Familial clustering of ruptured intracranial aneurysms in autosomal dominant polycystic kidney disease.

Ruptured intracranial aneurysm (RICA) is a life-threatening complication of autosomal dominant polycystic kidney disease (ADPKD). A family history of RICA may be a risk factor for RICA. Six hundred eight adult members of 199 ADPKD families were interviewed, and family pedigrees were constructed. Individuals were classified as having definite, probable, or possible RICAs from evidence and history obtained in interviews. Central nervous system (CNS) events not consistent with RICA were classified as other CNS events. Seventy-seven CNS events occurred in 906 subjects with ADPKD (8.5%) versus 13 events in 823 subjects without ADPKD (1.6%; P < 0.0001). No event in subjects without ADPKD was consistent with an RICA. Twenty-seven other (non-RICA) CNS events occurred in subjects with ADPKD (3%) versus 13 events in subjects without ADPKD (1.6%; P = 0.05). The frequency of RICA was increased in subjects with ADPKD: 21 definite RICAs in subjects with ADPKD (2%) versus none in subjects without ADPKD (P < 0.001); 28 definite and probable RICAs in subjects with ADPKD (3%) versus none in subjects without ADPKD (P < 0.001); and 50 definite, probable, and possible RICAs in subjects with ADPKD (5.5%) versus none in subjects without ADPKD (P < 0.001). The null hypothesis that RICAs are randomly distributed among subjects with ADPKD was tested for definite RICAs (n = 21), definite and probable RICAs (n = 28), and definite, probable, and possible RICAs (n = 50). In the three categories, the null hypothesis was rejected at P less than 0.05, P less than 0.05, and P less than 0.005, respectively. Vascular CNS events occurred more frequently in ADPKD than non-ADPKD family members, and clustering of RICAs occurred in families with 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.

Progression of autosomal-dominant polycystic kidney disease in children.

BACKGROUND: Although many case reports describe manifestations of autosomal-dominant polycystic kidney disease (ADPKD) in children, no longitudinal studies have examined the natural progression or risk factors for more rapid progression in a large number of children from ADPKD families. METHODS: Since 1985, we have studied 312 children from 131 families with a history, a physical examination, blood and urine chemistries, an abdominal ultrasonography, and gene linkage analysis. One hundred fifteen of 185 affected children were studied multiple times for up to 15 years. Renal volumes were determined by ultrasound imaging. Graphs of mean renal volumes according to age were compared between affected and unaffected children, ADPKD children with and without early severe disease, and children with and without high blood pressure. RESULTS: Affected children had faster renal growth than unaffected children. ADPKD children with severe renal enlargement at a young age continued to experience faster renal growth than those with mild enlargement or normal kidney size for their age, and affected children with high blood pressure had faster renal growth than those with lower blood pressure. Glomerular filtration rate did not decrease in any children except for two with unusually severe early onset disease. CONCLUSIONS: The progression of ADPKD clearly occurs in childhood and manifests as an increase in cyst number and renal size. This study identifies children at risk for rapid renal enlargement who may benefit the most from future therapeutic interventions.

Von Hippel-Lindau disease masquerading as autosomal dominant polycystic kidney disease.

The diagnostic confusion in differentiating the various causes of renal cystic diseases in adults is well documented. This confusion can include misclassifications between autosomal dominant polycystic kidney disease (ADPKD) and von Hippel-Lindau disease (VHL). We describe such a case of VHL. A review of the literature and of the patients in our database regarding typical features of each disease, mean age of onset, and frequency of these features was undertaken to provide helpful differentiating features. Pancreatic cysts are one differentiating feature. In VHL, pancreatic cysts can occur in 70% of patients, often are multiple, and rarely may cause exocrine or endocrine insufficiency. Pancreatic islet cell tumors occur. In ADPKD, pancreatic cysts are found in only 9% of patients, usually are single and asymptomatic, generally occur in conjunction with cystic liver disease, and are not found in children or unaffected family members. Pancreatic malignancies do not occur with increased frequency in ADPKD. A different pattern, especially in patients without a strong family history of ADPKD, may be a clue to VHL masquerading as ADPKD. Genetic mutation screening of the VHL gene should be used in these patients.

Progress in blood pressure control in autosomal dominant polycystic kidney disease.

