Table 1.
Treatment strategies in ADPKD: clinical trials and in vivo studies
| References; ClinicalTrials.gov numbers | Eligibility | Outcome | Duration (months) | Number of patients (drop out rate) | |
|---|---|---|---|---|---|
| Clinical trials: mTOR inhibitor | |||||
| Everolimus (mTOR inhibitor) | [188] NCT00414440 | eGFR 30–89 ml/min; age 18–65 years | Kidney volume increased less in everolimus group (significant after first year but not after second year); no significant difference in kidney function | 24 | 433 randomized, 329 completed (vehicle: 14.7 %; Everolimus: 32.7 %) |
| Sirolimus (mTOR inhibitor) | [187] NCT00346918 | eGFR at least 70 ml/min; age 18–40 years | No significance in TKV and eGFR; urinary albumin-to-creatinine ratio higher in sirolimus group | 18 | 100 randomized, 96 completed (vehicle: 2 Sirolimus: 2) |
| Sirolimus (mTOR inhibitor) SIRENA Study | [189] NCT00491517 | eGFR at least 40 ml/min; age 18–80 years | TKV and cyst volume increased less; parenchymal volume increased more; no significant difference in kidney function; albuminuria and proteinuria significantly increased with sirolimus | 6 | 21 randomized, 15 completed |
| Clinical trials: somatostatin analogue | |||||
| Octreotide (long-acting somatostatin analogue) | [178] NCT00426153 | No criteria for eGFR; Polycystic Liver Disease associated with ADPKD or isolated Autosomal Dominant Polycystic Liver Disease; age 18–80 years | Significantly less increase of total kidney and liver volume; no significant difference in GFR | 12 | 42 randomized, 42 completed |
| Lanreotide (long-acting somatostatin analogue) | [179] NCT00565097 | No patients requiring hemodialysis because of renal failure; patients with ADPKD and patients with Polycystic Liver Disease | Reduction of total kidney and liver volume; no significant difference in serum creatinine | 6 | 54 randomized, 53 completed (vehicle: 1) |
| Octreotide (long-acting somatostatin analogue) | NCT00309283 Estimated completion: Dec 2011 | eGFR over 40 ml/min; age 18–75 years | Parameters measured: TKV; kidney parenchymal volume; kidney cyst/intermediate volume | 36 | 78 (estimated) |
| Octreotide (long-acting somatostatin analogue) | NCT01377246 Estimated completion: Dec 2015 | eGFR 15–40 ml/min; age 18–75 years | Parameters measured: TKV; GFR; kidney parenchymal, cyst and intermediate volume; liver and liver cyst volume | 36 | 80 (estimated) |
| Clinical trial: HMG-CoA reductase inhibitor | |||||
| Parvastatin (HMG-CoA reductase inhibitor) in Lisinopril (ACE inhibitor) treated patients | [210] NCT00456365 Estimated completion: Apr 2011 | Normal kidney function; age 8–21 years | Parameters measured: TKV, left ventricular mass index, urinary albumin excretion | 36 | 100 |
| Clinical trial: ACE-inhibitor/angiotensin II receptor antagonist | |||||
| Lisinopril (ACE inhibitor) monotherapy vs. Telmisartan (angiotensin II receptor antagonist)/Lisinopril combination therapy with low or standard blood pressure control HALT-PKD studies | NCT00283686 Estimated completion: April 2013 | Study A: eGFR over 60 ml/min; Study B: eGFR 25–60 ml/min; Blood pressure over 130/80 or receiving treatment for hypertension; age 15–64 years | Study A: Change in TKV; Study B: Time to the 50 % reduction of baseline eGFR, end-stage renal disease, or death | 48 | 1,018 |
| Clinical trials: vasopressin V2R antagonists | |||||
| Tolvaptan (vasopressin V2R antagonist) TEMPO 2/4 Trial | [211, 212] NCT00413777 | eGFR at least 30 ml/min; no renal-replacement therapy; prior participation in designated tolvaptan ADPKD studies; age over 18 years | Assessment of long-term safety (48 months): all experienced adverse events; six of 12 withdrawals account for adverse events; assessment of disease progression (36 month): less increase in TKV; no significantly reduced increase in eGFR; increasing TKV correlated with decreasing eGFR | 36–48 | 63 (12) |
