Patricia A. Gabow

The Renin–Angiotensin–Aldosterone System and Autosomal Dominant Polycystic Kidney Disease

BACKGROUND A high incidence of hypertension (50 to 75 percent) occurs early in the course of autosomal dominant polycystic kidney disease. Cyst enlargement, causing bilateral renal ischemia and subsequent release of renin, is proposed as the cause of this form of hypertension. METHODS To investigate this hypothesis, we measured plasma renin activity and aldosterone concentrations during short-term and long-term converting-enzyme inhibition in 14 patients with hypertension due to polycystic kidney disease, 9 patients with essential hypertension, 11 normotensive patients with polycystic kidney disease, and 13 normal subjects. The groups were comparable with respect to age, sex, body-surface area, degree of hypertension, sodium excretion, and renal function. RESULTS During the short-term study, the mean (+/- SE) plasma renin activity was significantly higher in the hypertensive patients with polycystic kidney disease than in the patients with essential hypertension, in the supine (0.36 +/- 0.06 vs. 0.22 +/- 0.06 ng per liter.second, P = 0.05) and upright positions (1.03 +/- 0.14 vs. 0.61 +/- 0.08 ng per liter.second, P less than 0.03) and after converting-enzyme inhibition (1.97 +/- 0.28 vs. 0.67 +/- 0.17 ng per liter.second, P less than 0.0006). The mean arterial pressures measured in the supine and upright positions and the plasma aldosterone concentrations measured in the upright position were significantly higher in the normotensive patients with polycystic kidney disease than in the normal subjects. After six weeks of converting-enzyme inhibition, renal plasma flow increased (P less than 0.005), and both renal vascular resistance (P less than 0.007) and the filtration fraction (P less than 0.02) decreased significantly in the hypertensive patients with polycystic kidney disease but not in the patients with essential hypertension. CONCLUSIONS The renin-angiotensin-aldosterone system is stimulated significantly more in hypertensive patients with polycystic kidney disease than in comparable patients with essential hypertension. The increased renin release, perhaps due to renal ischemia caused by cyst expansion, probably contributes to the early development of hypertension in polycystic kidney disease.

Urinary Diagnostic Indices in Acute Renal Failure: A Prospective Study

A prospective analysis of the value of urinary diagnostic indices in ascertaining the cause of acute renal failure was undertaken. Our results show that in the setting of acute oliguria a diagnosis of potentially reversible prerenal azotemia is likely with urine osmolality greater than 500 mosm/kg H2O, urine sodium concentration less than 20 meq/litre, urine/plasma urea nitrogen ratio greater than 8, and urine/plasma creatinine ratio greater than 40. Conversely, a urine osmolality less than 350 mosm/kg, urine sodium concentration greater than 40 meq/liter, urine/plasma urea nitrogen ratio less than 3, and urine/plasma creatinine ratio less than 20 suggest acute tubular necrosis. A significant number of oliguric patients will not have urinary indices that fall within these guidelines. In this setting, urine sodium concentration divided by the urine-to-plasma creatinine ratio (the renal failure index) and the fractional excretion of filtered sodium provide a reliable means of differentiating reversible prerenal azotemia from acute tubular necrosis.

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.

Autosomal Dominant Polycystic Kidney Disease—More Than a Renal Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease, affecting a half million Americans. The clinical phenotype can result from at least two different gene defects. One gene that can cause ADPKD has been located on the short arm of chromosome 16. This discovery has made possible new methods for diagnosing the disorder in gene carriers prior to the development of renal cysts. Although renal cysts are clearly an important manifestation of the gene defect, other systemic manifestations are both common and clinically important. Cardiac valvular lesions, intracranial aneurysms, hepatic cysts, and diverticula are included in the array of systemic manifestations. Moreover, renal cysts are only one of a myriad of renal manifestations. Although ADPKD was long considered an adult cystic disease, it is also a common cause of childhood cystic disease and must be considered in the differential diagnosis in that setting.

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.

Linkage Heterogeneity of Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease has been shown to be closely linked to the alpha-hemoglobin complex on the short arm of chromosome 16. We describe a five-generation kindred, descendants of Sicilian immigrants, in which the disease occurs but without linkage to the alpha-hemoglobin complex. DNA probes were used in genetic-linkage studies on blood samples from 163 family members, of whom 71 were affected by or at risk for autosomal dominant polycystic kidney disease. Diagnoses were confirmed by ultrasound examination. In this family the frequency of recombination between the alpha-hemoglobin complex and the region previously shown to contain the mutation causing polycystic kidney disease exceeded 24 percent, indicating a mutation at a different locus. The clinical findings in this family were indistinguishable from those in other families with polycystic kidney disease. We conclude that there is a second gene for autosomal dominant polycystic kidney disease. This apparent heterogeneity means that prenatal and presymptomatic diagnosis must be approached with caution until a method is found to distinguish between the two forms of the disease.