Hypertension occurs commonly in autosomal dominant polycystic kidney disease (ADPKD) and is an important factor in the progression of the disease and cardiovascular mortality. The aim of this prospective 15-year study is to report the rate of blood pressure control and the potential effect of a 10-point education program developed by our center for ADPKD patients and their physicians. The patients' blood pressure treatment was managed by their primary care physicians. Three 5-year periods were analyzed in which similar rates of hypertension in patients with ADPKD were present (63% to 68%). In the first period (1985 to 1989), the rate of blood pressure control (<140/90 mm Hg) was 38% for 216 hypertensive patients with ADPKD. From 1990 to 1994, the percentage of blood pressure control increased to 55% in 194 hypertensive patients with ADPKD (P < 0.001 versus 1985 to 1989); and the level of blood pressure control increased to 64% in 181 hypertensive patients with ADPKD during 1995 to 1999 (P < 0.001 versus 1985 to 1989). Although this percentage of blood pressure control in patients with ADPKD remains suboptimal, it compares very favorably with the 27% estimated blood pressure control in patients with essential hypertension from 1991 to 1994 in the United States.

Evaluation of colonic diverticular disease in autosomal dominant polycystic kidney disease without end-stage renal disease.

A previous study had shown an increased prevalence (83%) of diverticula among patients with autosomal dominant polycystic kidney disease (ADPKD) with end-stage renal disease (ESRD) compared with other ESRD patients without ADPKD (32%). Others have also suggested an increased risk for diverticular complications in renal transplant recipients with ADPKD. To determine whether there was an increased occurrence of diverticula among non-ESRD patients with ADPKD, we studied 55 patients with ADPKD who were not receiving renal replacement therapy compared with 12 unaffected family members (non-ADPKD) and 59 random patients who had undergone barium enemas (control [C]). No study patient had a history of diverticular disease. All patients underwent a double-contrast barium enema after administration of glucagon. The occurrence, number, location, and size of diverticula were noted. There was no significant difference among the three groups in regard to sex (men: ADPKD, 42% versus non-ADPKD, 42% versus C, 37%) or age (ADPKD, 49.3 +/- 0.7 versus non-ADPKD, 51.2 +/- 2.1 versus C, 49 +/- 1 years). There was no significant difference in the percentage of patients with diverticula (ADPKD, 47% versus non-ADPKD, 58% versus C, 59%), the percentage with only right-colon diverticula (ADPKD, 5% versus non-ADPKD, 17% versus C, 5%), the mean number of diverticula in patients with diverticulosis (ADPKD, 13.8 versus non-ADPKD, 7.9 versus C, 9.9 diverticula), or the size of the largest diverticula (ADPKD, 9.5 versus non-ADPKD, 10.4 versus C, 10.5 mm). There was no significant difference in these variables between the patients with ADPKD with a creatinine clearance greater than 70 mL/min/1.73 m(2) (n = 25) or less than 70 mL/min/1.73 m(2). This study does not show the greater prevalence of diverticular disease in non-ESRD patients with ADPKD compared with the general population. Thus, patients with ADPKD need not be considered at greater risk for diverticular disease than the general population.

Renal asymmetry in children with autosomal dominant polycystic kidney disease.

Although for decades autosomal dominant polycystic kidney disease (ADPKD) was considered a disease of adults, our recent longitudinal studies on children from ADPKD families have shown that the disease is evident by ultrasound imaging in approximately 75% of children who are carriers of the ADPKD1 gene, the most common form of ADPKD. Here we report that, in contrast to adults, the disease appears to be unilateral initially in approximately 17% of children. Asymmetric enlargement of the kidneys is also frequently observed. This renal asymmetry can be extreme and lead to diagnostic confusion. We present 2 unusual cases of asymmetric renal involvement that we have observed during the last 10 years. The first is a 14-year-old boy who was scheduled for a nephrectomy to relieve pain and whose family requested a second opinion. The second is a 10-year-old girl who was diagnosed with ADPKD in utero by prenatal ultrasound. After birth, 1 kidney progressively developed cysts and enlarged, whereas the other had only a few tiny cysts and remained normal in size. A review of the literature shows that presentations like these often lead to a nephrectomy or surgical biopsy. A carefully obtained family history and examination of both parents with ultrasound can help to avoid unnecessary invasive procedures. If pain is a prominent symptom, it can be treated by cyst aspiration if there are only a few cysts or a single dominant cyst. The molecular mechanism for extremely asymmetric renal disease remains to be elucidated.

Frequency of ovarian cysts in patients with autosomal dominant polycystic kidney disease.

