John D. Harnett

The Cardinal Manifestations of Bardet–Biedl Syndrome, a Form of Laurence–Moon–Biedl Syndrome

To determine the interfamilial and intrafamilial variation in the expression of the Bardet-Biedl syndrome (a form of Laurence-Moon-Biedl syndrome), we looked for the five recognized features of the disorder (retinal dystrophy, obesity, polydactyly, mental retardation, and hypogonadism), plus possible renal manifestations, in some or all of 32 patients with this disorder. All 28 patients examined had severe retinal dystrophy, but only 2 had typical retinitis pigmentosa. Polydactyly was present in 18 of 31 patients, but syndactyly, brachydactyly, or both were present in all. Obesity was present in all but 1 of 25 patients. Only 13 of 32 patients were considered mentally retarded. Scores on verbal subtests of intelligence were usually lower than scores on performance tasks. Seven of eight men had small testes and genitalia, which was not due to hypogonadotropism. All 12 women studied had menstrual irregularities, and 3 had low serum estrogen levels (1 of these had hypogonadotropism, and 2 had primary gonadal failure). The remaining women who were of reproductive age had endocrinologic evidence of reproductive dysfunction. Diabetes mellitus was present in 9 of 20 patients. Renal structural or functional abnormalities were universal (n = 21), and three patients had end-stage renal failure. We conclude that the characteristic features of Bardet-Biedl syndrome are severe retinal dystrophy, dysmorphic extremities, obesity, renal abnormalities, and (in male patients only) hypogenitalism. Mental retardation, polydactyly, and hypogonadism in female patients are not necessarily present.

The clinical course of left ventricular hypertrophy in dialysis patients.

To determine the clinical and echocardiographic outcome of left ventricular hypertrophy a prospective study was undertaken of 104 nondiabetic dialysis patients without dilated cardiomyopathy, who were followed for 3-5 years. 33% of patients had normal echocardiogram, 41% mild and 27% severe hypertrophy (left ventricular wall thickness greater than or equal to 1.4 cm in diastole). In the first 2 groups 16% progressed to severe hypertrophy, 23% were admitted with congestive heart failure after starting dialysis therapy, and 2-year cumulative survivals were 97 and 85%. In the group with severe hypertrophy 88% already had severe hypertrophy on starting dialysis therapy, it was persistent in 87%, 50% were admitted at least once with congestive heart failure, and the 2-year cumulative survival was 53%. 71% of those who died in the severe group died from cardiac or cerebrovascular causes compared to none of those with normal echocardiogram, which accounted for the significantly worse (p = 0.001) survival. We conclude that severe left ventricular hypertrophy occurs frequently in dialysis patients, is often present at the start of end-stage renal disease therapy, is persistent, may predispose to congestive heart failure, and is associated with a high mortality.

Impact of renal transplantation on uremic cardiomyopathy

In chronic uremia, cardiomyopathy manifests itself as systolic dysfunction, concentric left ventricular (LV) hypertrophy, or LV dilatation. To determine the impact of renal transplantation on uremic cardiomyopathy, all dialysis patients participating in a long-term cohort study who received a successful renal transplant were followed with echocardiography. The transplanted group comprised 102 of 433 (24%) endstage renal disease (ESRD) patients. They were significantly younger and, on starting ESRD therapy, had significantly less ischemic heart disease and cardiac failure than the overall ESRD cohort. During followup, ischemic heart disease developed in only 1 patient and none experienced cardiac failure. In the 12% (n = 12) of patients with systolic dysfunction before renal transplant, fractional shortening normalized in all patients, increasing from 21.5 +/- 4.6% to 33.5 +/- 5.6% after transplantation. In the 41% (n = 41) with concentric LV hypertrophy before transplantation, the LV mass index improved from 158 +/- 39 g/m2 to 132 +/- 39 g/m2. LV dilatation was present in 32% (n = 32) of patients before transplantation. After transplantation, LV volume fell from 116 +/- 3.1 ml/m2 to 89 +/- 21 ml/m2, and LV mass index in this group fell from 166 +/- 55 g/m2 to 135 +/- 37 g/m2. It was not possible to associate risk factors characteristic of the uremic state with the improvement in cardiac structure and function, although the fall in LV mass was significantly associated with fall in blood pressure. We conclude that correction of the uremic state by renal transplantation leads to normalization of LV contractility in systolic dysfunction, regression of hypertrophy in concentric LV hypertrophy, and improvement of cavity volume in LV dilatation. The degree of improvement suggests that dialysis patients with uremic cardiomyopathy would benefit from renal transplantation.