Polycystic Kidney Disease: Prospective Analysis of Nonazotemic Patients and Family Members

To develop a profile of nonazotemic polycystic kidney disease as it occurs in families, we identified and studied 164 persons with autosomal-dominant polycystic kidney disease, 81 persons suspected of having the disease, and 250 family members without the disease. Because symptoms were absent in 32% of patients with the disease but present in 30% of persons without the disease, symptoms are not reliable in screening for the disease. Hypertension and palpable kidneys and liver were significantly commoner in patients with the disease, but systolic murmur unrelated to hypertension (10.5%) and peripheral edema (9.3%) also were common. Normal laboratory values do not exclude the diagnosis of polycystic kidney disease. Ultrasonography appears to be more sensitive than excretory urography in detecting the disease and also can detect hepatic cysts. Berry aneurysms can occur and are an important cause of mortality and morbidity. The relation of renal cysts to signs, symptoms and renal function is discussed.

Echocardiographic Findings in Autosomal Dominant Polycystic Kidney Disease

Echocardiography, including Doppler analysis, was performed to assess the prevalence of cardiac abnormalities in 163 patients with autosomal dominant polycystic kidney disease, 130 unaffected family members, and 100 control subjects. In these three groups, the prevalence of mitral-valve prolapse was 26, 14, and 2 percent, respectively (P less than 0.0005). A higher prevalence of mitral incompetence (31, 14, and 9 percent, respectively; P less than 0.005), aortic incompetence (8, 3, and 1 percent, respectively; P less than 0.05), tricuspid incompetence (15, 7, and 4 percent, respectively; P less than 0.02), and tricuspid-valve prolapse (6, 2, and 0 percent, respectively; P less than 0.02) was also found in the patients with polycystic kidney disease. These findings reflect the systemic nature of polycystic kidney disease and support the hypothesis that the disorder involves a defect in the extracellular matrix and the cardiac abnormalities are an expression of that defect.

Diagnostic Importance of an Increased Serum Anion Gap

Abstract Fifty-seven hospitalized patients with increased serum anion gaps, defined as [Na] − ([Cl] + [HCO3]), were studied to explore the biochemical basis and the diagnostic importance of the anion gap. We found that an anion gap greater than 30 meq per liter was usually due to an identifiable organic acidosis (lactic acidosis or ketoacidosis). However, 10 of 35 patients (29 per cent) with anion gaps of 20 to 29 meq per liter did not have lactic acidosis or ketoacidosis. In 22 patients, the composition of the anion gap was studied in detail. Lactate and ketoanions accounted for 62 per cent of the increments in anion gaps, and changes in the equivalents of total proteins, phosphorus, potassium, and calcium accounted for 15 per cent. However, nine patients had an increment in anion gap of 5.5 meq per liter or more (average, 8.7 meq per liter) that was not explained by any of the factors measured here. The possibility of unidentified anions or unrecognized changes in the ionic equivalents of normal plasma ...

Characteristics of very early onset autosomal dominant polycystic kidney disease.

Eleven children from eight families with autosomal dominant polycystic kidney disease who were diagnosed in utero (6 children) or in the first year of life (5 children) are reported here. Four children were evaluated for symptoms and three because of a sibling with very early onset disease. In three children, abnormal kidneys were found incidentally on a pregnancy screening ultrasound, and in only one child, the diagnosis was made by an ultrasound specifically directed at detecting polycystic kidney disease. Females were disproportionately represented among both the affected parents and offspring. Eight of the children were girls, and all affected parents were mothers. In three families, the parents diagnosis was established only after the birth of the affected child. In two of these and in one other family, the mothers disease appeared to be the result of a new mutation. The most consistent renal ultrasonographic findings in the children were enlargement and increased echogenicity. On follow-up over 3 to 15 yr (mean, 6.8 yr) two children had ESRD and eight children had normal or nearly normal renal function as assessed by creatinine clearance. Renal concentrating ability was reduced in four children in whom it was measured. All children had bilateral renal cysts on follow-up, and nine children were hypertensive. Possible risk factors for early-onset disease identified in this study were an affected mother, an affected sibling, and an apparent parental new mutation. Symptoms and complications occurred frequently, but outcome was better than reported previously.