Intensive blood-pressure control in hypertensive chronic kidney disease.

BACKGROUND: In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients. METHODS: We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years. RESULTS: During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01). CONCLUSIONS: In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)

Sequence of cellular events in pancreatic islets leading to impaired insulin secretion in chronic kidney disease.

OBJECTIVES: In chronic renal failure (CRF), a multitude of metabolic derangements occur in the pancreatic islets, resulting in impaired glucose-induced insulin secretion. These abnormalities include a rise in the basal level of cytosolic calcium ([Ca(2+)]i) in the islets, a decrease in their basal and stimulated adenosine triphosphate (ATP) and adenosine diphosphate (ADP) content, a reduction in the V(max) of Ca(2+) ATPase and Na(+)-K(+) ATPase, and an impaired glucose-induced calcium signal. The sequence of events that leads to these derangements and to the impairment in insulin secretion during the evolution of CRF has not been defined. This study examined this particular issue by measuring the metabolic profiles of pancreatic islets weekly during the evolution of CRF over a period of 6 weeks. RESULTS: The results showed that serum levels of parathyroid hormone (PTH) begin to rise during the first week of CRF. The V(max) of Ca(2+) ATPase and Na(+)-K(+) ATPase increased during weeks 1 to 3 of CRF but decreased to low levels thereafter. At week 3 of CRF, the basal level of [Ca(2+)]i began to rise, whereas basal and stimulated ATP and ADP content started to fall. Glucose-induced calcium signal, Δ[Ca(2+)]i, and insulin secretion became abnormally low between weeks 3 and 6 of CRF. CONCLUSION: The data obtained allow for the inference of the following formulation: as serum levels of PTH begin to rise, calcium entry into islets is augmented, which in turn will stimulate the activity of Ca(2+) ATPase and the Na(+)-Ca(2+) exchanger, and therefore, calcium extrusion out of the islets is increased. Thus, [Ca(2+)]i remains normal during the first 2 weeks of CRF. Activation of the Na(+)-Ca(2+) exchanger may result in accumulation of sodium in the islets, an event that would activate the Na(+)-K(+) ATPase. Because calcium entry is further augmented by the progressive rise in serum PTH levels, mitochondrial oxidation and ATP production would be reduced, resulting in lower ATP content. This fall in ATP causes a reduction in the V(max) of Ca(2+) ATPase and Na(+)-K(+) ATPase, and therefore calcium extrusion out of the islets is reduced; consequently, [Ca(2+)]i rises. With the decrease in ATP content and the rise in [Ca(2+)]i, glucose-induced insulin secretion is impaired because of alterations in the closure of ATP-dependent potassium channels and reduction in the glucose-induced calcium signal (Δ[Ca(2+)])i.

Isaac Judaeus Israeli: a Jewish founder of the origins of nephrology.

This paper discusses the Book of Urine in the Opera Omnia Isaci of Isaac Judaeus Israeli. Born in Egypt in the middle of the ninth century, Isaac Judaeus was considered a genius by his peers. The book accepted Galen's ideas and expanded them. Its original contribution was in the concept of the seeping of fluid and sediment from blood into the kidney and from the kidney to the bladder. This concept corresponds to glomerular filtration and tubular secretion.

Altered acetylcholine metabolism of brain in uremia: role of secondary hyperparathyroidism.

