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.

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.

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.

How reproducible is diurnal blood pressure rhythm in patients with secondary (renal) hypertension?

Abnormalities (reduction in/absence of) in diurnal bp rhythm are much more commonly seen in patients with chronic uremia than in patients with primary hypertension or in normal subjects. Target-organ damage is greater in these patients. However, the extent to which these diurnal bp rhythm changes are consistent or variable is untested. We retrospectively examined 223 ambulatory blood pressure monitoring (ABPM) traces in 92 patients with chronic uremia who had undergone ABPM at least twice (mean 2.3 ABPM traces/patient) over the period 1991-1997. ABPM technique and analysis were constant over this period. We found that for patients with chronic declining renal function but not yet on dialysis therapy, 67% retained the same diurnal rhythm from one ABPM recording to the next; if the known tendency for declining renal function to accompanied by a greater prevalence of "non-dipping" is taken into account, 82% of all patients had a "predictable" diurnal pattern. 79% of transplant patients, 87% of haemodialysis patients and 100% of CAPD patients retained the diurnal rhythmicity from one ABPM session to the next. Non-dipping was much more frequent than dipping (67% vs 33%). We conclude that abnormalities of diurnal BP rhythm are reasonably consistent in patients with renal hypertension, especially as renal function declines and patients enter the renal replacement therapy programme.

Progression of diabetic nephropathy--is diurnal blood pressure rhythm as important as absolute blood pressure level?

BACKGROUND: Hypertensive non-diabetic patients who lack the normal nocturnal decline in blood pressure ('non-dippers') have an increased incidence of cardiovascular complications. Poor blood pressure control is known to exacerbate the decline in glomerular filtration rate in patients with diabetic nephropathy. METHODS: The aim of this study was to assess the contribution of abnormal blood pressure diurnal rhythm to the progression of diabetic nephropathy. We retrospectively studied 26 diabetic patients with hypertension, proteinuria and relentless progressive impairment of renal function due to diabetic nephropathy between 1990 and 1996. Patients underwent ambulatory blood pressure monitoring and were classified as either 'dippers' or 'non-dippers' according to their blood pressure diurnal rhythm. Dippers were patients whose mean sleeping blood pressure (both systolic and diastolic) was 10% less than blood pressure whilst awake. Weight, glycated haemoglobin, serum creatinine (micromol/l) and blood pressure (mmHg) were recorded on a 3-monthly basis. Twenty four hour urine protein excretion and creatinine clearance were recorded annually. The rate of decline of creatinine clearance was derived from serum creatinine estimation. RESULTS: In the 'dipper' group, the rate of decline of creatinine clearance was -2.9 ml/min/year and in those with abnormal blood pressure diurnal rhythm it was -7.9 ml/min/year (P<0.05). There was no significant difference in day-time mean blood pressures, glycated haemoglobin, age and numbers with insulin-dependent diabetes mellitus. CONCLUSION: We found that there was a profound effect of non-dipping upon the rate of decline of renal function in patients with diabetic nephropathy.

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.

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.

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.

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.

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.

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.

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.