Extrarenal cysts occur in patients with autosomal dominant polycystic kidney disease (ADPKD) most frequently in the liver. Ovarian cysts have been reported in women with ADPKD, but their frequency has not been determined. Therefore, we analyzed the historical data in our database of 337 women with ADPKD and 199 of their unaffected female family members (NADPKD). In addition, we prospectively studied 25 nonpregnant, premenopausal women with ADPKD and 25 nonpregnant, premenopausal, age-matched control women recruited from the general population to assess the occurrence of ovarian cysts. No women in either the control or ADPKD groups were receiving exogenous estrogen or progesterone. All women underwent sonographic examination using a 5- or 7.5-MHz vaginal probe. A normal ovarian follicle was defined as a fluid-filled structure less than 2 cm in average diameter, and an ovarian cyst as one of 2 cm or greater. From the historical data, 28% of the women with ADPKD gave a history of ovarian cysts compared with 18% of the NADPKD women (P < 0.05). In the prospective study, the mean age of the women with ADPKD was not different from that of the control women (40.9 +/- 1.2 v 39.3 +/- 1.2 years; P = not significant [NS]). There was no difference in frequency of normal follicles found in women with ADPKD or controls (80% v 96%; P = NS), nor was there a difference in the frequency of ovarian cysts found in women with ADPKD or controls (12% v 12%; P = NS). There was no difference in the calculated ovarian volumes between the women with ADPKD and controls (9.9 +/- 2. 5 v 7.2 +/- 1.2 cm3). Among the women with ADPKD, there was no correlation between mean ovarian volume and mean renal volume, nor was there a significant relationship between the occurrence of hepatic cystic disease and ovarian cysts. Therefore, a prospective imaging study suggests that ovarian cysts have no increased frequency in women with ADPKD compared with women in the general population.

From the bedside to the boardroom.

There is a need for physicians, including women physicians, to pursue medical management careers within our health care institutions. The physician's training provides skills that are important and transferable to management. These skills are discussed. However, there are gaps in our training related to population approaches, personnel management, and finances that must be learned. Success in a management career is highly dependent on building a high-functioning, integrated team, and the approach to this is discussed.

Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease.

Recent experiments in cultured cyst epithelial cells from kidneys of patients with autosomal dominant polycystic kidney disease (ADPKD) have shown that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is present in the apical surface of these cells and mediates chloride (Cl-) and fluid secretion in vitro. To determine whether the presence of CF with the expression of mutated CFTR proteins modifies cyst formation in ADPKD, we studied a large family with both inherited diseases. ADPKD in this family is linked to PKD1. The family is composed of 26 members; 11 members with ADPKD, 4 members with CF, and 2 members with both diseases. Renal volumes measured by computerized tomography (CT), calculated creatinine clearances, and other clinical parameters in the family members with ADPKD and CF were compared with those in the family members with ADPKD alone, as well as to a large population of patients with ADPKD. The patients with CF and ADPKD, but not the CF heterozygote carriers with ADPKD, had less severe polycystic kidney and liver disease, as indicated by normal renal function; smaller renal volume, even when corrected for height and body surface area; and the absence of hypertension and liver cysts. These observations suggest that the coexistence of CF may reduce the severity of ADPKD.

Identification of patients with autosomal dominant polycystic kidney disease at highest risk for end-stage renal disease.

To identify those potential factors that, early in the course of disease, mark a population of patients with autosomal dominant polycystic kidney disease (ADPKD) who have worse renal survival, survival analysis and risk ratio calculation for 1215 ADPKD patients were performed. Survival times were calculated as time to dialysis, transplantation, or death. Risk ratios were calculated using the Cox proportional hazards model. Three hundred eighty-eight patients entered end-stage renal disease and 205 patients died. ADPKD2 subjects had longer renal survival than ADPKD1 subjects (median survival, 68 versus 53 yr; P < 0.0005; risk ratio, 2.5). Women had significantly better renal survival than men (56 versus 52 yr; P < 0.0001; risk ratio, 1.6). Subjects who were diagnosed before age 30 and those who developed hypertension before age 35 had worse renal survival than those subjects who were diagnosed after age 30 or those who remained normotensive after age 35, respectively (age of diagnosis: 49 versus 59 yr; P < 0.0001; risk ratio, 3.2; hypertension: 51 versus 65 yr; P < 0.0001; risk ratio, 4.4). Similarly, those who had an episode of gross hematuria before age 30 had a worse renal outcome than those who did not (49 versus 59 yr; P < 0.0001; risk ratio, 2.6). We have also calculated risk ratios for a combined model. When therapeutic interventions become available for this disease, these populations with high risk ratios should be considered for such interventions.

A peer approach to high risk youth.

Denver's Gang Rescue and Support Project (GRASP) is a peer run intervention for youth involved in gangs and those feeling pressure to affiliate with them. GRASP utilizes small group meetings and mentoring to encourage young people to pursue positive life-style changes.

Utility of ultrasonography in the diagnosis of autosomal dominant polycystic kidney disease in children.

