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.

Intracranial aneurysms in autosomal dominant polycystic kidney disease.

BACKGROUND AND METHODS: Intracranial aneurysms are a feature of autosomal dominant polycystic kidney disease, but their prevalence is uncertain. We studied 92 subjects with autosomal dominant polycystic kidney disease who had no symptoms or signs of any neurologic disorder. To determine the prevalence of intracranial aneurysms, we performed high-resolution computed tomography (CT) in 60 subjects, four-vessel cerebral angiography in 21, and both procedures in 11. RESULTS: Four of the 88 subjects in whom the radiologic studies were successfully completed had intracranial aneurysms (4 percent; 95 percent confidence interval, 0.1 to 9 percent), as compared with the prevalence of 1 percent reported for an angiographic study of the general population. Three of the four subjects had multiple aneurysms. Seven subjects for whom the results of CT studies were suspicious underwent cerebral angiography: two had aneurysms, and five had normal vascular structures that accounted for the suspicious results of tomography. Four subjects who had normal CT imaging studies also had normal angiographic examinations. Eight of the 32 subjects who underwent angiography (25 percent) had transient complications, as compared with 22 of 220 control subjects (10 percent) who did not have polycystic kidney disease (P less than 0.05). We could not identify any risk factor in these subjects that was related to the occurrence of aneurysm. CONCLUSIONS: Asymptomatic intracranial aneurysms appear to be more frequent in people with polycystic kidney disease than in the general population, although our 95 percent confidence interval includes the possibility of no difference. Because cerebral angiography is associated with increased morbidity in people with polycystic kidney disease, we recommend high-resolution CT as a screening test.

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease.

Autosomal-dominant polycystic kidney disease results in renal failure at a varying age from childhood to old age. We postulated that factors other than the culprit gene alone contribute to the course of progression of the renal failure. We studied 580 subjects with autosomal-dominant polycystic kidney disease and 194 unaffected family members. We calculated survival curves to end-stage renal failure or death and developed a linear model for testing the effects of single or multiple variables on the progression of renal failure as estimated from the reciprocal of serum creatinine. Fifty-two subjects died and 94 reached end-stage renal failure during the period of observation, yielding functional survivals of 71% at age 50 years, 53% at 58 years and 23% at 70 years. The following variables were independently associated with worse mean renal function at a given age (P value less than 0.01): the PKD1 gene, younger age at diagnosis, male gender, hypertension, increased left ventricular mass, hepatic cysts in women, three or more pregnancies, gross hematuria, urinary tract infections in men and renal size expressed as renal volume. The following were not associated significantly with the course of renal function: gender of affected parent, mitral valve prolapse, intracranial aneurysms, any pregnancy, hepatic cysts in men and urinary tract infections in women. The identification of unalterable maleficent factors such as the PKD1 gene and male gender permit more informed counseling while the identification of alterable factors such as hypertension, number of pregnancies and recurrent urinary tract infections provides the clinician with the opportunity to modify these factors and improve the management of patients with autosomal-dominant polycystic kidney disease.

Renal structure and hypertension in autosomal dominant polycystic kidney disease.

Hypertension has been reported to occur in 50 to 75 percent of subjects with autosomal dominant polycystic kidney disease (ADPKD) prior to the onset of marked renal insufficiency but concurrent with cystic deformation of the renal parenchyma. The present study was undertaken to examine whether the renal structural abnormalities are greater in hypertensive (HBP) versus normotensive (NBP) male and female patients with ADPKD who were matched within gender groups for age, body surface area, serum creatinine concentration (males HBP 1.2 +/- 0.02 vs. NBP 1.1 +/- 0.03 mg/dl. NS: females HBP 0.9 +/- 0.03 vs. NBP 0.9 +/- 0.02 mg/dl, NS) and creatinine clearance (males HBP 100 +/- 3 vs. NBP 108 +/- 3 ml/min/1.73 m2, NS: females HBP 97 +/- 3 vs. NBP 96 +/- 2 ml/min/1.73 m2, NS). Renal volume was significantly greater in the HBP compared to the NBP group (males HBP 624 +/- 47 vs. NBP 390 +/- 43 cm3, P less than 0.0005; females HBP 446 +/- 32 vs. NBP 338 +/- 24 cm3, P less than 0.002). Since increased renal volume is due to increased cysts, the results indicate that the early high incidence of hypertension in ADPKD correlates with the renal structural abnormalities in this disorder.