OBJECTIVE: Cholinergic system and its neurotransmitter, acetylcholine (ACh), play a major role in both behavior and motor function of the nervous system. Cholinergic neurons synthesize ACh from choline and acetyl-CoA by choline acetyltransferase in the nerve ending. The release of ACh in response to nerve impulses is dependent on the intracellular calcium ([Ca2+]i) concentration and its gradient. The regulation of a synthesis of ACh after depolarization and ACh release is controlled by mass-action effect on choline acetyltransferase equilibrium. Behavioral and motor changes in uremia may be due in part to derangements in ACh metabolism and such possible abnormalities may be related to the state of secondary hyperparathyroidism of chronic renal failure (CRF). DESIGN: We studied ACh and choline content, choline release, choline kinase activity in brain synaptosomes of CRF with and without secondary hyperparathyroidism and in CRF rats treated with verapamil which normalize [Ca2+]i in brain synaptosomes of CRF rats. RESULTS: The content of ACh of brain synaptosomes increased progressively with the duration of CRF from 3 to 6 weeks. ACh and choline release as well as choline uptake were significantly higher in CRF rats at all time intervals studied. CONCLUSION: Choline content and the activity of choline kinase of brain synaptosomes were deceased after 3 weeks of CRF and were significantly lower than in synaptosomes of normal. Normalization of ACh and choline content as well as ACh release and the activity of choline kinase by parathyroidectomy or treatment with verapamil but these maneuvers did not prevent the rise in choline uptake and choline release. Resting levels of cytosolic calcium of brain synaptosomes in rats with CRF were significantly higher (437 +/- 9 nM) as compared to normal rats (345 +/- 9 nM). This rise in [Ca2+]i was prevented either by parathyroidectomy prior induction of CRF or by treatment of CRF rats with calcium channel blocker verapamil.

Management of vascular calcification in CKD patients.

Vascular calcification is common in patients with chronic kidney disease (CKD) and it may affect almost every artery. It is associated with a significant increase in morbidity and mortality. Therefore, the detection, prevention and treatment of vascular calcification in CKD patients are critical for the overall approach for the management of these patients. Hyperphosphatemia, especially when the blood levels of serum phosphorus are above 5.5 mg/dl, plays a major role in the development of vascular calcification. Hyperphosphatemia induces vascular calcification by both passive and active processes. By increasing calcium-phosphate product, hyperphosphatemia results in direct deposition of calcium salts in the arteries and in cardiac valves. The active process involves the uptake of phosphate by the smooth muscle cells of the arteries by a Na-P co-transporter. This increase in cell phosphate then induces phenotypic changes of these cells, rendering them into osteoblasts which in turn, begin laying calcium salts in the arterial walls. Therefore, it is critical that the blood levels of serum phosphorus be maintained below 5.5 mg/dl in CKD patients. Inflammation and the production of C-reactive protein (CRP) and interleukin 6 are also risk factors for vascular injury and vascular calcification. In a study of 254 dialysis patients with elevated blood levels of CRP (>1.0 mg/l) and 258 patients with CRP levels equal to or less than 1.0 mg/l, it was found that higher levels of CRP are significantly associated with the presence of both atheromatous and medial calcification of the aorta and hand arteries. Also, it was reported that a significant association between CRP levels and cardiac valves calcification in patients undergoing continuous ambulatory peritoneal dialysis. The reasons for the elevation in CRP in dialysis patients are not clear, but certainly, is more evident in those with obvious inflammatory processes. Therefore, any inflammation that is detected should be treated appropriately.

Clinical practice guidelines for bone metabolism and disease in chronic kidney disease: an overview.

The National Kidney Foundation developed and oversees the Kidney Disease Outcomes Quality Initiative, a process that develops clinical practice guidelines in nephrology. Recent guidelines address the aberrations in bone metabolism and disease that occur as a complication of chronic kidney disease. These guidelines provide, for the first time, a standard approach to the detection and management of alterations in calcium, phosphorus, and parathyroid hormone metabolism. The problems and sequelae of soft-tissue calcification are discussed, and recommendations are provided for reducing the associated morbidity and mortality.

Liver metabolism in CRF.