To determine the utility of ultrasonography (US) in diagnosing autosomal dominant polycystic kidney disease (ADPKD) in children, this study examined 106 children who were at 50% risk for the disease. The children underwent a history, physical examination, abdominal US, and gene linkage analysis (GLA) with tightly linked markers for ADPKD1 and ADPKD2 genes. Only ADPKD1 children were studied. A child was considered affected by US if any cysts were detected and affected by GLA if he or she shared the same haplotype as the affected parent. Forty-two children (40%) were considered to be unaffected by both GLA and US. Forty-eight children (45%) were considered affected by both modalities. Only two of these children had a single cyst. Fourteen children (13%) were considered affected by GLA with normal initial US. These children tended to have larger kidneys than children who were unaffected by GLA. Eight of these 14 children had subsequent positive ultrasonograms. Two children had a positive ultrasonogram with GLA showing them to be unaffected; in one of these children, a subsequent ultrasonogram was interpreted to be normal with a medullary pyramid. Thus, overall the false negative rate was 25%, and the false positive rate was 2%. The false negative rate was highest in the children who were 3 months to 5 years of age (38%). Clinicians must understand the utility of US in diagnosing ADPKD in at-risk children and must not interpret a normal study as absence of disease in this population.

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.

Insurance for autosomal dominant polycystic kidney disease patients prior to end-stage renal disease.

There recently has been substantial dialogue about access to health insurance for Americans. This discussion has highlighted the issues of pre-existing diseases and portability as barriers to adequate health insurance coverage. For these reasons we decided to investigate the issues relating to health insurance and life insurance coverage experienced by patients with autosomal dominant polycystic kidney disease (ADPKD). A questionnaire-based study was conducted. Two hundred thirty-eight of 354 subjects responded. There was no significant difference in gender, age, number of children, or level of renal function between responders and nonresponders. Twenty-eight of the 238 respondents had eight-stage renal disease and were eligible for Medicare; these patients were not used in the analyses relating to health insurance, but were used in the analyses relating to life insurance. Although 87% of the ADPKD patients were concerned about the availability of health insurance, 88% were currently insured. Eight-three percent of subjects with health insurance obtained it through their own or their spouse's employer. Of those individuals with employer-based health insurance who were aware of their ADPKD, only 25% informed their employer and 35% informed their insurer at the start of coverage. Fifty-seven percent of those with employer-based health insurance had this availability determine their job choice and 37% stayed in the job because of health insurance. Thirty percent of the subjects had previously been denied health insurance. Although subjects were less concerned about life insurance, many of the same types of issues and factors were present. Thus, the current lack of universal health care in this country creates anxiety and difficulties for patients with ADPKD. The effect of a pre-existing condition and the lack of portability resulted in denials, work choice limitation, and unwillingness to share health information for this patient population with a hereditary, systemic disease.

Genetic studies in a black family with autosomal dominant polycystic kidney disease and sickle-cell trait.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by at least two different genes. The ADPKD1 gene is located on chromosome 16p and a second locus is at 4q. Although the ADPKD1 gene is responsible for the majority of the disease in whites, there was no information regarding the gene type in blacks. We studied a black family which presented with both ADPKD and sickle-cell trait (SA) to determine which ADPKD gene was present in this family, and to examine linkage between the ADPKD in this family and markers for the beta-hemoglobin gene on chromosome 11. The ADPKD in this family was linked to markers on chromosome 16, and no linkage was found with the beta-hemoglobin gene. Family members with SA and ADPKD had an early onset of end-stage renal disease. The hemoglobin haplotype was identified as the Central African Republic-type, which has been reported to be associated with a higher incidence of renal failure in sickle-cell anemia.

Improving identification of and intervention for alcoholism.

A retrospective hospital medical record review was done using 45 diagnoses or laboratory findings that are associated with alcohol abuse. The reviewer assessed the level of documentation of alcohol consumption in relation to alcohol-related disorders before and after an intervention to heighten house staff's recognition of alcoholism. Of the patients with at least 1 alcohol-related disease, 58% were explicitly asked about their consumption of alcohol. The mean number of alcohol-related diseases was 3.8 +/- 2.3 in the group questioned compared with 1.9 +/- 1.4 in the group not asked (P < .01). After the intervention, 90% of patients with at least 1 alcohol-related disease were asked about alcohol consumption. Once again, those asked had an average of 3.9 diseases compared with 2.1 in the other group (P < .01). Only younger age, increased specificity of alcohol-related disease, and the promotion of physician awareness were important factors for influencing documentation. Introducing a program for detecting alcoholism can have a beneficial effect on physicians' identification of alcoholism in patients with alcohol-related illnesses.