Left Ventricular Hypertrophy in End-Stage Renal Disease

To determine the prevalence of left ventricular hypertrophy (LVH; left ventricular wall thickness greater than or equal to 1-2 cm in diastole) among end-stage renal disease (ESRD) patients and the most important risk factors that independently relate to LVH, 189 non-diabetic ESRD patients without dilated cardiomyopathy in two centres had echocardiography and full clinical review. 104 of 189 (55%) patients had LVH consisting of 52 of 83 (65%) patients on haemodialysis, 18 of 20 (90%) peritoneal dialysis patients and 34 of 86 (40%) transplanted patients. Using multiple logistic regression, the most important factors which independently related to LVH, in all patients studied, were dialysis as current ESRD treatment (p less than 0.001), followed by age (p = 0.008), hypertension as defined by number of blood pressure medications (p = 0.007), followed by high serum alkaline phosphatase which probably reflects hyperparathyroidism (p = 0.03). In a subset of patients with severe LVH (left ventricular wall thickness greater than or equal to 1.4 cm), a high serum alkaline phosphatase level was the best predictor of LVH (p less than 0.001), followed by high diastolic blood pressure (p = 0.004) and age (p = 0.02). In dialysis patients, the most important variable were age (p = 0.009) and high serum alkaline phosphatase (p = 0.03). In the transplant group, patients with LVH were taking significantly more antihypertensive medications than those without LVH (p = 0.002). This variable was the only predictor of LVH in the transplant group.(ABSTRACT TRUNCATED AT 250 WORDS)

The Spectrum of Renal Disease in Laurence–Moon–Biedl Syndrome

To determine the nature, extent, and severity of renal involvement in Laurence-Moon-Biedl syndrome (obesity, mental retardation, polydactyly, hypogonadism, and pigmented retinal dystrophy), we evaluated 20 of 30 patients with the disorder identified from ophthalmologic records in Newfoundland. The mean age was 31 years, and seven were male. All 20 patients had structural or functional abnormalities of the kidneys or both. Three had end-stage renal disease, with two requiring maintenance hemodialysis. The remaining 17 patients had normal serum creatinine values and estimated creatinine clearances. Half the subjects had hypertension. Fourteen of 17 patients could not concentrate urine above 750 mOsm per kilogram of body weight even after vasopressin, whereas all 10 normal controls could. Urinary pH decreased below 5.3 after ammonium chloride administration in all 15 normal controls, but in only 13 of 18 patients. Calyceal clubbing or blunting was evident in 18 of 19 patients studied by intravenous pyelography; 13 patients had calyceal cysts or diverticula. Seventeen of 19 patients had lobulated renal outlines of the fetal type. Four patients had diffuse renal cortical loss, but only two of these had renal insufficiency. We conclude that Laurence-Moon-Biedl syndrome includes the presence of renal abnormalities.

