Calcium balance during calcitriol and paricalcitol administration in healthy humans.

OBJECTIVE: Secondary hyperparathyroidism in hemodialysis patients requires optimal correction of vitamin D deficiency with active vitamin D and analogues. It has been postulated that new vitamin D analogues, i.e. paricalcitol, efficiently suppress parathyroid hormone serum levels (PTH), but do not increase intestinal calcium absorption as much as calcitriol. The effects of calcitriol and paricalcitol on calcium balance can best be characterized under standardized conditions in healthy individuals with normal renal function, because the urinary calcium excretion at steady state corresponds to the net calcium absorption in the gut. METHODS: In a randomized, double-blind, placebo-controlled, 3-way crossover Phase I study in 13 healthy individuals we investigated the changes compared to placebo in PTH and urinary calcium excretion during 6-day treatment periods with paricalcitol (1.5 microg/day) and calcitriol (0.5 microg/day). RESULTS: 24-hour urinary calcium excretion was stable during 6 days of placebo administration. Neither paricalcitol nor calcitriol significantly changed calcium excretion. Urinary creatinine, magnesium and phosphate excretion also remained unchanged over the study periods irrespective of the treatment. However, calcitriol was shown to be effective in reducing iPTH levels during 6 days of treatment (mean reduction 4.03+/-0.69 pmol/l), whereas paricalcitol had no effect. CONCLUSION: Using a dosing ratio of 1:3 for calcitriol:paricalcitol, i.e. the same conversion factor used previously in studies on hemodialysis patients, only calcitriol was able to reduce iPTH levels in healthy individuals. Low-dose calcitriol reduced iPTH levels without raising calcium absorption and without including any hypercalcemia.

Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS.

Longer treatment time (TT) and slower ultrafiltration rate (UFR) are considered advantageous for hemodialysis (HD) patients. The study included 22,000 HD patients from seven countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Logistic regression was used to study predictors of TT > 240 min and UFR > 10 ml/h/kg bodyweight. Cox regression was used for survival analyses. Statistical adjustments were made for patient demographics, comorbidities, dose of dialysis (Kt/V), and body size. Europe and Japan had significantly longer (P < 0.0001) average TT than the US (232 and 244 min vs 211 in DOPPS I; 235 and 240 min vs 221 in DOPPS II). Kt/V increased concomitantly with TT in all three regions with the largest absolute difference observed in Japan. TT > 240 min was independently associated with significantly lower relative risk (RR) of mortality (RR = 0.81; P = 0.0005). Every 30 min longer on HD was associated with a 7% lower RR of mortality (RR = 0.93; P < 0.0001). The RR reduction with longer TT was greatest in Japan. A synergistic interaction occurred between Kt/V and TT (P = 0.007) toward mortality reduction. UFR > 10 ml/h/kg was associated with higher odds of intradialytic hypotension (odds ratio = 1.30; P = 0.045) and a higher risk of mortality (RR = 1.09; P = 0.02). Longer TT and higher Kt/V were independently as well as synergistically associated with lower mortality. Rapid UFR during HD was also associated with higher mortality risk. These results warrant a randomized clinical trial of longer dialysis sessions in thrice-weekly HD.

Long-term comparison of a calcium-free phosphate binder and calcium carbonate--phosphorus metabolism and cardiovascular calcification.

BACKGROUND: Calcium carbonate used as a phosphate binder may contribute to cardiovascular calcification. Long-term comparisons of sevelamer, a non-calcium polymeric phosphate binder, and calcium carbonate (CC) are lacking. METHODS: 114 adult hemodialysis patients were randomly assigned to open label sevelamer or CC for 52 weeks. Study efficacy endpoints included changes in serum phosphorus, calcium, calcium-phosphorus product, and lipids. In addition, initial and sequential electron beam computerized tomography scans were performed to assess cardiovascular calcification status and change during follow-up. Safety endpoints were serum biochemistry, blood cell counts and adverse events. RESULTS: Patients receiving sevelamer had a similar reduction in serum phosphorus as patients receiving CC (sevelamer -0.58 +/- 0.68 mmol/l, CC -0.52 +/- 0.50 mmol/l; p = 0.62). Reductions in calcium-phosphorus product were not significantly different (sevelamer -1.4 +/- 1.7 mmol2/l2, CC -0.9 +/- 1.2 mmol2/l2; p = 0.12). CC produced significantly more hypercalcemia (> 2.8 mmol/l in 0% sevelamer and 19% CC patients, p < 0.01) and suppressed intact parathyroid hormone below 150 pg/ml in the majority of patients. Sevelamer patients experienced significant (p < 0.01) reductions in total (-1.2 +/- 0.9 mmol/l, -24%) and LDL cholesterol (-1.2 +/- 0.9 mmol/l, -30%). CC patients had significant increases in coronary artery (median +34%, p < 0.01) and aortic calcification (median +32%, p < 0.01) that were not observed in sevelamer-treated patients. Patients on sevelamer required more grams of binder (sevelamer 5.9 g vs. CC 3.9 g) and experienced more dyspepsia than patients on calcium carbonate. CONCLUSIONS: Sevelamer is an effective phosphate binder that unlike calcium carbonate is not associated with progressive cardiovascular calcification in hemodialysis patients.

