Larry T. Cook’s research while affiliated with University of Kansas and other places

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst and kidney growth, which is hypothesized to cause loss of functioning renal mass and eventually end-stage kidney disease. However, the time course of decline in glomerular filtration rate (GFR) is poorly defined. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease study is a 14-year observational cohort study of 241 adults with ADPKD. As an estimate of the rate of kidney growth, participants were stratified into 5 subclasses based on baseline age and magnetic resonance imaging measurements of total kidney volume (TKV) according to the method of Irazabal. GFR trajectories spanning over four decades of life were reconstructed and fitted using mixed polynomial models, which were validated using data from the HALT-PKD study. GFR trajectories were nonlinear, with a period of relative stability in most participants, followed by accelerating decline. The shape and slope of these trajectories were strongly associated with baseline Irazabal class. Patients with PKD1 mutations had a steeper GFR decline than patients with PKD2 mutations or with no detected mutation, largely mediated by the effect of genotype on Irazabal class. Thus, GFR decline in ADPKD is nonlinear, and its trajectory throughout adulthood can be predicted from a single measurement of kidney volume. These models can be used for clinical prognostication, clinical trial design, and patient selection for clinical interventions. Our findings support a causal link between growth in kidney volume and GFR decline, adding support for the use of TKV as a surrogate endpoint in clinical trials.

In autosomal dominant polycystic kidney disease, progressive renal enlargement secondary to expanding cysts is a hallmark. The total cyst load and range of cyst diameters are unknown. The purpose of this study was to quantify the total number and range of diameters of individual cysts in adults with preserved GFR. A retrospective, morphometric analysis of renal cyst number and diameter using magnetic resonance images from eight adult autosomal dominant polycystic kidney disease patients was performed at baseline and after 6.9 years. Cyst number and diameter were measured in microscopic sections of nephrectomy specimens from five different adults. The diameters of 1010 cysts ranged from 0.9 to 77.1 mm in baseline T2 magnetic resonance images, and the mean total number of cysts increased from 682 to 1002 in 6.9 years. However, magnetic resonance imaging detects only cysts above the lower limit of detection. In 405 cysts measured in nephrectomy specimens, 70% had diameters <0.9 mm. Cyst counts by magnetic resonance in eight subjects compared with histology revealed approximately 62 times more cysts below the limit of magnetic resonance imaging detection than above it. This study presents quantitative data indicating that renal cysts develop in a minority of renal tubules. Increased numbers detected by magnetic resonance imaging are caused primarily by cysts below detection at baseline enlarging to a detectable diameter over time. The broad range of diameters, with a heavy concentration of microscopic cysts, may be most appropriately explained by a formation process that operates continuously throughout life.

In autosomal dominant polycystic kidney disease, cysts derived from tubules are detected at birth by ultrasound (threshold for detection >7.0 mm); thus, fetal cyst growth rates must exceed 2300%/yr. In adults, the combined renal cyst component enlarges at approximately 12%/yr by growth of individual cysts. To explore this discrepancy, the growth rates of individual cysts were determined in adult polycystic kidneys. Diameter, volume, and growth rates of individual cysts were measured by magnetic resonance in 30 individual cysts in three adult patients over a span of 3 years. Results were confirmed in 22 cysts measured in five patients by computed tomography over a span of 11 years. Mean cyst diameters were 20.4 +/- 9.9 mm (range 7.1 to 40.5 mm) at baseline and 25.8 +/- 15.6 mm (range 7.8 to 49.6 mm) after 3 years. Mean cyst volumes, determined by manual segmentation and summation of magnetic resonance cross sections, were 8.7 +/- 12.9 cm(3) (0.3 to 43.3 cm(3)) and 24.2 +/- 66.3 cm(3) (0.3 to 364.8 cm(3)) after 3 years. Mean cyst growth rates ranged from 6.9 to 23.9%/yr; the maximum growth rate was 71.1%/yr, far less than required to develop a 7-mm diameter cyst in utero. Results were similar in 22 cysts examined by computed tomography. It was concluded that renal cysts detected by ultrasound in newborns must have grown at exuberant rates in utero; thereafter, expansion appears to proceed at much slower rates.

