Lisa M. Guay-Woodford

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.

Genetic disorders of renal electrolyte transport.

In the 1950s and 1960s, several inherited disorders of fluid and electrolyte metabolism were described in which the principal disturbance appeared to be a specific functional defect in the renal tu...

Kidney Volume and Functional Outcomes in Autosomal Dominant Polycystic Kidney Disease

BACKGROUND AND OBJECTIVESnAutosomal 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.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnThis 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.nnnRESULTSnAfter 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).nnnCONCLUSIONSnBaseline 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.

Magnetic Resonance Measurements of Renal Blood Flow and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Whether changes in renal blood flow (RBF) are associated with and possibly contribute to cystic disease progression in autosomal dominant polycystic kidney disease (ADPKD) has not been ascertained. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was created to develop imaging techniques and analyses to evaluate progression. A total of 131 participants with early ADPKD had measurements of RBF and total kidney (TKV) and cyst (TCV) volumes by magnetic resonance and of GFR by iothalamate clearance at baseline and 1, 2, and 3 yr. The effects of age, gender, body mass index, hypertension status, mean arterial pressure (MAP), TKV, TCV, RBF, renal vascular resistance (RVR), GFR, serum uric acid, HDL and LDL cholesterol, 24-h urine volume, sodium (UNaE) and albumin (UAE) excretions, and estimated protein intake were examined at baseline on TKV, TCV, and GFR slopes. TKV and TCV increased, RBF decreased, and GFR remained stable. TKV, TCV, RVR, serum uric acid, UAE, UNaE, age, body mass index, MAP, and estimated protein intake were positively and RBF and GFR negatively correlated with TKV and TCV slopes. TKV, RBF, UNaE, and UAE were independent predictors of TKV and TCV slopes (structural disease progression). TKV, TCV, RVR, and MAP were negatively and RBF positively correlated with GFR slopes. Regression to the mean confounded the analysis of GFR slopes. TKV and RBF were independent predictors of GFR decline (functional disease progression). In ADPKD, RBF reduction (1) parallels TKV increase, (2) precedes GFR decline, and (3) predicts structural and functional disease progression.

Comparison of Methods for Determining Renal Function Decline in Early Autosomal Dominant Polycystic Kidney Disease: The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease Cohort

A decline in renal function suggests progression of chronic kidney disease. This can be determined by measured GFR (e.g., iothalamate clearance), serum creatinine (SCr)-based GFR estimates, or creatinine clearance. A cohort of 234 patients with autosomal dominant polycystic kidney disease and baseline creatinine clearance>70 ml/min were followed annually for four visits. Iothalamate clearance, SCr, and creatinine clearance were obtained at each visit. Estimated GFR (eGFR) was determined with the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault equations. Renal function slopes had a mean residual SD of 10.7% by iothalamate clearance, 8.2% by MDRD equation, 7.7% by Cockcroft-Gault equation, and 14.8% by creatinine clearance. By each method, a decline in renal function (lowest quintile slope) was compared among baseline predictors. Hypertension was associated with a decline in iothalamate clearance (odds ratio [OR] 5.8; 95% confidence interval [CI] 2.3 to 14), eGFR (OR [MDRD] 2.0 [95% CI 1.0 to 4.2] or OR [Cockcroft-Gault] 1.9 [95% CI 0.9 to 3.9]), and creatinine clearance (OR 2.0; 95% CI 1.0 to 4.2). Each doubling of kidney volume at baseline was associated with a decline in iothalamate clearance (OR 2.4; 95% CI 1.5 to 3.7), eGFR (OR 1.7 [95% CI 1.1 to 2.6] or 2.1 [95% CI 1.4 to 3.3]), and creatinine clearance (OR 1.7; 95% CI 1.1 to 2.5). Predictor associations were strongest with measured GFR. Misclassification from changes in non-GFR factors (e.g., creatinine production, tubular secretion) conservatively biased associations with eGFR. Misclassification from method imprecision attenuated associations with creatinine clearance.

MRI-based kidney volume measurements in ADPKD: reliability and effect of gadolinium enhancement.

