Kelvin L. Lynn

Effects of Early and Late Intervention with Epoetin α on Left Ventricular Mass among Patients with Chronic Kidney Disease (Stage 3 or 4): Results of a Randomized Clinical Trial

It is not known whether prevention of anemia among patients with chronic kidney disease would affect the development or progression of left ventricular (LV) hypertrophy. A randomized controlled trial was performed with 155 patients with chronic kidney disease (creatinine clearance, 15 to 50 ml/min), with entry hemoglobin concentrations ([Hb]) of 110 to 120 g/L (female patients) or 110 to 130 g/L (male patients). Patients were monitored for 2 yr or until they required dialysis; the patients were randomized to receive epoetin alpha as necessary to maintain [Hb] between 120 and 130 g/L (group A) or between 90 and 100 g/L (group B). [Hb] increased for group A (from 112 +/- 9 to 121 +/- 14 g/L, mean +/- SD) and decreased for group B (from 112 +/- 8 to 108 +/- 13 g/L) (P < 0.001, group A versus group B). On an intent-to-treat analysis, the changes in LV mass index for the groups during the 2-yr period were not significantly different (2.5 +/- 20 g/m(2) for group A versus 4.5 +/- 20 g/m(2) for group B, P = NS). There was no significant difference between the groups in 2-yr mean unadjusted systolic BP (141 +/- 14 versus 138 +/- 13 mmHg) or diastolic BP (80 +/- 6 versus 79 +/- 7 mmHg). The decline in renal function in 2 yr, as assessed with nuclear estimations of GFR, also did not differ significantly between the groups (8 +/- 9 versus 6 +/- 8 ml/min per 1.73 m(2)). In conclusion, maintenance of [Hb] above 120 g/L, compared with 90 to 100 g/L, had similar effects on the LV mass index and did not clearly affect the development or progression of LV hypertrophy. The maintenance of [Hb] above 100 g/L for many patients in group B might have been attributable to the relative preservation of renal function.

End-Stage Reflux Nephropathy

Forty-two of 371 patients (11.3%) entering a dialysis-transplant program had end-stage reflux nephropathy. Thirteen of these 371 patients were under 16 years of age, with 6 of them having reflux nephropathy. Most patients presented with severely impaired renal function, hypertension, and proteinuria. Documented urinary tract infections occurred in only 4 of the 18 male and 14 of the 24 female patients. Thirty-five patients had hypertension, which in 22 had not been detected before presentation. Five presented with accelerated hypertension. Eight of the 24 women presented during a pregnancy. Twenty-nine patients are still alive, 20 with a functioning renal transplant. Reflux nephropathy is an important cause of end-stage renal failure, particularly in younger people. All patients presenting with renal insufficiency and proteinuria, with or without urinary tract infections or hypertension, should have reflux nephropathy excluded.

A Comparative Study of Blood Pressure Control with Short In-Center versus Long Home Hemodialysis

We conducted a randomized crossover trial to establish, within patients, whether long-slow hemodialysis (HD) was associated with better blood pressure (BP) control than standard HD. Nine home HD patients, not on antihypertensive drugs, were dialyzed to the same eKt/Vurea and target weights for 6–8 h (LD) at home and for 3.5–4.5 h (SD) in the dialysis center 3 times weekly in randomized sequence, with each phase lasting 8 weeks. Ambulatory BP, bioimpedance, neurohormones and autonomic function were measured in each phase. Pre- and postdialysis systolic, ambulatory systolic and diastolic BP were all higher with SD than with LD and intradialysis hypotension was more common. Weight, ECF volume and neurohormones did not differ between treatments. Muscle sympathetic activity was increased in both phases and cardiac sympathetic activity tended higher during SD. These findings suggest that additional factors to ECF volume may contribute to the superior BP control produced by long-slow HD.

Long-Term Followup of Infants with Gross Vesicoureteral Reflux

The majority of children (1 year old or less) with gross vesicoureteral reflux already have renal damage at the time of presentation or reflux nephropathy develops during the first few years of life. We report the long-term followup of 31 patients (16 boys) presenting in infancy with gross vesicoureteral reflux (Rolleston classification) between 1952 and 1970. They had a total of 44 grossly refluxing ureters (13 bilateral, 18 unilateral) and presented between ages 1 day and 48 weeks (mean 15.3 weeks). Of the 31 infants 5 died within the first year of life, 4 were followed for up to 11 years before being lost to followup and 1 was killed in a motor vehicle accident after 19.5 years of followup. The remaining 21 patients have been followed for 16 to 37 years (mean 23.9 years); 4 have normal kidneys, and 13 have unilateral and 4 have bilateral reflux nephropathy. Of those patients with unilateral reflux nephropathy proteinuria, hypertension and renal failure developed in 1 born with a single kidney and he is now on hemodialysis, while 2 others have a diastolic blood pressure of 90 mm. Hg or greater. Of the 4 patients with bilateral reflux nephropathy 2 have proteinuria and renal insufficiency, with 1 progressing towards end stage renal failure. Infants who present with gross vesicoureteral reflux within the first year of life appear to do well if free of severe bilateral reflux nephropathy at presentation. Patients with reflux nephropathy should remain under regular nephrological supervision with particular attention given to proteinuria, renal function and blood pressure.

