Selected highlights

The Translational PKD Center has published a number of high-impact publications since its inception. This is a selected list of publication highlights from the past 12 months.

Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner

Journal of Clinical Investigation. 2015;125:607.

Gainullin VG, Hopp K, Ward CJ, Hommerding CJ, Harris PC.

This study demonstrated that PC1 and PC2 first interact in the ER before PC1 cleavage at the GPS/GAIN site and that PC2 acts as an essential chaperone for PC1 maturation and surface localization. In Pkd2–/– mice, complete loss of PC2 prevented PC1 maturation.

Interbreeding between various Pkd1 and Pkd2 models revealed that animals with reduced levels of functional PC1 and PC2 in the kidney exhibited severe, rapidly progressive disease. This study highlights the interdependence of PKD1 and PKD2 at the molecular level.

Identification of biomarkers for PKD1 using urinary exosomes

Journal of the American Society of Nephrology. 2014, in press.

Hogan MC, Bakeberg JL, Gainullin VG, Irazabal MV, Harman AJ, Lieske JC, Charlesworth MC, Johnson KL, Madden BJ, Zenka RM, McCormick DJ, Sundsbak JL, Heyer CM, Torres VE, Harris PC, Ward CJ.

Label-free quantitative proteomic studies of urine exosomes revealed that out of 2,008 exosome proteins, nine (0.32 percent) were expressed at significantly different levels in samples from PKD1 patients compared with controls. In PKD1 patients, levels of PC1 and PC2 were reduced to 54 percent and 53 percent of normal, and TMEM2 was 2.1-fold higher in PKD1 patients.

The ratio of PC1/TMEM2 or PC2/TMEM2 could be used to distinguish individuals with PKD1 mutations from controls, and the PC1/TMEM2 ratio correlated inversely with height-adjusted total kidney volume. Therefore, measuring the urine exosomal PC2/TMEM2 ratio may have utility in monitoring PKD severity.

Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model

Journal of the American Society of Nephrology. 2015;26:39.

Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE.

The efficacy of the AC6 inhibitors tolvaptan and pasireotide, individually and in combination, were tested in the Pkd1RC/RC model in a five-month preclinical trial. Treatment with tolvaptan or pasireotide alone markedly reduced cyst progression but in combination showed a clear additive effect. The combination treatment also reduced cystic and fibrotic volume and decreased cAMP to wild-type levels.

The observed additive effect reinforces the central role of AC6 and cAMP in ADPKD pathogenesis and highlights the likely benefit of combination therapy for patients with ADPKD.

HALT-PKD trial

Blood pressure in early autosomal dominant polycystic kidney disease

New England Journal of Medicine. 2014;371:2255.

Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, Winklhofer FT, Brosnahan G, Czarnecki PG, Hogan MC, Miskulin DC, Rahbari-Oskoui FF, Grantham JJ, Harris PC, Flessner MF, Bae KT, Moore CG and Chapman AB, for the HALT-PKD Trial Investigators.

Angiotensin blockade in late autosomal dominant polycystic kidney disease

New England Journal of Medicine. 2014;371:2267.

Torres VE, Abebe KZ, Chapman AB, Schrier RW, Braun WE, Steinman TI, Winklhofer FT, Brosnahan G, Czarnecki PG, Hogan MC, Miskulin DC, Rahbari-Oskoui FF, Grantham JJ, Harris PC, Flessner MF, Moore CG and Perrone RD, for the HALT-PKD Trial Investigators.

These two studies reported the results of the HALT-PKD double-blind, placebo-controlled trial of ADPKD patients. They concluded that addition of an ARB to an ACE inhibitor did not slow the rate of decline in renal function or the rate of expansion of kidney size in ADPKD patients.

However, in younger patients, control of blood pressure to a low blood pressure target (95/60 to 110/75 mm Hg) compared to the standard target (120/70 to 130/80 mm Hg) slowed the rate of increase in kidney size, showed a greater decline in left-ventricular-mass index and a greater reduction in urinary albumin excretion, although did not slow the rate of decline in renal function. Therefore, low blood pressure targets may be of value in younger ADPKD patients.