Cardiac Function and Hematocrit Level

Patients on dialysis have an age-adjusted death rate 3.5 times that of the general population. The most common cause of death in patients on dialysis is cardiovascular disease. We prospectively followed a cohort of 433 patients in three centers for a mean of 41 months. Mean hemoglobin level at the beginning of dialysis was 8.39 (+/- 1.7) g/dL, and the mean hemoglobin level during follow-up was 8.84 (+/- 1.5) g/dL. Using Coxs regression model, we found that anemia predicted mortality independently of age, diabetes mellitus, cardiac failure, hypoalbuminemia, serum creatinine, mean arterial pressure, or echocardiographic heart disease. The independent relative risk (RR) of mortality was 1.18 per 1.0 g/dL decrease in hemoglobin level. Anemia also independently predicted the de novo occurrence of congestive heart failure when the same covariates were controlled for (RR, 1.49 per 1.0 g/dL decrease). Anemia was also independently predictive of heart failure at the start of dialysis (RR, 1.14 per 1.0 g/dL decrease) and heart failure recurrence (RR, 1.25 per 1.0 g/dL decrease). Left ventricular hypertrophy is present in 75% of patients on dialysis at the start of therapy for end-stage renal disease. It independently predicts mortality. Our prospective cohort study identified increasing age, hypertension, and anemia as risk factors for its development. One controlled study and several uncontrolled studies demonstrated improvement (but not complete regression) of elevated left ventricular mass in patients on dialysis treated with recombinant human erythropoietin (epoetin).

The importance of renal impairment in the natural history of bardet-biedl syndrome

Bardet-Biedl syndrome is a rare autosomal recessive disease characterized by dysphormic extremities, retinal dystrophy, obesity, hypogenitalism in males, and renal structural abnormalities. Because the clinical outcome of these patients is not well known, 21 families with Bardet-Biedl syndrome (BBS) were studied to determine the natural history of the disease. In a prospective cohort study, 38 patients with the syndrome and 58 unaffected siblings were identified. Patients were studied in 1987 and again in 1993. Age of onset of blindness, hypertension, diabetes, renal impairment, and death was determined. The prevalence of obesity, gonadal dysfunction, and renal structural abnormalities was assessed. All but 5 BBS patients (86%) were legally blind, 26% being blind by the age of 13 years and 50% by 18 years. Eighty-eight percent were above the 90th percentile for height and weight. Twenty-five (66%) patients had hypertension, 25% of BBS patients by age 26 years, and 50% by age 34 years, whereas in the unaffected group, 25% had hypertension by age 49 years (P < 0.0001). Twelve (32%) BBS patients developed diabetes mellitus, compared with none of the unaffected group. Only 2 patients were insulin dependent. Twenty-five percent of BBS patients had diabetes by the age of 35 years. In 12 women of reproductive age, 1 (8%) had primary gonadal failure. In 10 men, 4 had primary testicular failure. Nine (25%) patients developed renal impairment, with 25% of the BBS group affected by the age of 48 years. Imaging procedures of the kidney were performed in 25 patients with normal renal function. Whereas fetal lobulation and calyceal cysts/diverticula/clubbing were characteristic, occurring in 96% of patients, 20% (n = 5) had diffuse and 4% (n = 1) focal cortical loss. Eight patients with BBS died, 3 with end-stage renal failure and 3 with chronic renal failure. On life-table analysis, 25% of BBS patients had died by 44 years, whereas at that age 98% of unaffected siblings were still alive (P < 0.0001). Bardet-Biedl syndrome has an adverse prognosis, with early onset of blindness, obesity, hypertension, and diabetes mellitus. Renal impairment is frequent and an important cause of death. Survival is substantially reduced.

The natural history of myocardial disease in dialysis patients.

Among dialysis patients, only 23% have a normal echocardiogram, about 10% have recurrent or chronic congestive heart failure, and 17% have asymptomatic ischemic heart disease. The predisposing factors for congestive heart failure are dilated cardiomyopathy, hypertrophic hyperkinetic disease, and ischemic heart disease. Dilated cardiomyopathy, a disorder of systolic function, includes among its risk factors age, hyperparathyroidism, and smoking. Hypertrophic disease results in diastolic dysfunction, and its predictors include age, hypertension, aluminum accumulation, anemia, and, perhaps, hyperparathyroidism. Ischemic heart disease is due to the presence of coronary artery disease and also to nonatherosclerotic disease caused by the reduction in coronary vasodilator reserve and altered myocardial oxygen delivery and use. The clinical outcome of congestive heart failure is comparable to that of nonrenal patients with medically refractory heart failure. Left ventricular hypertrophy is an important independent determinant of survival. A subset have hyperkinetic disease with severe hypertrophy and have a bad survival, as low as 43% have a 2-yr survival after the first admission to hospital with cardiac failure. The prognosis for those with dilated cardiomyopathy is less severe but is worse than those with normal echocardiogram. The survival of patients with symptomatic ischemic heart disease was little different from that of patients without symptoms, suggesting that the underlying cardiomyopathies had an adverse impact on survival independent of ischemic disease. Much research needs to be undertaken on the risk factors, natural history, and therapy of the various types of cardiac disease prevalent in dialysis patients.