| Tolvaptan (vasopressin V2R antagonist) TEMPO 3/4 Trial | [211, 212] NCT00428948 Estimated completion: May 2012 | eGFR at least 60 ml/min; TKV at least 750 cm3; prior exposure to tolvaptan or other experimental PKD therapies; age 18–50 years | Parameters measured: TKV change; time to onset of multiple ADPKD outcomes (e.g., worsening of renal function, hypertension, albuminuria); evaluation of long-term safety | 36 | 1,445 |
| Tolvaptan (vasopressin V2R antagonist) TEMPO 4/4 Trial | [211, 212] NCT01214421 Estimated completion: Aug 2014 | Successful completion of a phase 1, 2, or 3 tolvaptan ADPKD or renal impairment trial; age 18 years or older | Parameters measured: TKV; eGFR; evaluation of safety endpoints and multiple ADPKD outcomes | 24 | 1,500 |
| Clinical trial: Triptolide | |||||
| Triptolide (active diterpene in the traditional Chinese medicine Tripterygium wilfordii) | NCT00801268 Estimated completion: Sep 2012 | eGFR over 30 ml/min; age 15–70 years | Parameters measured: TKV; eGFR; end-stage renal disease | 36 | 150 |
| Clinical trials: Multi kinase inhibitor | |||||
| Bosutinib/SKI-606 (primary targets: Abl, Src, HDAC) | NCT01233869 Estimated completion: Feb 2019 | eGFR at least 60 ml/min; TKV at least 750 cm3; 18–50 years of age | Safety endpoints; rate of kidney enlargement; renal function | 24 | 275 |
| References | In vivo model | In vivo results | Treatment schedule; administration of the drug | |
|---|---|---|---|---|
| Preclinical studies: mTOR inhibitor | ||||
| Rapamycin (mTOR-Inhibitor) | [97] | Orpk-rescue mouse (Tg737orpk/orp;TgRsq) | Decrease in cystic index and kidney volume (MRI: day P150, P164, P178); apoptosis increased in cyst lining epithelium | P150–P178; daily intraperitoneal injection |
| Bpk mouse | Decrease in cystic index, kidney weight as % of BW, and blood urea nitrogen | P7–P21; daily intraperitoneal injection | ||
| [208] | Pkd1cond/cond; NestinCre | Decrease in cystic index, kidney weight as % of BW, blood urea nitrogen, renal fibrosis, proliferation and apoptosis | P28–P49; daily intraperitoneal injection | |
| Sirolimus (mTOR-Inhibitor) | [209] | Pkd2WS25/− mouse | Decrease in kidney weight as % of BW and cystic volume density, fibrosis (no significant difference in blood urea nitrogen) | 4–16 weeks of age; daily intraperitoneal injection |
| Preclinical studies: Vasopressin V2R antagonists | ||||
| OPC31260 (vasopressin V2 receptor antagonist) | [180] | PCK rat | Decrease in kidney weight as % of BW, cyst volume as % of BW, blood urea nitrogen, fibrosis volume as % of BW, apoptosis index (%), mitotic index (%), and systemic blood pressure (PCK rat only) | 3–10 weeks of age; 10–18 weeks of age; added to chow |
| Pcy mouse | 4–30 weeks of age; 15–30 weeks of age; added to chow | |||
| [181] | Pkd2–/tm1Som mouse | Decrease in kidney weight as % of BW, cyst volume as % of BW, and blood urea nitrogen; no significant decrease in systemic blood pressure | 3–16 weeks of age; added to chow | |
| Genetic arginine vasopressin (AVP) depletion (Brattleboro rats) | [182] | PCK; AVP +/+ PCK; AVP ± PCK; AVP-/- | Decrease in kidney weight as % of BW, cyst volume (%), fibrosis volume (%), urine volume, and blood urea nitrogen | 12–20 weeks of age; ± V2 receptor agonist (1-deamino-8-D -arginine vasopressin); continuous subcutaneous administration |
| Preclinical studies: Triptolide | ||||
| Triptolide (Tripterygium wilfordii) | [185] | Pkd1-/- mouse | Decrease in % cystic burden | E10.5 until birth; daily intraperitoneal injection of pregnant mice |
