Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4-year results from the randomized EXIST-1 and EXIST-2 studies.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. OBJECTIVE: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. MATERIALS AND METHODS: Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. RESULTS: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). CONCLUSION: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

The UK guidelines for management and surveillance of Tuberous Sclerosis Complex.

BACKGROUND: The severity of Tuberous Sclerosis Complex (TSC) can vary among affected individuals. Complications of TSC can be life threatening, with significant impact on patients' quality of life. Management may vary dependent on treating physician, local and national policies, and funding. There are no current UK guidelines. We conducted a Delphi consensus process to reach agreed guidance for the management of patients with TSC in the UK. METHODS: We performed a literature search and reviewed the 2012/13 international guideline for TSC management. Based on these, a Delphi questionnaire was formed. We invited 86 clinicians and medical researchers to complete an online survey in two rounds. All the people surveyed were based in the UK. Clinicians were identified through the regional TSC clinics, and researchers were identified through publications. In round one, 55 questions were asked. In round two, 18 questions were asked in order to obtain consensus on the outstanding points that had been contentious in round one. The data was analysed by a core committee and subcommittees, which consisted of UK experts in different aspects of TSC. The Tuberous Sclerosis Association was consulted. RESULTS: About 51 TSC experts took part in this survey. Two rounds were required to achieve consensus. The responders were neurologists, nephrologists, psychiatrist, psychologists, oncologists, general paediatricians, dermatologist, urologists, radiologists, clinical geneticists, neurosurgeons, respiratory and neurodisability clinicians. CONCLUSIONS: These new UK guidelines for the management and surveillance of TSC patients provide consensus guidance for delivery of best clinical care to individuals with TSC in the UK.

Maintenance of adequate dialysis in a patient with peritoneal calcification using tidal peritoneal dialysis.

A case report of a 50-year-old woman who has been treated with peritoneal dialysis for 9 years, with a short period off dialysis following transplantation. The patient had long-standing secondary hyperparathyroidism and had declined parathyroidectomy, she had had two episodes of peritonitis in the preceding eight years. She presented with blood-stained dialysate effluent and intermittent abdominal pain. Investigation revealed widespread peritoneal calcification with large plaques of calcium on the visceral peritoneum. She was treated with tidal automated peritoneal dialysis; adequate creatinine clearances have been maintained and the patient has had little further abdominal pain and bleeding. In this report we have illustrated an unusual complication of peritoneal dialysis, peritoneal calcification, and suggest that tidal peritoneal dialysis is a useful therapeutic tool in such cases.

Renal biopsy in the elderly: clinicopathological correlations in 143 patients.

The clinical presentation and spectrum of renal histopathology is described in 143 patients aged 60 years or more, with renal disease. In 82 patients renal biopsy revealed primary renal disease. In the remainder, changes associated with systemic conditions were found. These included amyloidosis, polyarteritis nodosa and hypertension. Fifty patients present with the nephrotic syndrome, one third of whom had a membranous glomerulonephritis on the renal biopsy. Three patients had a carcinoma associated with this renal histology. Two patients had a minimal change lesion and their nephrotic syndrome responded to corticosteroids. Renal biopsies from the 45 patients present with renal failure revealed a variety of histopathology which included idiopathic crescentic nephritis and antiglomerular basement membrane disease. Percutaneous renal biopsy is a valuable diagnostic aid in elderly patients with renal disease.

Changes in diurnal blood pressure variation and red cell and plasma volumes in patients with renal failure who develop erythropoietin-induced hypertension.

Hypertension is the most common side-effect of treatment with recombinant human erythropoietin (EPO) for the anemia of chronic renal failure. To elucidate why this occurs in some patients we measured changes in blood volumes and diurnal blood pressure (BP) variation during treatment. Isotope labelled measurements of red cell and plasma volume (RCV and PV) were carried out along with ambulatory BP monitoring before starting EPO and after target hemoglobin (Hb) was reached. RCV did not differ between the patient group developing EPO-induced hypertension (EpHT, n = 11) and the group with no change in BP (NC, n = 13) either before or after treatment. However PV was significantly lower in the EpHT group after treatment (2.97 vs 3.92 litres; p < 0.025). Mean BPs differed little between groups because antihypertensive medications were increased as necessary for clinical safety but after achieving target Hb, day-night difference in diastolic BP was greater in the EpHT than the NC group (11.5 vs 4.6 mmHg; p < 0.025) due to a greater rise in daytime BP. There were significant correlations between high day-night diastolic BP differences after EPO in all the studied patients and low plasma volumes either pre- or post-EPO. The study group was heterogeneous but the changes were in the same direction irrespective of type of renal replacement therapy. These results suggest that EPO-induced hypertension is associated with increased daytime vasoconstriction and greater hemoconcentration due to lower plasma volume.

