Patricia A. Gabow

PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein

A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.

Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13–q23

At least two loci are known to exist for autosomal dominant polycystic kidney disease (ADPKD). One was localized to 16p, but the second less common locus has remained unlinked. Over 100 microsatellite markers, distributed across all chromosomes, have been typed on informative family members from the large Sicilian kindred in which the genetic heterogeneity was first discovered. Both the affected and the unaffected status of every family member used in the study were confirmed by renal ultrasonography. This search has resulted in the successful localization of a second ADPKD gene to chromosome 4q. It was found to be flanked by the markers D4S231 and D4S414, defining a segment that spans about 9 cM. The new locus has been designated PKD4. This second localization will allow researchers to target another ADPKD gene for isolation in an effort to understand the pathogenesis of this common disorder. Furthermore, when flanking markers for the second ADPKD gene are used in conjunction with flanking markers for PKD1, the accuracy of the diagnosis of the subtype of ADPKD present in any particular family will be enhanced. This will improve the accuracy of linkage-based presymptomatic diagnoses by reducing the error due to genetic heterogeneity.

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance < or = 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 [95% CI, 73.8 to 78.1] versus 68.1 [95% CI, 66.0 to 70.2] yr) and CRF (72.5 [95% CI, 70.1 to 74.9] versus 63.7 [95% CI, 61.4 to 66.0] yr). Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P < 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.

Diuretics versus Angiotensin-Converting Enzyme Inhibitors in Autosomal Dominant Polycystic Kidney Disease

Hypertension, which occurs commonly and early in autosomal dominant polycystic kidney disease (ADPKD), affects both renal and patient outcome. However, there is no consensus about the type of antihypertensive therapy that is most appropriate for patients with ADPKD. This historical prospective, nonrandomized study was designed to investigate the effect on renal function of diuretics versus angiotensin-converting enzyme (ACE) inhibitors in hypertensive patients with ADPKD who entered the study with comparable renal function. Among hypertensive ADPKD patients followed in our center, patients taking diuretics without any ACE inhibitors were included in the diuretic group (n = 14, male/female ratio 5/9, mean age 47 years), whereas patients taking ACE inhibitors but no diuretics were included in the ACE inhibitor (ACEI) group (n = 19, male/female ratio 11/8, mean age 41 years). For comparable blood pressure control, 21% of the ACEI group and 64% of the diuretic group (p < 0.05) needed additional antihypertensive medications. After an average follow-up period of 5.2 years, the creatinine clearance decreased significantly in the diuretic group (74 vs. 46 ml/min/1.73 m2, p < 0.0001) and in the ACEI group (83 vs. 71 ml/min/1.73 m2, p = 0.0005). The decrement in creatinine clearance was significantly larger in the diuretic group than the ACEI group (p < 0.05). The annual decrease in creatinine clearance was 5.3 ml/min/1.73 m2 in the diuretic group and 2.7 ml/min/1.73 m2 in the ACEI group (p < 0.05). A significant increase in urinary protein excretion occurred in the diuretic but not in the ACEI group. Hypertensive ADPKD patients treated with diuretics had a faster loss of renal function as compared with patients treated with ACE inhibitors, despite similar blood pressure control. This result will need to be further examined in a randomized study.

For Many Patients Who Use Large Amounts Of Health Care Services, The Need Is Intense Yet Temporary

Patients who accumulate multiple emergency department visits and hospital admissions, known as super-utilizers, have become the focus of policy initiatives aimed at preventing such costly use of the health care system through less expensive community- and primary care-based interventions. We conducted cross-sectional and longitudinal analyses of 4,774 publicly insured or uninsured super-utilizers in an urban safety-net integrated delivery system for the period Mayxa01, 2011-Aprilxa030, 2013. Our analysis found that consistently 3xa0percent of adult patients met super-utilizer criteria and accounted for 30xa0percent of adult charges. Fewer than half of super-utilizers identified as such on Mayxa01, 2011, remained in the category seven months later, and only 28xa0percent remained at the end of a year. This finding has important implications for program design and for policy makers because previous studies may have obscured this instability at the individual level. Our study also identified clinically relevant subgroups amenable to different interventions, along with their per capita utilization and costs before and after being identified as super-utilizers. Future solutions include improving predictive modeling to identify individuals likely to experience sustained levels of avoidable utilization, better classifying subgroups for whom interventions are needed, and implementing stronger program evaluation designs.

Ten Strategies To Lower Costs, Improve Quality, And Engage Patients: The View From Leading Health System CEOs

Patient-centeredness--the idea that care should be designed around patients needs, preferences, circumstances, and well-being--is a central tenet of health care delivery. For CEOs of health care organizations, patient-centered care is also quickly becoming a business imperative, with payments tied to performance on measures of patient satisfaction and engagement. In A CEO Checklist for High-Value Health Care, we, as executives of eleven leading health care delivery institutions, outlined ten key strategies for reducing costs and waste while improving outcomes. In this article we describe how implementation of these strategies benefits both health care organizations and patients. For example, Kaiser Permanentes Healthy Bones Program resulted in a 30 percent reduction in hip fracture rates for at-risk patients. And at Virginia Mason Health System in Seattle, nurses reorganized care patterns and increased the time they spent on direct patient care to 90 percent. Our experiences show that patient-engaged care can be delivered in ways that simultaneously improve quality and reduce costs.

Exclusion of autosomal dominant polycystic kidney disease type II (ADPKD2) from 160 cM of chromosome 1.

Autosomal dominant polycystic kidney disease is a heritable disorder and recent studies have shown genetic heterogeneity, with some, but not all, families showing linkage with markers on chromosome 16p. Members of a large ADPKD family, unlinked to chromosome 16, have been typed for 12 marker loci located on both arms of chromosome 1. Multipoint analysis excluded ADPKD2 from the region between D1S81 (pTHH33) and D1S67 (pHHH106) on the long arm and between Rh and PGM1 on the short arm. This excludes the disease locus from about 61% of chromosome 1.

The Fall: Aligning The Best Care With Standards Of Care At The End Of Life

When her mother is hurt, a health care executive finds that the standardized care she championed isnt always appropriate.

Adrenal insufficiency after unilateral radical nephrectomy

A case of adrenal insufficiency occurring after unilateral radical nephrectomy is presented. Recommendations for identification and treatment of this condition are discussed.