The reliability and validity of echocardiographic measurement of left ventricular mass index in hemodialysis patients.

We assessed the reliability and validity of a formula, based on echocardiographically derived parameters, to calculate left ventricular mass index (LVMI) in a group of 15 chronic hemodialysis patients. All patients had M-mode echocardiography before and after a hemodialysis session. Echocardiograms were interpreted by 2 observers blind to each others measurements. Interobserver reliability for LVMI was high (r = 0.94, p < 0.0007). LVMI decreased in 11 of 15 patients during dialysis and increased in 4. The mean difference in LVMI between pre- and posthemodialysis was 26.2 +/- 15 g/m2 (p < 0.0001). End-diastolic diameter decreased from 53.5 +/- 5.9 to 49.5 +/- 7.5 mm (p = 0.0016). These data indicate that measurement of LVMI is highly reproducible in hemodialysis patients but that it changes significantly over the course of a hemodialysis session. Its use as an outcome measure in clinical trials in hemodialysis patients should be interpreted with caution.

Hepatitis B disease in dialysis and transplant patients. Further epidemiologic and serologic studies.

As hepatitis B virus (HBV) infection in renal transplant recipients is associated with a high incidence of progressive liver disease it may be inadvisable to transplant hemodialysis patients with hepatitis B antigenemia. To determine the natural history of HBV disease in hemodialysis patients, all 49 patients on hemodialysis treatment for at least 1 year, at 3 centers, who developed circulating hepatitis B surface antigen (HBsAG), were studied. A subgroup of these patients (n = 31) aged less than or equal to 50 years, followed for 55 +/- 6 months after detection of HBsAg was compared with 22 previously studied HBsAg-positive transplant patients followed for 81 +/- 9 months. Significantly more transplant patients developed chronic hepatitis defined biochemically (P less than .001) and none of the transplant patients became HBsAg-negative compared with 19% of the hemodialysis group. Taking difference in follow-up into account, mortality was significantly higher in the transplant recipients (P less than .005) following development of HBsAg antigenemia, and the mortality difference was attributable to deaths from liver disease. A total of 36 serum samples from 14 of the 22 HBsAg-positive renal transplant recipients was analyzed for hepatitis B e antigen (HBeAg), antibody to hepatitis D virus (anti-HD), and hepatitis B virus deoxyribonucleic acid (HBVDNA) concentration. No serum sample was anti-HD-positive. Twelve of the 14 patients were HBeAg-positive. Five patients became HBeAg-negative, 3 of whom developed aggressive liver disease. One HBeAg-negative anti-HBe-positive patient had progression of liver disease from asymptomatic carrier status to chronic active hepatitis (CAH). Of 14 patients, 9 developed progressive CAH. HBVDNA concentration was not diagnostic of disease activity on liver biopsy. However only 1 sample of 10 measured in 5 patients with nonprogressive disease had a level greater than 100 pg/L, compared with 9 of 17 in the group who progressed to CAH. During the interval when the liver histology progressed from asymptomatic carriage or chronic persistent hepatitis (CPH) to CAH, the HBVDNA concentration increased by greater than 10 times baseline in 4 of 5 patients who had serial samples, whereas this did not occur in 4 patients with nonprogressive disease. We conclude that the long-term outcome of hepatitis B infection in transplant recipients is significantly worse than in hemodialysis patients. Therefore it may be inadvisable to transplant HBsAg-positive hemodialysis patients.(ABSTRACT TRUNCATED AT 400 WORDS)