First and subsequent nonmelanoma skin cancers: incidence and predictors in a population of New Zealand renal transplant recipients

BACKGROUND Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancers (NMSCs). The aims of this study were to determine the incidence and subsequent history of NMSCs in RTRs, together with risk factors. METHODS All patients transplanted between July 1972 and March 2007, and followed up at Christchurch Hospital, New Zealand, were studied. Immunosuppression regimens were mostly prednisone, azathioprine, cyclosporine and prednisone, mycophenolate mofetil, cyclosporine since 1998. RESULTS Of 384 RTRs, 96 developed at least one NMSC. The median time to first NMSC was 18.3 years (95% CI 14.2, 22.9) from transplant, as estimated by survival analysis. Individual predictors of first NMSC in RTRs were older age at first transplant (P < 0.0001), male sex (P = 0.006) and initial immunosuppression regimen (P = 0.001); only age (P < 0.0001) and male gender (P = 0.003) were significant predictors in a joint model. The mean rate of subsequent NMSCs was 1.67 per year (95% CI = 1.32, 2.11). Older age at first renal transplant (P = 0.009) or at discovery of the first NMSC (P = 0.01) was associated with a higher annual rate of new NMSC following the discovery of the first NMSC. The median survival time to a second NMSC was 2.2 years (CI 1.4, 3.0). Fourteen patients died of metastatic squamous cell carcinoma (15% case fatality). CONCLUSIONS NMSCs are a major health issue for RTRs, especially in older males. Once RTRs have developed their first NMSC, ongoing surveillance and prompt treatment are essential.

Hyponatremic-Hypertensive Syndrome With Renal Ischemia: An Underrecognized Disorder

Renal artery stenosis or occlusion causing the hyponatremic-hypertensive syndrome has been rarely reported. Our impression, however, was that the disorder is not uncommon. Case records from patients in one city (population 350 000) presenting between 1980 and 1997 with hypertension, hyponatremia, and evidence of renal ischemia were scrutinized. Thirty-two patients fulfilling inclusion criteria were identified. Admission supine arterial pressures were high (mean 228/124 mm Hg), but there was a vigorous fall in pressure on standing (26/12.7 mm Hg recorded in 27 patients). Mean plasma concentrations of sodium (129.7 mmol/L) and potassium (2.7 mmol/L) were low, and 24-hour urine protein excretion was elevated in 19 of 26 patients. Twenty-two of the 32 patients were female, the majority were asthenic, and all but 5 were smokers. Symptoms precipitating hospitalization were headache, clouding of consciousness, confusion, weakness, weight loss, thirst, and polyuria. Plasma renin levels, measured in 20 patients, were elevated in most cases and correlated inversely (r=-0.63, P<0.01) with the plasma sodium concentration. The hyponatremic-hypertensive syndrome in patients with renal ischemia is not rare: Rather, it is underreported. It tends to affect elderly asthenic women who smoke heavily. Stimulation of renin release from the ischemic kidney is probably central to the pathophysiology. The syndrome deserves better recognition to ensure appropriate investigations and management.

Inverted formin 2 mutations with variable expression in patients with sporadic and hereditary focal and segmental glomerulosclerosis

Focal and segmental glomerulosclerosis (FSGS) is a major cause of end-stage kidney disease. Recent advances in molecular genetics show that defects in the podocyte play a major role in its pathogenesis and mutations in inverted formin 2 (INF2) cause autosomal dominant FSGS. In order to delineate the role of INF2 mutations in familial and sporadic FSGS, we sought to identify variants in a large cohort of patients with FSGS. A secondary objective was to define an approach for genetic screening in families with autosomal dominant disease. A total of 248 individuals were identified with FSGS, of whom 31 had idiopathic disease. The remaining patients clustered into 64 families encompassing 15 from autosomal recessive and 49 from autosomal dominant kindreds. There were missense mutations in 8 of the 49 families with autosomal dominant disease. Three of the detected variants were novel and all mutations were confined to exon 4 of INF2, a regulatory region responsible for 90% of all changes reported in FSGS due to INF2 mutations. Thus, in our series, INF2 mutations were responsible for 16% of all cases of autosomal dominant FSGS, with these mutations clustered in exon 4. Hence, screening for these mutations may represent a rapid, non-invasive and cost-effective method for the diagnosis of autosomal dominant FSGS.