Comparison of the efficacy cost and complication rate of APD and CAPD as long-term outpatient treatments for renal failure.

We compared 10 patients treated with overnight APD in their homes with a parallel group of 30 patients having CAPD (Freeline II) over two years 1990 and 1991. Our aim was to discover if APD was an efficient and cost effective alternative to CAPD. The average amount of dialysate used per day in APD patients was 11 litres (range 9 to 14 litres) compared to 6.8 litres (range 6 to 10 litres) for CAPD. The average plasma creatinine was 920 umol/L, plasma urea of 21 mmol/L on APD and 825 umol/L and 24 mmol/L respectively on CAPD. In 1990 there were 2 incidences of peritonitis (2 in 1991) in the APD patients compared to 24 incidences (24 in 1991) in the CAPD patients with 6 recurrences (5 in 1991) and 19 exist site infections (24 in 1991). The average fluid costs plus disposables were comparable. However the cost of treating complications per patient for APD was for 1990 32 pounds (108 pounds in 1991) and for CAPD 832 pounds (1308 pounds in 1991). All the APD patients who had previously experienced CAPD preferred this treatment for its convenience and social acceptability. APD is a cost-effective alternative to CAPD and has advantages in some patients.

Tuberose sclerosis complex: analysis of growth rates aids differentiation of renal cell carcinoma from atypical or minimal-fat-containing angiomyolipoma.

AIM: To study the radiological characteristics of renal masses in individuals with tuberous sclerosis complex (TSC) using serial CT, and to examine how renal cell carcinoma (RCC) may be differentiated from indeterminate cysts or masses. METHODS: This was a retrospective study of 12 cases of TSC in which dedicated renal CT followed after US had demonstrated cystic or sonographically unusual renal masses. The CT density of all masses was measured and the masses categorized as simple cysts, complex cysts, angiomyolipomas or indeterminate solid masses. Subjects were maintained on regular follow-up with repeat CT or MRI and interval renal US. Indeterminate masses that showed rapid growth were considered suspicious for renal cell carcinoma and biopsy or nephrectomy followed. RESULTS: Comparative data were available for a median of 4 years. In each case the renal masses were multiple and bilateral; mean mass diameter was 3.6 cm. Among a total of 206 masses, 18 were simple cysts and 3 were complex cysts. Of the complex cysts, 1 proved to be an angiomyolipoma on histology and the other 2 showed no growth. Of the solid masses, 133 were typical angiomyolipomas (AMLs) and 52 were indeterminate. On follow-up, only 3 indeterminate masses showed rapid growth (>0.5 cm/year), of which only 1 proved to be an RCC on biopsy. The other 2 were minimal-fat AMLs, and the remainder of the masses showed no or slow growth. CONCLUSION: Many renal masses associated with TSC are radiologically indeterminate. A growth threshold of >0.5 cm/year identified the only RCC in this study (0.5% of all masses). Yearly radiological follow-up of indeterminate renal masses is recommended for individuals with TSC.

The effect of nadolol on heart rate in hyperthyroidism. A controlled trial.

Twenty hyperthyroid patients were randomly assigned in a double-blind fashion to receive either nadolol 80 mg/day or placebo for 2 weeks; all patients then took carbimazole as well from 2-6 weeks. Twenty-four hour Holter ECG recordings at 0, 2 and 6 weeks showed that nadolol reduced the mean maximum heart rate by 19.9% (P less than 0.0005) at 2 weeks and by 30.3% (P less than 0.0005) at 6 weeks compared to 5.2% (ns) and 18.3% (P less than 0.0005) in patients taking placebo. There was no alteration of the normal circadian variation of heart rate by nadolol. The minimum heart rate before therapy was significantly correlated with FT4 (r = 0.52) and with FT3 (r = 0.44). The percentage of time per hour during which the heart rate was greater than 100 was reduced by 79% at week 2 by nadolol compared to 22% in the placebo group. At the 6 week point the placebo group still had a tachycardia (mean maximum heart rate 101.6 beats/min +/- 15.2 SD) compared to the nadolol group (80.4 +/- 7.7). Nadolol did not cause excessive bradycardia. It is effective in the early management of hyperthyroidism and should be given for at least the first 4-6 weeks.