Mesenchymal stromal cells improve renovascular function in polycystic kidney disease

Cell Transplant. 2014, in press.

Franchi F, Peterson KM, Xu R, Miller B, Psaltis PJ, Harris PC, Lerman LO, Rodriguez-Porcel M.

The potential of adult mesenchymal stem cells (MSCs) to restore renal structure and function in PKD was tested. MSC were intrarenally infused in PCK rats and four weeks later a lower decline in renal function was found compared to untreated rats. MSCs also preserved vascular density and glomeruli diameter, measured using micro-CT. MSCs treatment reduced fibrosis, while cyst size and number were unaltered by the cell infusion. In conclusion, MSC-based therapy constitutes a novel treatment option in PKD.

Centrosomal abnormalities characterize human and rodent cystic cholangiocytes and are associated with Cdc25A overexpression

American Journal of Pathology. 2014;184:110.

Masyuk TV, Lee SO, Radtke BN, Stroope AJ, Huang B, Banales JM, Masyuk AI, Splinter PL, Gradilone SA, Gajdos GB, LaRusso NF.

The hypothesis that centrosomal defects occur in cystic cholangiocytes was tested in Pkd2WS25/- mice, PCK rats and PLD patients. Cystic cholangiocytes had atypical centrosome positioning, supernumerary centrosomes, multipolar spindles, extra cilia and structurally aberrant cilia.

Depletion of Cdc25A resulted in decreased centrosome number and multiciliated cholangiocytes, longer cilia, cell cycle disruption, decreased cell proliferation and reduced cyst growth in vitro and in vivo. This data supports the hypothesis that centrosomal abnormalities in cholangiocytes are associated with aberrant ciliogenesis and are likely associated with overexpression of Cdc25A.

Imaging classification of autosomal dominant polycystic kidney disease: A simple model for selecting patients for clinical trials

Journal of the American Society of Nephrology. 2015;26:160.

Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, Bae KT, Chapman, Grantham JJ, Mrug M, Hogan MC, El-Zoghby ZM, Harris PC, Erickson BJ, King BF, Torres VE, and the CRISP Investigators.

The disease spectrum in autosomal dominant polycystic kidney disease (ADPKD) is highly variable, so predictive information about disease severity can be helpful in selecting patients for studies and in the future for treatment. By examining a large population of patients with CT or MRI images, from which height-adjusted total kidney volume (HtTKV) was estimated and with more than three estimated glomerular filtration rate (eGFR) measurements, the team was able to create a model based on HtTKV and age to predict future eGFR decline. This model can be used as a simple way to prioritize patients for enrollment in clinical trials.

Phosphodiesterase 1A modulates cystogenesis in zebrafish

Journal of the American Society of Nephrology. 2014;25:2222.

Sussman CR, Ward CJ, Leightner AC, Smith JL, Agarwal R, Harris PC, Torres VE.

Elevated cyclic adenosine monophosphate (cAMP) has been implicated in PKD. Inhibition of cAMP by phosphodiesterases (PDEs) is thought to also play a role in cyst development in PKD. By using a zebrafish model to study PDE, the team determined that depletion of PDE1 results in the formation of cysts and that it plays an important role in regulating the level of cAMP. This work identifies PDE1 as a potential new drug target for PKD.

Supervised segmentation of polycystic kidneys: A new application for stereology data

Journal of Digital Imaging. 2014;27:514.

Warner JD, Irazabal MV, Krishnamurthi G, King BF, Torres VE, Erickson BJ.

Kidney volume estimation using traditional imaging methods can be quite time-consuming. Using a volume-estimation method called stereology, the team developed a novel method to analyze polycystic kidneys. This method allows for true segmentation of PKD kidneys that opens the way for more elaborate analysis of these complex structures.