Louis H. Wetzel

Magnetic Resonance Imaging Evaluation of Hepatic Cysts in Early Autosomal-Dominant Polycystic Kidney Disease: The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease Cohort

The objective of this study was to investigate the prevalence of hepatic cysts by age and gender in patients with early autosomal-dominant polycystic kidney disease (ADPKD) and to determine whether hepatic cyst volume is related to renal and renal cyst volumes by using magnetic resonance imaging (MRI). A total of 230 patients with ADPKD (94 men and 136 women) who were aged 15 to 46 yr and had relatively preserved renal function were studied. MRI images of the kidney and liver were obtained to measure renal, renal cyst, and hepatic cyst volumes. These volume measurements and hepatic cyst prevalence were compared in all patients and in subgroups on the basis of gender and age (15 to 24, 25 to 34, and 35 to 46 yr). The overall prevalence of hepatic cysts was 83%; the prevalence was 58, 85, and 94% in the sequential age groups and 85% in women and 79% in men. The prevalence was related directly to renal volume (chi2 = 4.30, P = 0.04) and to renal cyst volume (chi2 = 5.59, P = 0.02). The total hepatic cyst volume was significantly greater in women than in men (a logarithmic transformation mean of 5.27 versus 1.94 ml; P = 0.003). The average hepatic cyst volume was 0.25, 5.75, and 22.78 ml in sequential age groups. Hepatic cysts are evident in 94% of patients who are older than 35 yr and in 55% of individuals who are younger than 25 yr. Hepatic cysts are more prevalent and larger in total cyst volume in women than in men. Hepatic cyst prevalence and aggregate total hepatic cyst volume increased with age.

Kidney Volume and Functional Outcomes in Autosomal Dominant Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES Autosomal dominant polycystic kidney disease (ADPKD) is characterized by increased total kidney volume (TKV) and renal failure. This study aimed to determine if height-adjusted TKV (htTKV) predicts the onset of renal insufficiency. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective, observational, longitudinal, multicenter study included 241 adults with ADPKD and preserved renal function. Magnetic resonance imaging and iothalamate clearance were used to measure htTKV and GFR, respectively. The association between baseline htTKV and the attainment of stage 3 CKD (GFR <60 ml/min per 1.73 m(2)) during follow-up was determined. RESULTS After a mean follow-up of 7.9 years, stage 3 CKD was attained in 30.7% of the enrollees. Using baseline htTKV, negative correlations with GFR increased from -0.22 at baseline to -0.65 at year 8. In multivariable analysis, a baseline htTKV increase of 100 cc/m significantly predicted the development of CKD within 8 years with an odds ratio of 1.48 (95% confidence interval: 1.29, 1.70). In receiver operator characteristic curve analysis, baseline htTKV of 600 cc/m most accurately defined the risk of developing stage 3 CKD within 8 years with an area under the curve of 0.84 (95% confidence interval: 0.79, 0.90). htTKV was a better predictor than baseline age, serum creatinine, BUN, urinary albumin, or monocyte chemotactic protein-1 excretion (P<0.05). CONCLUSIONS Baseline htTKV ≥600 cc/m predicted the risk of developing renal insufficiency in ADPKD patients at high risk for renal disease progression within 8 years of follow-up, qualifying htTKV as a prognostic biomarker in ADPKD.

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

Potentially Modifiable Factors Affecting the Progression of Autosomal Dominant Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was created to identify markers of disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Linear mixed models were utilized to model effects of baseline parameters on changes in natural-log (ln)-transformed total kidney volume (TKV) and iothalamate clearance (GFR) across time in CRISP participants (creatinine clearance at entry >70 ml/min). Stepwise selection was used to obtain a final main effect model. RESULTS TKV increased from year to year, whereas GFR uncorrected for body surface area (BSA) decreased only at year 6. Higher lnTKV and urine sodium excretion (U(Na)V), lower serum HDL-cholesterol, and younger age at baseline associated with greater lnTKV growth from baseline to year 3 and to year 6. Higher lnTKV at baseline associated with greater GFR decline from year 1 to year 3 and to year 6. Higher BSA and 24-hour urine osmolality at baseline associated with greater GFR decline from year 1 to year 6. Higher U(Na)V and lower serum HDL-cholesterol at baseline associated with greater GFR decline from year 1 to year 6 by univariate analysis only. Associations seen during year 1 to year 6 (not seen during year 1 to year 3) reflect the time lag between structural and functional disease progression. CONCLUSIONS Serum HDL-cholesterol, U(Na)V, and 24-hour urine osmolality likely affect ADPKD progression. To what extent their modification may influence the clinical course of ADPKD remains to be determined.

Evidence of Extraordinary Growth in the Progressive Enlargement of Renal Cysts

BACKGROUND AND OBJECTIVES 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 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. RESULTS 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. CONCLUSIONS 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.

Analysis of baseline parameters in the HALT polycystic kidney disease trials

HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m(2). Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m(2). We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity.

Pallidotomy microelectrode targeting: neurophysiology-based target refinement.