The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) recently showed that renal enlargement in autosomal-dominant polycystic kidney disease mimicked exponential growth. We determined the effects of cyst initiation rate, total number, and growth rate on the time-dependent change of total cyst volume (TCV). Mathematical models with equations integrating cyst surface area, volume, and an invariant growth rate constant were used to compute the time-dependent change in volume of solitary and multiple cysts. Multiple expanding cysts increased TCV in an exponential-like pattern even when individual cysts formed at different rates or exhibited different but constant growth rates. TCV depended on the rate of cyst initiation and on the total number of cysts; however, the compounding effect of exponential-like growth was the most powerful determinant of long-term cyst expansion. Extrapolation of TCV data plots for individual subjects back to an age of 18 predicted TCV values within an established range. We conclude that cysts started early in life were the main contributor to eventual TCV while their growth rate primarily determined renal size; although the rate of formation and the ultimate number of cysts also contributed. The good fit between the exponential models and the extrapolated CRISP data indicates that the TCV growth rate is a defining trait for individual patients and may be used as a prognostic marker.

The cost of recording and archiving digital diagnostic imaging data is presented for a Radiology Department serving a 614 bed University-Hospital with a large outpatient population. Digital diagnostic imaging modalities include computed tomography, nuclear medicine, ultrasound, and digital radiography. The archiving media include multiformat video film recordings, magnetic tapes, and disc storage. The estimated cost per patient for the archiving of digital diagnostic imaging data is presented.

We are developing a clinical ultrasonic imaging system for real-time estimation and display of tissue elastic properties. We have demonstrated that real-time feedback of elasticity images is essential for obtaining high-quality data (consecutive images with high spatial coherence). The key element to successful scanning is real-time visual feedback which guides the patient positioning and compression direction. Our data have clearly demonstrated nonlinearity in the strain properties of different tissue types. We have also demonstrated that a comparison of the area of a breast lesion observed in strain images versus B-mode images is a sensitive criterion for differentiating malignant from benign tumors. Frame-to-frame variability in strain images somewhat degrades the ability to observe these phenomena. Three strategies for reducing frame-to-frame strain image noise are described. The combination of these post-processing strategies provides a significant improvement in the quality of long sequences of strain images.

We are developing a system for real-time estimation and display of tissue elastic properties using a clinical ultrasonic imaging system. Results in phantoms are in excellent agreement with that predicted with finite element analysis. Results in volunteer patients have shown that high quality elasticity images are easily obtained in vivo in breast and thyroid pathologies. The key element to successful scanning is real-time visual feedback which guides the patient positioning and compression direction. Results show that the frame-to-frame changes in strain image contrast appear to be unique to specific lesion types. In addition, the size of a lesion displayed in a strain image, relative to that in a standard B-mode image, is about the same for benign lesions but the size is considerably larger for malignant lesions. The observations will likely significantly improve the discrimination of radiologically indeterminant lesions.

A system for high?speed calculation of tissue elastic properties using a clinical ultrasonic imaging system will be presented. The hypothesis driving this development is that real?time feedback of elasticity images is essential in obtaining high?quality data (consecutive images with high spatial coherence). Extensive experience with laboratory fixtures and off?line processing of elasticity data showed that problems occurring in data acquisition often resulted in poor elasticity image quality. The delay in observing the resulting images, due to off?line processing, resulted in slow progress in developing experimental techniques and signal processing strategies. When high?quality data were obtained, high contrast?to?noise images were available. Initial experience with real?time freehand elasticity imaging shows that images with similar high contrast to noise can be obtained. Results in volunteer patients have shown that high?quality elasticity images are easily obtained in vivo for a variety of breast pathologies, and the changes in breast tumor elasticity during the course of chemotherapy can be monitored. Video of real?time elasticity imaging will demonstrate the ease with which these results are obtained. [We are grateful for the support by USAMRAA DAMD17?00?1?0596, Siemens Medical Systems, and NSF BES?9708221.]