A report of overdose with astemizole.

A case is reported of a 14-year-old girl who took an overdose of 200 mg of astemizole. There were no serious adverse clinical or laboratory sequelae, with only mild sedation and no anticholinergic adverse effects. The apparent half-life of this dose over the next 37 h was 31 h.

Drug removal in continuous haemofiltration and haemodialysis.

Although both continuous haemofiltration and continuous haemodialysis are techniques routinely employed in the management of critically ill patients, deciding on a drug dosing regimen is often difficult. This article highlights the factors influencing drug removal by both processes, the difficulties associated with the interpretation of research in this area and offers a number of approaches which can be used when selecting a dosing regimen for a patient receiving one of these therapies.

Haemodynamic changes measured by transthoracic bioimpedance during treatment with recombinant human erythropoietin.

Hypertension complicates the treatment of anaemia of chronic renal failure with recombinant human erythropoietin (EPO) in some patients. We conducted a prospective study measuring changes in cardiac index (CI) and systemic vascular resistance index (SVRI) in 29 patients from before commencement of EPO to attainment of target haemoglobin concentration. We used the operator-independent technique of trans-thoracic bioimpedance. The group of patients who developed EPO-induced hypertension (EpHT) were separately analysed and compared with the group who had no change in blood pressure (NC). Our results showed there was a significant rise in SVRI after treatment in EpHT group patients but in the NC group there was a small fall. CI increased significantly in the NC group after treatment but no change was recorded in the EpHT group. These findings clearly demonstrate how the cardiovascular changes differ in patients who develop EPO-induced hypertension.

Long-term effects of endralazine (BQ-22-708) in patients with renal impairment and hypertension.

Endralazine, a new peripheral vasodilator, was studied in 21 patients with hypertension and chronic renal failure. Nineteen patients had unacceptable control of hypertension with their previous therapy, and 2 were suffering adverse effects for other third line drugs. All patients continued to receive a beta-adrenergic blocking agent. Five patients failed to complete the study, two because of poor compliance, and 3 as a result of failure to control raised blood pressure. In the remaining 16 patients, satisfactory blood pressure reduction was seen at 6 months and was maintained in 12 patients followed for 18 months. Endralazine was well tolerated. No patient developed the lupus syndrome nor evidence of drug-induced immunological abnormality.

Quinine clearance in continuous venovenous hemofiltration.

OBJECTIVE: To describe a case involving the removal of quinine by continuous venovenous hemofiltration (CVVH) in a patient with malaria and acute renal failure and to present recommendations on the dosing of quinine in such patients. CASE SUMMARY: A 50-year-old white man developed Plasmodium falciparum malaria following a visit to Nigeria. Although he received intravenous quinine, his condition deteriorated and he required intensive care management, including CVVH for the management of his acute renal failure. Quinine plasma concentrations were measured to determine both total body and extracorporeal clearance of the drug. DISCUSSION: To our knowledge this is the first report quantifying the removal of quinine by CVVH. The drug is not significantly removed by this extracorporeal process. The filter clearance accounted for less than 1.5% of the total body clearance. CONCLUSIONS: Initially the dosage of quinine administered to patients presenting with P. falciparum infection should not be reduced because of renal failure. This is particularly important when cerebral involvement is suspected. Subsequent dosage modification should reflect the severity of the patient's clinical condition and the plasma quinine concentration achieved, and should not be limited by the degree of renal impairment present.

Effect of nadolol on plasma lipids in hyperthyroidism.

The effect of Nadolol treatment on lipid subfractions in a group of 23 hyperthyroid patients was assessed in a randomised double-blind placebo controlled trial lasting six weeks, carbimazole being given to both groups from weeks 2 to 6. Clinical and biochemical euthyroidism was seen in both groups at 6 weeks; no effect of nadolol on peripheral monodeiodination of T4 to T3 was observed. At time 0 there were significant negative correlations between total cholesterol and free T3 (r = 0.68), and free T4 (r = 0.54). In the Nadolol group there were significant rises between 0 and 6 weeks in total cholesterol (52.6%, P less than 0.01), LDL cholesterol (30.3%, P less than 0.01) and HDL cholesterol (18.2%, P less than 0.05). HDL cholesterol rose significantly in the placebo group (12.4%, P less than 0.05) but there were no significant increases in LDL cholesterol or total cholesterol. The rise in triglyceride during this period in the Nadolol group (64.7%, P less than 0.05) was significantly greater (P less than 0.05) than the rise in the placebo group (8.8%). Nadolol increases triglyceride more than placebo during the early management of hyperthyroidism.