The El Salvador earthquakes of january and february 2001 : Context, characteristics and implications for seismic risk

The small Central American republic of El Salvador has experienced, on average, one destructive earthquake per decade during the last hundred years. The latest events occurred on 13 January and 13 February 2001, with magnitudes Mw 7.7 and 6.6, respectively. The two events, which were of different tectonic origin, follow the patterns of the seismicity of the region although neither event has a known precedent in the earthquake catalogue in terms of size and location. The earthquakes caused damage to thousands of traditionally built houses and triggered hundreds of landslides, which were the main causes of fatalities. The earthquakes have clearly demonstrated trends of increasing seismic risk in El Salvador due to rapid population expansion in areas of high shaking and landslide hazard, exacerbated by deforestation and uncontrolled urbanisation. The institutional mechanisms required for the control of land use and building practice are very weak and present a major obstacle to risk mitigation.(AU)

Cardiovascular disease determinants in chronic renal failure: clinical approach and treatment.

INTRODUCTION: Cardiovascular disease (CVD), as the leading cause of morbidity and mortality in patients on renal replacement therapy (RRT), has a central role in everyday nephrological practice. METHODS: Consensus was reached on key points relating to the clinical approach and treatment of the main cardiovascular risk factors in RRT patients (hypertension, anaemia, hyperparathyroidism, dyslipidaemia, new emerging risk factors). In addition, the role of convective treatments on cardiovascular outcomes was examined. RESULTS: Hypertension should be managed by aiming at blood pressure values of < or =140/90 mmHg (< or =160/90 mmHg in the elderly), firstly by ensuring target dry body weight is achieved. No single class of drug has proved superior to others in RRT patients, provided that the blood pressure target is achieved, although ACE inhibitors have shown specific organ protection in high-risk patients (HOPE study) and are well tolerated. Anaemia should be managed by using erythropoietin and iron supplements, aiming at haemoglobin levels of 12 g/dl and keeping serum ferritin levels < 500 ng/ml. The management of hyperparathyroidism is currently unsatisfactory, as calcium supplements have the potential to increase cardiovascular calcification. While awaiting new calcium- and aluminium-free phosphate binders, it is essential to ensure dialysis adequacy. Clinical studies are in progress to assess the real impact of lipid-lowering drugs in RRT. In the meantime, serum LDL-cholesterol < 160 mg/dl and triglycerides < 500 mg/dl may be desirable targets. The impact of new emerging risk factors (inflammation and chronic infection, hyperhomocysteinaemia, metabolic waste-product accumulation) and their proper management are still under research. Convective dialysis treatments may confer some degree of protection from dialysis-related amyloidosis and mortality, but clinical data on this important issue are still controversial and no definitive conclusions can be drawn at present. CONCLUSION: CVD prevention and treatment is a great challenge for the nephrologist. Achieving evidence-based consensus can help in encouraging the implementation of best clinical practice in line with the progress of current knowledge.

Attaining long-term survival when treating diabetic patients with ESRD by hemodialysis.

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD). The United States Renal Data System's report indicates that survival of diabetic patients has improved but continues to be reduced compared with that of nondiabetic patients. Several ways to decrease morbidity and mortality in diabetic patients are discussed: (1) Instructions and treatment in the predialysis period markedly influence compliance of patients, and this plays a determinant role in development and progression of diabetic complications before and during maintenance hemodialysis. (2) After the start of hemodialysis therapy, insulin therapy must be adjusted and respect impaired glucose use and prolongation of insulin half-life. (3) By avoiding of puncture of veins prospectively used for arteriovenous fistulae and timely installation of the fistulae, native arteriovenous fistulae can be achieved in more than 70% of diabetic patients. (4) Hypertension, left ventricular hypertrophy, and cardiovascular problems commonly found in diabetic patients require optimal removal of fluid overload. This is difficult to achieve in the presence of accelerated arteriosclerosis and autonomic polyneuropathy in diabetic patients and requires long and smooth dialysis procedures. (5) Infected necroses caused by diabetic polyneuropathy and peripheral vascular disease require appropriate therapy by experienced nephrologists and surgeons.