OBJECTIVE Microelectrode recording can refine targeting for stereotactic radiofrequency lesioning of the globus pallidus to treat Parkinsons disease. Multiple intraoperative microelectrode recording/stimulating tracks are searched and assessed for neuronal activity, presence of tremor cells, visual responses, and responses to kinesthetic input. These physiological data are then correlated with atlas-based anatomic data to approximate electrode location. On the basis of these physiological properties, one or more tracks are selected for lesioning. This study analyzes the track physiological factors that seem most significant in determining the microelectrode recording track(s) that will be chosen for pallidal lesioning. METHODS Thirty-six patients with Parkinsons disease underwent microelectrode-guided pallidotomy. Between one and five microelectrode recording tracks were made per patient. Usually, one (n = 23) or two (n = 12) of these tracks were lesioned. Electrode positions in the x (mediolateral) and y (anteroposterior) axes were recorded and related to track neurophysiological findings and final lesion location. The stereotactic location and sequence of microelectrode tracks were recorded and plotted to illustrate individual search patterns. These patterns were then compared with those noted in other patients. Neurophysiological data obtained from recording tracks were analyzed. A retrospective analysis of track electrophysiology was performed to determine the track characteristics that seemed most important in the surgeons choice of the track to lesion. Track physiological properties included general cell spike amplitude, tremor synchronous neuronal firing, kinesthetically responsive neuronal firing, and optic track responses (either phosphenes reported by the patient during track microstimulation or neuronal firing in response to light stimulus into the patients eyes). Orthogonally corrected postoperative magnetic resonance images were used to confirm the anatomic lesion locations. RESULTS In patients who had a single mapped track lesioned, specific track electrophysiological characteristics identified the track that would be lesioned most of the time (20 of 24 patients). Tracks that exhibited a combination of tremor synchronous firing, joint kinesthesia, and visual responsivity were lesioned 17 (85%) of 20 times. Analysis of intraoperative electrode movement in the x and y axes indicated a significant subset of moves but did not result in microelectrode positioning closer to the subsequently lesioned track. Accuracy of initial electrode movement in the x and y axes was most highly correlated with a measure of first-track electrophysiological activity. The number of microelectrode recording tracks did not correlate with clinical outcome. Anatomic analysis, using postoperative magnetic resonance imaging, revealed that all lesions were placed in the globus pallidus. Most patients (35 of 36) improved after surgery. CONCLUSION The level of electrophysiological activity in the first track was the best predictive factor in determining whether the next microelectrode move would be closer to the ultimately lesioned track. The analysis of electrode track location and neurophysiological properties yields useful information regarding the effectiveness of microelectrode searching in the x and y axes. Within an institution, the application of this modeling method may increase the efficiency of the microelectrode refinement process.

Detected Renal Cysts Are Tips of the Iceberg in Adults with ADPKD

BACKGROUND AND OBJECTIVES 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 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. RESULTS 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. CONCLUSIONS 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.

Wide area networks for teleradiology.

Teleradiology networks transmit digital radiographic images from one location to another. These networks are wide area networks. Teleradiology networks are used for diagnostic purposes and preview tasks. Wide area networks for teleradiology use public service switching. The use of fiber optics networks provide reduced costs and increased flexibility. An example is presented that compares the cost of teleradiology networks.

Cardiac Magnetic Resonance Assessment of Left Ventricular Mass in Autosomal Dominant Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES Autosomal dominant polycystic kidney disease (ADPKD) is associated with a substantial cardiovascular disease burden including early onset hypertension, intracranial aneurysms, and left ventricular hypertrophy (LVH). A 41% prevalence of LVH has been reported in ADPKD, using echocardiographic assessment of LV mass (LVM). The HALT PKD study was designed to assess the effect of intensive angiotensin blockade on progression of total kidney volume and LVM. Measurements of LVM were performed using cardiac magnetic resonance (MR). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Five hundred forty-three hypertensive patients with GFR >60 ml/min per 1.73 m(2) underwent MR assessment of LVM at baseline. LVM was adjusted for body surface area and expressed as LVM index (LVMI; g/m(2)). RESULTS Baseline BP was 125.1 ± 14.5/79.3 ± 11.6 mmHg. Average duration of hypertension was 5.79 years. Prior use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was present in 59.5% of patients. The prevalence of LVH assessed using nonindexed LVM (g) was 3.9% (n = 21, eight men and 13 women) and 0.93% (n = 5, one man and four women) using LVMI (g/m(2)). In exploratory analyses, the prevalence of LVH using LVM indexed to H(2.7), and the allometric index ppLVmass(HW), ranged from 0.74% to 2.23% (n = 4 to 12). Multivariate regression showed significant direct associations of LVMI with systolic BP, serum creatinine, and albuminuria; significant inverse associations with LVMI were found with age and female gender. CONCLUSIONS The prevalence of LVH in hypertensive ADPKD patients <50 years of age with short duration of hypertension, and prior use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is low. Early BP intervention in ADPKD may have decreased LVH and may potentially decrease cardiovascular mortality.