Uric acid handling in autosomal dominant polycystic kidney disease with normal filtration rates.

PURPOSE: Patients with autosomal dominant polycystic kidney disease (ADPKD) are alleged to have more frequent or more pronounced alterations of uric acid homeostasis than are seen in most other types of chronic renal diseases. We performed this study to examine the hypothesis that individuals with ADPKD have abnormal uric acid homeostasis that is manifest before the development of renal insufficiency. PATIENTS AND METHODS: We studied 301 subjects, 163 with ADPKD and 138 relatives without ADPKD (NADPKD), by ultrasonography. The subjects were interviewed and examined. Venous blood and two 24-hour urine collections were obtained for uric acid and creatinine determinations. RESULTS: Presence of hyperuricemia, serum uric acid levels, uric acid clearance, and fractional excretion of uric acid did not differ between ADPKD and NADPKD subjects with normal renal function (creatinine clearance greater than 80 mL/minute/1.73 m2). Clearance of uric acid decreased and fractional excretion increased in subjects with decreased renal function in both groups. Female gender enhanced renal excretion of uric acid in both groups and hypertension depressed it except in men with ADPKD, who had higher fractional excretions of uric acid than did hypertensive NADPKD men. CONCLUSIONS: Uric acid homeostasis is preserved in individuals with ADPKD with normal renal function when compared to unaffected family members. Hyperuricemia and decreased renal excretion of uric acid develop as renal function worsens in ADPKD, similar to that in control subjects. The expected depressing effect of hypertension on renal handling of uric acid was not seen in men with ADPKD, speculatively due to an effect of atrial natriuretic factor.

Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease.

Hepatic cysts are a major manifestation of autosomal dominant polycystic kidney disease. This study examined 239 autosomal dominant polycystic kidney disease patients and 189 unaffected family members to define the factors that influence the presence and severity of hepatic cysts. Autosomal dominant polycystic kidney disease patients with hepatic cysts were older than autosomal dominant polycystic kidney disease patients without such cysts (44.6 +/- 1.1 yr vs. 32.9 +/- 1.1 yr; p less than 0.0001). The number of hepatic cysts increased with age (r = 0.43; p less than 0.0001). Women were more likely to have massive hepatic cystic disease (greater than 15 cysts) than men (p less than 0.04). Women also had larger maximal cyst size (4.2 +/- 0.4 cm vs. 2.7 +/- 0.3 cm; p less than 0.004). Women with hepatic cysts were more likely to have been pregnant (p less than 0.001) and to have had more pregnancies (2.9 +/- 0.3 pregnancies vs. 1.6 +/- 0.2 pregnancies; p less than 0.0009). Kidney volume (p less than 0.0001), number of cysts (p less than 0.004), percentage of cystic parenchyma (p less than 0.001) and predominant cyst size (p less than 0.001) were greater and creatinine clearance was lower (64.5 +/- 3.1 ml/min/1.73 m2 vs. 94.5 +/- 3.4 ml/min/1.73 m2; p less than 0.001) in autosomal dominant polycystic kidney disease patients with hepatic cysts. By logistic regression, the frequency of hepatic cysts was related to increased age, increased severity of renal cystic disease and decreased creatinine clearance. Number and size of hepatic cysts correlated with the occurrence of pregnancy, female gender, increased age and severity of the renal lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical utility of renal concentrating capacity in polycystic kidney disease.

We studied 177 adult nonazotemic subjects with autosomal dominant polycystic kidney disease (ADPKD) and 123 unaffected family members (NADPKD). In order to assess the factors influencing renal concentrating capacity maximal urinary osmolality (UOsm) after overnight water deprivation and vasopressin was measured. UOsm was reduced in ADPKD (680 +/- 14) compared to NADPKD subjects (812 +/- 13 mOsm/kg). A greater severity of the architectural abnormality as assessed by cyst number and size and remaining volume of normal parenchyma was associated with a greater impairment of renal concentrating capacity. The concentrating defect was present in the youngest ADPKD subjects and the rate of decline of concentrating capacity with age in ADPKD paralleled that in NADPKD subjects. Based on the initial 135 subjects studied, we developed an algorithm for diagnostic screening for ADPKD utilizing blood pressure, serum creatinine and UOsm designed to maximize sensitivity. When applied to a subsequent population of 165 adults, 121 with ADPKD and 44 unaffected relatives, this algorithm would have spared 20% of unaffected subjects from the cost of ultrasound while failing to detect less than 2% of affected subjects. This simple protocol thus offers a rapid and inexpensive way to screen for ADPKD.