A Controlled Trial of the Effect of Folate Supplements on Homocysteine, Lipids and Hemorheology in End-Stage Renal Disease

Elevated plasma homocysteine (Hcy), dyslipidemia and hemorheological abnormalities all occur commonly in end-stage renal disease (ESRD) and are recognized risk factors for arteriosclerosis. To study the effect of folate supplementation on these factors we conducted a randomized controlled trial. Thirteen hemodialysis (HD) and 8 continuous ambulatory peritoneal dialysis (CAPD) patients received either 5 mg folic acid daily or placebo for 3 months. After 1 and 3 months, fasting blood samples were taken for Hcy, lipid profile, blood and plasma viscosity, red blood cell (RBC) osmotic fragility, plasma fibrinogen concentration and in vivo platelet aggregability. At baseline, the CAPD patients had a higher mean plasma fibrinogen concentration than the HD patients and they also tended to have higher mean plasma viscosity. Folate-treated patients showed marked increases in RBC folate and an average decrease in plasma Hcy concentration of 33%. Mean total cholesterol, LDL cholesterol and triglyceride concentrations decreased significantly in the CAPD patients who took folate. Folate had no significant effect on hemorheology. In conclusion, folate supplements in ESRD reduce plasma Hcy concentrations and may improve lipid profiles. In our patients, hemorheological abnormalities were more marked in patients on CAPD than in those on HD and were not improved by folate supplementation.

Hypotensive and Natriuretic Actions of Adrenomedullin in Subjects With Chronic Renal Impairment

Abstract—Plasma levels of adrenomedullin are increased in chronic renal failure. The significance of this finding is uncertain, because the biological effects of adrenomedullin in renal impairment are unknown. Therefore, we studied the effects of adrenomedullin infusion in subjects with chronic renal impairment. Eight males with IgA nephropathy and plasma creatinine of 0.19±0.03 mmol/L (mean±SEM) were studied in a vehicle-controlled crossover design. Each subject was studied twice; subjects were administered either adrenomedullin at a low dose and then a high dose (2.9 and 5.8 pmol/kg per minute, respectively, for 2 hours each) or a 4-hour vehicle control (Hemaccel), in random order, on day 4 of controlled metabolic diets. Adrenomedullin infusion achieved plasma adrenomedullin concentrations in the pathophysiological range after the low (31.2±5.1 pmol/L) and high (47.4±4.3 pmol/L) dose, and plasma cAMP was increased. Compared with vehicle control, high-dose adrenomedullin increased peak heart rate (+21.7±3.3 bpm, P <0.01) and cardiac output (+2.9±0.2 L/min, P <0.01) and lowered both systolic and diastolic blood pressures by >10 mm Hg (P <0.05). Plasma renin activity, angiotensin II, and norepinephrine increased by up to 50% above baseline levels (P <0.05 for all), whereas aldosterone and epinephrine were unchanged. Urinary volume and sodium excretion increased significantly (P <0.05) with low-dose adrenomedullin, whereas creatinine clearance was stable, and proteinuria tended to decrease. In subjects with chronic renal impairment due to IgA nephropathy, adrenomedullin infusion lowered blood pressure, stimulated sympathetic activity and renin release, and caused diuresis and natriuresis. Adrenomedullin may have a role in modulating blood pressure and kidney function in renal disease.

Autonomic dysfunction and ambulatory blood pressure in renal transplant recipients.

Background. Abnormal circadian blood pressure (BP) rhythm (nondipping) and autonomic dysfunction are both common in end-stage renal disease (ESRD). It is not known whether these abnormalities are related or if they are associated with greater left ventricular hypertrophy. Methods. Nineteen renal transplantation (RT) recipients, aged 22–67 years, who were transplanted at least 12 months (1–29 years) previously, were studied with 24-hr ambulatory blood pressure monitoring (ABPM). Autonomic function was tested by automated analysis of heart rate variations and echocardiography was used to estimate left ventricular mass index (LVMI). Results. Thirteen patients (68%) were nondippers. Although seven (37%) patients had significant parasympathetic dysfunction, this was not related to dipper status. Neither abnormality showed a tendency to diminish with time after RT. Systolic hypertension, diagnosed by ABPM, occurred in 5% of patients during the awake period and in 52% during sleep, whereas diastolic hypertension occurred in 47% when awake and in 63% when asleep. Awake systolic BP was the strongest predictor of LVMI (r=0.7, P <0.001), and was considerably better than systolic BPs recorded at the clinic (r=0.48, P <0.05). Conclusions. Nondipping is common after RT but is not related to the degree of autonomic dysfunction. These findings suggest that autonomic dysfunction is not a major contributor to nondipping in ESRD. In RT patients, ABPM is a more sensitive measure of hypertension and a stronger predictor of LVMI than clinic BP.