Reversible acute renal failure induced by losartan in a renal transplant recipient.

A 56-year-old man who received a live-related renal transplant in 1988 was started in 1995 on the selective angiotensin II antagonist losartan (Dupont-Merke) to treat worsening hypertension. Two months later because of pulmonary oedema, loop diuretics were started. Within two weeks, serum creatinine had increased from 245 to 571 mumol/l, and the patient became oliguric. A systolic bruit was noted over the graft. Renal angiography showed a 90% stenosis of the transplant renal artery. Losartan was withdrawn, with prompt improvement in renal function. A successful percutaneous transluminal angioplasty performed a few days later resulted in further improvement in renal function accompanied by a significant diuresis.

An investigation of the effect of advancing uraemia, renal replacement therapy and renal transplantation on blood pressure diurnal variability.

BACKGROUND: Ambulatory blood pressure recordings have been shown to correlate better with target organ damage than have isolated clinic blood pressure readings. There have been some small studies demonstrating that abnormal blood pressure diurnal rhythm is common in uraemia and in patients on renal replacement therapy. Abnormal blood pressure diurnal rhythm itself may be a risk factor for accelerated target organ damage. METHODS: We retrospectively studied 480 ambulatory blood pressure recordings in 380 patients with essential hypertension, secondary hypertension, and on renal replacement therapy. We examined diurnal blood pressure rhythm in each group. RESULTS: Abnormal blood pressure diurnal rhythm (non-dipping) is significantly more prevalent in patients with underlying renal disease, even with normal excretory renal function (53%) than in age-, sex-, and race-matched controls with essential hypertension ((30%), P < 0.01). In patients with renal disease the prevalence of non-dipping rose with worsening renal function, reaching statistical significance once plasma creatinine was greater than 400 mumol/l. There was a direct correlation between plasma creatinine and percent decline in blood pressure at night for both systolic (r = 0.23) and diastolic (r = 0.24) blood pressure in patients with underlying renal disease and impaired excretory renal function. High prevalences of abnormal diurnal BP rhythm are seen in patients on haemodialysis (82%), peritoneal dialysis (78%), patients with plasma creatinine > 600 mumol/l (75%), and in renal transplant recipients (74%). CONCLUSIONS: Abnormal blood pressure diurnal rhythm ('non-dipping') is significantly more common in secondary than in primary hypertension, even with normal renal function. Abnormal blood pressure diurnal rhythm becomes increasingly common with advancing uraemia. Once the plasma creatinine is greater than 600 mumol/l the prevalence of non-dipping is the same as that seen with renal replacement therapy. This phenomenon is not modulated by successful renal transplantation.

Tremor: an alternative approach for investigating adrenergic mechanisms in thyrotoxicosis?

The effects of nadolol (or placebo) and carbimazole on thyrotoxic tremor were investigated in 18 thyrotoxic patients. Both nadolol and carbimazole produced significant reductions in tremor power although nadolol did not cause any change in serum free tri-iodothyronine and free thyroxine concentrations. The results are discussed in terms of the pathogenesis of thyrotoxic tremor and the potential usefulness of tremor in the investigation of adrenergic mechanisms in thyrotoxicosis.

Glomerulonephritis, non-Hodgkin's lymphoma and leucocytoclastic vasculitis.

2 cases of active focal proliferative glomerulonephritis, lymphocytic malignant lymphoma and leucocytoclastic vasculitis are described. 1 presented with the nephrotic syndrome and progressive renal impairment, the other with acute renal failure. Cryoglobulins were detected in the serum of 1 patient, but not in that of the other. Initial renal and skin biopsies in the 2 patients were strikingly similar. As well as demonstrating glomerular lesions, the renal biopsies contained interstitial lymphomatous infiltrate which, in 1 case, was initially incorrectly interpreted and resulted in delay in specific treatment. Immunosuppressive therapy markedly improved renal function and induced remission of the vasculitis and lymphoma. Repeat renal biopsy in 1 case confirmed regression of the glomerulonephritis. A common immunological aetiology may explain the co-existence of these three conditions in the 2 patients.