BACKGROUND AND OBJECTIVESnTo evaluate the inter- and intrareader reliability and the effect of gadolinium enhancement on kidney volume measurements obtained from pre- and postgadolinium T1 MR images in patients with autosomal dominant polycystic kidney disease (ADPKD).nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnTwenty subjects were randomly selected with approximately equal frequency from three kidney-size groups. Pre- and postgadolinium 3D T1 (pre-T1, post-T1) MR images were obtained. The stereology method was applied to segment and measure kidney volumes. The measurement process was repeated at two-wk intervals by two radiologists. Reliability was assessed with correlation coefficients. Intra- and inter-reader bias and measure differences were assessed with paired T-tests. The size effect on the pre- and post-T1 measurements was evaluated with one-way ANOVA.nnnRESULTSnThe intra- and inter-reader reliability was extremely high in all measurements. No systematic intrareader bias but a small inter-reader bias for the post-T1 measurements was observed. All kidney volumes measured on the pre- and post-T1 images were highly correlated with each other for both readers. The post-T1 volumes were significantly higher than pre-T1 volumes. While the post-pre volume differences were relatively constant across the three kidney-size groups, the post-pre percent volume differences were significantly smaller as the size of the kidney increased.nnnCONCLUSIONSnKidney volume measurements can be made with minimum intra- and inter-reader variability on both pre- and post-T1 MR images. Kidney volumes measured on the pre-T1 were smaller than those on post-T1, and percent differences between pre-T1 and post-T1 kidney volumes decreased with increasing kidney size.

Confirmation of the ATP6B1 gene as responsible for distal renal tubular acidosis

Abstract.Primary distal renal tubular acidosis (dRTA) type I is a hereditary renal tubular disorder, which is characterized by impaired renal acid secretion resulting in metabolic acidosis. Clinical symptoms are nephrocalcinosis, nephrolithiasis, osteomalacia, and growth retardation. Biochemical alterations consist of hyperchloremic metabolic acidosis, hypokalemia with muscle weakness, hypercalciuria, and inappropriately raised urinary pH. Autosomal dominant and rare forms of recessive dRTA are known to be caused by mutations in the gene for the anion exchanger AE1. In order to identify a gene responsible for recessive dRTA, we performed a total genome scan with 303 polymorphic microsatellite markers in six consanguineous families with recessive dRTA from Turkey. In four of these there was an association with sensorineural deafness. The total genome scan yielded regions of homozygosity by descent in all six families on chromosomes 1, 2, and 10 as positional candidate region. In one of these regions the gene ATP6B1 for the ß1 subunit of the vacuolar H+-ATPase is localized, which has recently been identified as causative for recessive dRTA with sensorineural deafness. Therefore, we conducted mutational analysis in 15 families and identified potential loss-of-function mutations in ATP6B1 in 8. We thus confirmed that defects in this gene are responsible for recessive dRTA with sensorineural deafness.

First NIH/Office of Rare Diseases Conference on Cystinosis: past, present, and future

Consensus Statement First NIH/Office of Rare Diseases Conference on Cystinosis: past, present, and future Robert Kleta, Frederick Kaskel, Ranjan Dohil, Paul Goodyer, Lisa M. GuayWoodford, Erik Harms, Julie R. Ingelfinger, Vera H. Koch, Craig B. Langman, Mary B. Leonard, Roslyn B. Mannon, Minnie Sarwal, Jerry A. Schneider, Flemming Skovby, Barbara C. Sonies, Jess G. Thoene, Doris A. Trauner and William A. Gahl 19

Chapter 40 – Polycystic Kidney Disease

Polycystic kidney disease (PKD) results from single gene defects transmitted as either autosomal dominant or autosomal recessive traits. Different ages of onset, variability in kidney disease progression, and a diverse array of extrarenal manifestations distinguish these disorders. In autosomal dominant PKD (ADPKD), defects in either of two causative genes, PKD1 or PKD2, can initiate cyst formation resulting from a germline mutation in one allele and a somatic mutation in the second allele. The respective protein products, polycystin-1 (PC1) and polycystin-2 (PC2), form a receptor-channel complex that is variably expressed in the plasma cell membrane, as well as in the primary apical cilia membrane. Autosomal recessive PKD (ARPKD) results from mutations in the PKHD1 gene, which encodes the protein product, fibrocystin/polyductin (FPC), which is also expressed in primary cilia. This chapter discusses PKD genetics, clinical and genetic diagnosis, management of organ-specific complications, and future directions for disease monitoring and potential therapies.