| [213] | Pkd1flox/-; Ksp-Cre mouse | Decrease in kidney weight as % of BW, cystic burden, cyst number and size, proliferation | P1–P4; daily intraperitoneal injection of lactating mother | |
| Decrease in kidney weight as % of BW and blood urea nitrogen | P1–P8; daily intraperitoneal injection of lactating mother (P1–P5) and P6–P8 intraperitoneal injections in pubs | |||
| [214] | Pkd1flox/flox; Mx1Cre mouse; (cyst induction P10/P12) | Decrease in number of renal cysts, cystic burden, proliferation, and blood urea nitrogen (P22 and P35); reduction in microcysts | P16–P35; daily intraperitoneal injection | |
| Preclinical studies: Multi kinase inhibitor | ||||
| Bosutinib/SKI-606 (primary targets: Src, Abl, HDAC) | [186] | Bpk mouse | Decrease in kidney weight as % of BW, cystic index, blood urea nitrogen and creatinine; increase in maximum urinary concentrating ability; less biliary ductal ectasia | P7–P21; daily intraperitoneal injection |
| PCK rat (male) | Decrease in kidney weight as % of BW, renal cystic volume, liver weight as % of BW, blood urea nitrogen and creatinine; increase in maximum urinary concentrating ability; reduction in biliary ductal cysts and hepatic fibrosis | P7–P89; daily intraperitoneal injection | ||
| [215] | C57/Pkd1 ± mouse | Decrease in cyst number and kidney weight | 5–8 months of age; (8–11 month of age); daily added in drinking water | |
| Preclinical studies: HDAC inhibitor | ||||
| Trichostatin A (pan HDAC inhibitor) | [199] | Pkd2–/– mouse | Decrease in cystic area (%); HDAC5 heterozygosity reduces cyst formation | 10.5–18.5 day post-conception; daily subcutaneous injection in pregnant mice |
| Valproic acid (class I HDAC inhibitor) | [198] | Pkd1flox/flox; Pkhd1-Cre mouse | Decrease in kidney weight as % of BW, cystic index and blood urea nitrogen; | P10–P25; daily intraperitoneal injection |
| Various preclinical studies | ||||
| Roscovitine (cyclin-dependant kinase-inhibitor) | [216] | Jck mouse | Decrease in kidney weight as % of BW, cyst volume as % of BW, blood urea nitrogen (significant only with (1) and (2)); decreased proliferation; decreased apoptosis | Starting at P26: (1) treatment for 5 weeks; (2) treatment for 3 weeks, followed by 2 weeks without treatment; (3) 1 week on treatment followed by 1 week off treatment for a total of 5 weeks; daily intraperitoneal injection |
| Cpk mouse | Decrease in kidney weight as % of BW, cyst volume as % of BW, blood urea nitrogen, and creatinine | P7–P21; daily intraperitoneal injection | ||
| Vitamin K3 and PM-20 (Cdc25A inhibition) or genetic inactivation of Cdc25A | [202] | PCK rat; Pkd2ws25/− mouse; Cdc25A+/−; Pkhd1del2/del2 mouse | Decrease in liver and kidney weights, hepato-renal cystic and fibrotic areas, and mitotic and apoptotic indices; reduced liver weights and liver fibrosis in Cdc25A+/−:Pkhd1del2/del2 mice compared with Pkhd1del2/del2 | PCK rats starting age 3 weeks and Pkd2ws25/− mice starting age 5 months; PM-20: 4 weeks of treatment; daily intraperitoneal injection (Pkd2ws25/− mice only) Vitamin K3: 4 and 8 weeks of treatment; in drinking water every other day (PCK rats and Pkd2ws25/− mice); Cdc25A+/−: Pkhd1del2/del2 mouse: 7–9 months of age |
| PD184352 (MAP/ERK kinase inhibitor) | [217] | Pcy mouse | Decrease in kidney weight as % of BW, cystic index, serum creatinine, systemic blood pressure, and water intake; urine osmolality increased | 10–17 weeks of age; added to chow; daily for the first week and then every third day for 6 additional weeks |