Amoxapine-associated agranulocytosis with thrombocytosis occurring early during recovery.

Agranulocytosis developed in a 35-year-old woman after she received 18 g of amoxapine, a tricyclic antidepressant, over 57 days. On the fifth day after cessation of amoxapine treatment, her platelet count rose from normal to a peak value of 999,000/mm3 on the 13th day. No cause for this thrombocytosis was apparent. Granulocytes appeared in the peripheral blood on the 15th day, and the thrombocytosis abated with the platelet count returning to a normal level by day 22. This confirms a previous report that amoxapine may be associated with agranulocytosis and suggests that thrombocytosis may occur as an early sign of recovery of the bone marrow in drug-associated toxic agranulocytosis.

Syndromes of toluene sniffing in adults.

Clinical and laboratory findings in 25 adults, ages ranging from 18 to 40 years, who were hospitalized for problems related to paint sniffing are presented. All but one were chronically unemployed. Three different patterns of symptoms led to hospitalization: muscle weakness (n = 9), gastrointestinal complaints including abdominal pain and hematemesis (n = 6) and neuropsychiatric disorders including altered mental status, cerebellar abnormalities, and peripheral neuropathy (n = 10). Hypokalemia (n = 13), hypophosphatemia (n = 10), hyperchloremia (n = 22), and hypobicarbonatemia (n = 23) were common. The average serum potassium and phosphorus concentrations of 1.7 mmol/L and 1.5 mg/dL were significantly lower in the muscle weakness group than in the other two groups. Rhabdomyolysis occurred in 10 patients. Hyperchloremic acidosis was found in 19 of 22 patients evaluated. The muscle weakness and gastrointestinal syndromes resolved within 1 to 3 days with abstinence from sniffing and repletion of fluid and electrolyte stores. Inhalation of paint or glue vapors should be considered in the differential diagnosis of the symptoms and laboratory findings described above.

Respiratory response to HCl acidosis in dogs after carotid body denervation.

To test the participation of the carotid bodies in the respiratory response to metabolic acidosis, six dogs were infused with HCl for 2 h followed by HCl feeding to prolong the acidosis to 48 h. This protocol was repeated after carotid body denervation (CBD). Mean control PCO2 rose by 7.3 Torr after CBD. PCO2 fell comparably during acidosis before and after CBD at all time periods from 30 to 48 h and returned to control levels by 72 h. The pH ranged from 7.10 to 7.30 during acidosis pre- and post-CBD. The decreases in pH and bicarbonate concentration did not differ significantly at any time interval between the pre- and post-CBD studies. This study indicates that in dogs moderately severe HCl acidosis stimulates ventilation acutely and chronically through a central mechanism in the absence of the carotid bodies.

Acute nephritis and pulmonary alveolitis following pneumococcal pneumonia.

Acute glomerulonephritis developed in a man with pneumococcal pneumonia. Serum complement studies revealed decreased levels of C4, properdin, and C3. Renal immunofluorescence studies demonstrated pneumococcal antigen, C1q, C4, C3 proactivator, properdin, C3, IgG, and IgM. Circulating cryoglobulin contained pneumococcal antigen and antibody, C3, and immunoglobulins. Serial pneumococcal antigen and antibody levels did not display patterns that were characteristic of classical immune elimination, but the patterns may have been influenced by the reentry of antigen. A diffuse, pulmonary alveolitis also developed in the patient. Lung immunofluorescence studies revealed pneumococcal antigen, IgG, and C3 in alveolar walls and capillary basement membranes. The glomerulonephritis and alveolitis resolved after a prolonged course. These findings provide presumptive evidence for pneumococcal, immune complex glomerulonephritis with complement activation via both classical and alternative pathways and suggest an immunologic pathogenesis for the pulmonary alveolitis.