition, the cilia of Tsc1(-/-) and Tsc2(-/-) MEFs are 17-27% longer than cilia from wild-type MEFs. These data suggest a novel type of ciliary disruption in TSC, associated with enhanced cilia development. The TSC1 and TSC2 proteins function as a heterodimer to inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1). The enhanced ciliary formation in the Tsc1(-/-) and Tsc2(-/-) MEFs was not abrogated by rapamycin, which indicates a TORC1-independent mechanism. Polycystin 1 (PC1), the product of the PKD1 gene, has been found to interact with TSC2, but Pkd1(-/-) MEFs did not have enhanced ciliary formation. Furthermore, while activation of mTOR has been observed in renal cysts from ADPKD patients, Pkd1(-/-) MEFs did not have evidence of constitutive mTOR activation, thereby underscoring the independent functions of the TSC proteins and PC1 in regulation of primary cilia and mTOR. Our data link the TSC proteins with the primary cilium and reveal a novel phenotype of enhanced ciliary formation in a cyst-associated disease.

Topics: Animals; Cell Line; Cells, Cultured; Cilia; Fibroblasts; Humans; Kidney; Mice; Mice, Knockout; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Sirolimus; Transcription Factors; TRPP Cation Channels; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

The aim of our study was to determine total cystic volume in a mouse model of PKD using MR imaging to monitor therapeutic effects in vivo.. We imaged eight female pcy-mice in two groups: four belonged to an untreated control group and four were treated with the anticystic agent rapamycin, which has proven to be effective in reducing cystogenesis in animal models. The mice were imaged using a 9.4 Tesla animal scanner. MRI measurements were taken at six time points during the therapy. Total renal volumes and total cyst volumes were calculated using a thresholding approach.. During the course of the treatment, the total cyst volume increased significantly faster than the total renal volume in the untreated group, indicating that growth of the total renal volume in the untreated group was primarily due to the growth of the cysts, rather than the parenchyma. The measured total renal volume in the control (placebo) group was significantly higher than the volume in the treated group.. Using MRI, we were able to monitor the cystic volume in a mouse model of PKD to assess the therapeutic effect of anticystic treatment.

Topics: Animals; Female; Kidney; Magnetic Resonance Imaging; Mice; Polycystic Kidney, Autosomal Dominant; Sirolimus

Topics: Anti-Bacterial Agents; Brain; Combined Modality Therapy; Disease Progression; Fatal Outcome; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Nephrogenic Fibrosing Dermopathy; Plasmapheresis; Polycystic Kidney, Autosomal Dominant; Renal Dialysis; Sirolimus

Topics: Antidiuretic Hormone Receptor Antagonists; Apoptosis; Body Fluids; Caspases; Cell Proliferation; Clinical Trials as Topic; Cyclic AMP; Hormone Antagonists; Humans; Kidney; Nephrology; Polycystic Kidney, Autosomal Dominant; Receptors, Vasopressin; Sirolimus; Treatment Outcome

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease in the United States and causes end-stage renal failure requiring dialysis and renal transplantation. There is no effective treatment for ADPKD in humans. However, there are now multiple clinical trials testing a host of therapeutic interventions in children and adults with ADPKD. The major therapeutic interventions being tested in patients with ADPKD include Tolvaptan, Octreotide, Sirolimus, Everolimus, and statins, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Child; Clinical Trials as Topic; Growth Hormone; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Failure, Chronic; Octreotide; Polycystic Kidney, Autosomal Dominant; Protein Kinases; Sirolimus; Tolvaptan; TOR Serine-Threonine Kinases

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by dysregulated tubular epithelial cell growth, resulting in the formation of multiple renal cysts and progressive renal failure. To date, there is no effective treatment for ADPKD. The mammalian target of rapamycin (mTOR) is an atypical protein kinase and a central controller of cell growth and proliferation. We examined the effect of the mTOR inhibitor sirolimus (rapamycin) on renal functional loss and cyst progression in the Han:SPRD rat model of ADPKD.. Five-week-old male heterozygous cystic (Cy/+) and wild-type normal (+/+) rats were administered sirolimus (2 mg/kg/day) orally through the drinking water for 3 months. The renal function was monitored throughout the treatment phase, and rats were sacrificed thereafter. Kidneys were analysed histomorphometrically, and for the expression and phosphorylation of S6K, a well-characterized target of mTOR in the regulation of cell growth.. The steady increase in BUN and creatinine in Cy/+ rats was reduced by 39 and 34%, respectively with sirolimus after 3 months treatment. Kidney weight and 2-kidney/total body weight (2K/TBW) ratios were reduced by 34 and 26% in sirolimus-treated Cy/+ rats. Cyst volume density was also reduced by 18%. Of importance, Cy/+ rats displayed enhanced levels of total and phosphorylated S6K. Sirolimus effectively reduced total and phosphorylated levels of S6K.. We conclude that oral sirolimus markedly delays the loss of renal function and retards cyst development in Han:SPRD rats with ADPKD. Our data also suggest that activation of the S6K signalling pathway plays an important role in the pathogenesis of PKD. Sirolimus could be a useful drug to retard progressive renal failure in patients with ADPKD.

Topics: Administration, Oral; Animals; Biomarkers; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Disease Progression; Immunosuppressive Agents; Male; Phosphorylation; Polycystic Kidney, Autosomal Dominant; Protein Kinases; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Increased tubular epithelial cell proliferation is a prerequisite for cyst formation and expansion in polycystic kidney disease (PKD). Rapamycin is a potent antiproliferative agent. The aim of the present study was to determine the effect of rapamycin on tubular cell proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 wk of age and then treated with rapamycin 0.2 mg/kg per d intraperitoneally or vehicle (ethanol) for 5 wk. Vehicle-treated Cy/+ rats had a more than doubling of kidney size compared with +/+ rats. Rapamycin reduced the kidney enlargement by 65%. Rapamycin significantly reduced the cyst volume density in Cy/+ rats by >40%. Blood urea nitrogen was 59% increased in vehicle-treated Cy/+ rats compared with +/+ rats. Rapamycin reduced the blood urea nitrogen to normal in Cy/+ rats. The number of proliferating cell nuclear antigen (PCNA)-positive cells per noncystic tubule was eightfold increased in vehicle-treated Cy/+ compared with +/+ rats. Rapamycin significantly reduced the number of PCNA-positive cells in noncystic tubules of Cy/+ rats. In addition, the number of PCNA-positive cells per cyst in Cy/+ rats was significantly reduced by rapamycin. In summary, in a rat model of PKD, rapamycin treatment (1) decreases proliferation in cystic and noncystic tubules, (2) markedly inhibits renal enlargement and cystogenesis, and (3) prevents the loss of kidney function.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Cell Division; Disease Progression; Immunosuppressive Agents; Male; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Renal Insufficiency; Sirolimus

Topics: Adult; Antilymphocyte Serum; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Plasmapheresis; Platelet Count; Polycystic Kidney, Autosomal Dominant; Postoperative Complications; Sirolimus; Thrombosis; Treatment Outcome