| Leflunomide/teriflunomide (STAT6-inhibitor) or genetic inactivation of STAT6 | [194] | bpk/bpk mouse | Decrease in kidney weight as % of BW, cystic index, and blood urea nitrogen | P7–P21; daily intraperitoneal injection, every 2 days |
|
bpk/bpk: STAT6+/+ bpk/bpk: STAT6+/− bpk/bpk: STAT6−/− |
Decrease in kidney weight as % of BW, blood urea nitrogen, mean cyst diameter and number of renal proliferating cells; increase in number of normal tubules in bpk/bpk: STAT6−/− compared to bpk/bpk: STAT6+/+ animals; no change in apoptosis rate in the kidney | No treatment | ||
| Curcumin (inhibits mTOR, Wnt/beta-actin and STAT3 signaling) | [218] | iKsp-Pkd1del mice; (cyst induction P40–P42) |
Short treatment: Decrease in proliferation index, cystic index and kidney weight as % of BW Long treatment: renal failure significantly postponed in mice with severe PKD |
Starting 1 week after cyst induction; Short treatment: 11 weeks Long treatment: until renal failure occurs; added to chow |
| Genz-123346 (glucosylceramide synthase inhibitor, Akt-mTOR inhibitor) | [219] | Jck mouse | Decrease in kidney weight as % of BW, cyst volume as % of BW, blood urea nitrogen (jck and PKD1cond mouse), fibrosis (pcy mouse), apoptosis and proliferation (jck mouse) | 4–9 weeks of age; added to chow |
| Pcy mouse | 4–15 weeks of age; added to chow | |||
| Pkd1flox/−; Tamoxifen inducible Cre (Pkd1tm1Gzbd allele) (induction at day P5) | P7–P33; added to chow | |||
| Metformin (AMPK activator, mTOR and CFTR channel inhibitor) | [192] | Pkd1 flox/−; Ksp-Cre mouse | Decrease in cystic index | P4–P6; daily intraperitoneal injection |
| Pkd1 flox/−; pCX-CreER mouse;(cyst induction at P9 or P10) | Decrease in cystic index | P7–P17; daily intraperitoneal injection | ||
| Pioglitazone (PPAR-γ receptor agonist; inhibits mTOR and ERK signaling; inhibits CFTR expression) | [220] | PCK rat | Decrease in kidney and liver weight as % of BW, renal cyst volume, renal and liver fibrosis, and serum albumin | 3–10 weeks of age or 4–18 weeks of age; added to chow |
| [196] | PCK rat | Decrease in kidney and liver weight as % of BW, renal and liver cystic area, serum urea nitrogen, renal and hepatic proliferation, and fibrotic index in liver | 4–20 weeks of age; daily administration by gavage | |
| Tetrazolo-CFTRinh-172 and Ph-GlyH-101 (CFTR inhibitor) | [184] | Pkd1flox/+; Ksp-Cre mouse | Decrease in renal cyst number, kidney weight as % of BW, serum urea and creatinine | P2 through P5 or P9; subcutaneous injection every 6 h |
| R-568 (type II calcimimetic) | [221] | Pkd2−/WS25 mouse; PCK rat | No detectable effect on cystogenesis; decrease in renal interstitial fibrosis (PCK rats only); increase in urine output and osmolar clearance | Starting at 3 weeks of age; treatment for 10 (PCK rats) or 16 (mice) weeks of age; added to chow |
| [222] | Cy/+ male rat (Han: SPRD-Cyiu) | After 18 weeks: Decrease in kidney weight as % of BW, cyst volume, fibrosis (except calcium alone), blood urea nitrogen |
Starting at 20 weeks of age; treatment for 14–18 weeks: (1) no treatment, (2) R-568 only, (3) R-568 plus calcium, (4) calcium only; R-568 added in chow |
|
eGFR estimated glomerular filtration rate, TKV total kidney volume, BW body weight, MRI magnetic resonance imaging, mTOR mammalian target of rapamycin, HMG-CoA reductase 3-hydroxy-3-methylglutaryl co-enzyme A reductase, ACE inhibitor angiotensin-converting enzyme inhibitor, AVP arginine vasopressin, HDAC histone deacetylase inhibitor, MAP kinase mitogen-activated protein kinase, ERK extracellular signal-regulated kinase, STAT6 signal transducer and activator of transcription 6, AMPK 5′ adenosine monophosphate-activated protein kinase, CFTR cystic fibrosis transmembrane regulator, PPARγ peroxisome proliferator activator receptor γ