Renal failure in multiple myeloma "the myeloma kidney":state of the art.

Renal failure is present in about 20% of patients with multiple myeloma (MM) at diagnosis. Renal function impairment is usually caused by the so-called "myeloma kidney" and is associated with shortened survival in patients treated with conventional therapy. Renal failure is reversible in up to 50% of patients, particularly when its degree is moderate and it is related to precipitating factors such as hypercalcemia. In our experience, approximately 10% of newly diagnosed patients with MM have renal failure severe enough to require dialysis. Despite its frequency, there are few reports dealing with MM and renal failure.

[Radiologic diagnosis of the kidneys in dialysis patients]. / Radiologische Diagnostik der Nieren bei Dialysepatienten.

The kidneys of patients with chronic renal failure undergoing maintenance hemodialysis may show different variances or complications. Most common are secondarily acquired renal cysts, which may be found in as many as 92% of patients after 8 years of hemodialysis. Single (in 12.5% of patients) or multiple (8.3%) cysts with bleeding are common; additionally, hematuria or ruptured cysts may be found. Bleeding into cysts is more common in patients with autosomal dominant polycystic kidney disease. Due to the decreasing urinary production development of kidney stones is very uncommon, but calcifications in or around cysts can be found in 71% of patients. Kidney tumors occur 41 times more often in patients with chronic renal failure than in patients without kidney disease. We detected tumors in 4.2% of our patients on long-term dialysis. Diagnostic differentiation of the relatively slow growing and fairly late metastasizing malignant tumors from adenomas is not possible. Nevertheless, we screen our patients every 3-4 years. Computed tomography is superior to ultrasonography for this purpose, because ultrasonography lacks the necessary sensitivity in this group of patients.

Osteodystrophy in the millennium.

Despite three decades of intensive research on the derangements of calcium phosphate metabolism of renal failure, several unresolved issues are still with us at the turn of the millennium: poor control of hyperphosphatemia, relative inefficacy of active vitamin D to prevent progressive parathyroid hyperplasia, and persistence of bone disease despite lowering of parathyroid hormone (PTH) and administration of active vitamin D. Although predictions are problematic, it is not unreasonable to hope that, barring unforeseen side effects, calcimimetics will prove to be valuable for suppressing or even preventing hyperparathyroidism, thus potentially replacing, at least in part, active vitamin D. There is also reason to hope that more effective phosphate binders with fewer side effects will become available and that controlled studies will provide a rationale for the administration of estrogens to dialyzed women. As regards understanding the pathological mechanisms, one can anticipate that the disturbances leading to autonomous growth of parathyroid cells will be elucidated and the signals involved in osteoclast/osteoblast differentiation pathways and osteoclast/osteoblast coupling will be clarified, with obvious impact on patient management.

Acute effects of haemodialysis on cutaneous microcirculation in patients with peripheral arterial occlusive disease.

BACKGROUND: Peripheral arterial occlusive disease (PAOD) is an increasing problem in patients on maintenance haemodialysis. Alterations in microvascular perfusion accompany and complicate arteriosclerosis of large vessels and might contribute to the disease process. The aim of the study was to investigate the acute effects of haemodialysis on the cutaneous microcirculation in 26 patients with and without intermittent claudication. METHODS: Cutaneous perfusion was assessed by measuring transcutaneous oxygen pressure (tcPO2) and skin temperature at the dorsum of the foot. After standardized cooling to 15 degrees C of a 2cm2 skin area, the time to reach baseline skin temperature was evaluated as an indirect parameter of reactive hyperaemia. RESULTS: During haemodialysis, tcPO2 dropped significantly in both groups. The decrease in tcPO2 was more pronounced in patients with PAOD (20% vs 15% n.s.). The reactive hyperaemia response was reduced significantly in patients with intermittent claudication indicated by a prolonged time to reach baseline skin temperature after cooling. Values of tcPO2 and reactive hyperaemia did not reach baseline values at the end of haemodialysis in either group. CONCLUSIONS: Nutritive skin perfusion is impaired during haemodialysis. These changes are more pronounced in patients with PAOD and persist after dialysis. These findings are relevant for the treatment of patients with vascular disease on maintenance haemodialysis.