Alteration in liver function are not typically present in patients with uremic syndrome, but varying degrees of liver dysfunction were observed in animals with experimental uremia and, to a lesser degree, in patients with chronic renal failure. This article summarizes the data obtained during the last 2 decades on protein, carbohydrate, and lipid metabolism by the liver in uremia and molecular aspects of regulation of lipids and protein synthesis. Particular attention is given to the role of cytosolic calcium ([Ca(2+)](i)) regulation and calcium signal transduction in hepatocytes in chronic renal failure. It is proposed that the parathyroid hormone (PTH)-mediated increase in the [Ca(2+)](i) of hepatocytes in chronic renal failure is a major signal for the downregulation of hepatic receptors for PTH-PTHrP, vasopressin and angiotensin II as well as as hepatic lipase. It is possible that the mRNA of other hormone receptors and various proteins of the liver cells are affected similarly by the elevated basal levels of [Ca(2+)](i) in CRF.

C-reactive protein is a significant predictor of vascular calcification of both aorta and hand arteries.

Although evidence has accumulated indicating a close relationship between inflammation and atherosclerosis, the relationship between inflammation and vascular calcification in patients with chronic renal failure is unclear. In the present study, the relationship between C-reactive protein (CRP) and vascular calcification in dialysis patients was examined. Vascular calcification of the aorta and hand arteries of 512 hemodialysis patients without significant infection (age 58.8 +/- 10.1 y; 305 men, 207 women) were examined by roentgenography of the lateral abdomen and hands, respectively. Patients with a mean CRP level greater than 1.0 mg/L (n = 254) were older than those with a CRP level less than or equal to 1.0 mg/L (n = 258) and had a longer duration of dialysis, lower serum albumin level, and higher phosphate level ( P < .01, P < .05, P < .001, and P < .01, respectively). Prevalence of vascular calcification of aorta and hand arteries in the former group was significantly higher than in the latter (65.0% versus 43.8% for aorta, P < .0001; and 25.0% versus 14.7% for hand arteries, P < .01). In a multivariate logistic regression analysis adjusted for age, hemodialysis duration, sex, levels of calcium and phosphate, and presence of diabetes, CRP level was a significant predictor for the presence of aortic calcification (odds ratio for highest versus lowest quartile, 2.669; 95% confidence interval, 1.539-5.421, P = .0010) and of calcification of hand arteries (odds ratio, 2.243; 95% confidence interval, 1.039-4.841; P = .0395). In conclusion, the present study shows that increased levels of CRP are significantly associated with the presence of vascular calcification in both aorta and hand arteries (ie, with both atheromatous and medial forms of calcification), indicating evidence for a relationship between inflammation and vascular calcification in hemodialysis patients.

[The medical school of Padua and its Jewish graduates].

During the period between the 12th and 16th century, most European universities were under Papal control and Jews were restricted. An exception to this was the University of Padua, established in 1222. As "Universa Universis Patavina Liberta", outside of papal control, Jewish students were permitted to study and qualify for academic degrees. The Medical School, opened in 1250, was generally regarded as the best medical school in Europe. The universities tolerant and liberal approach attracted students the world-over, particularly drawing European Jews to Padua to study medicine. However, these young Jews lacked the necessary prerequisites, including a basic knowledge of Latin, the official university language. They benefited from the generous support of the Jewish community of Padua and, in particular, that of the Paduan medical alumni, the best known of whom was Dr. Salomo Conigliano. Between the years 1409 and 1816, 325 Jewish physicians graduated from the University of Padua. Among them were many distinguished scholars including Joseph Del Medigo, Joseph Hamiz, Benjamin Mussafia and Tovia Cohen, and many families of physicians who returned to their home countries to practice medicine. In addition to their medical contribution, Jewish graduates served their communities as religious and social leaders. They shared a common university background and cultural heritage, common interests and values. They also maintained close contact among themselves and among non-Jewish colleagues and hence were influenced by new social and cultural movements in Europe. These Jewish graduates of Padua played a crucial role in the developments of the Jewish culture and society, including the "Haskala" movement.

History of circumcision: a religious obligation or a medical necessity.

Circumcision is the oldest documented surgical procedure. Practiced for ritual religious and likely medical purposes, it seems to have emerged in Egypt and was adopted by the western Semitic tribes. In biblical times, circumcision became a religious doctrine described in the Covenant between God and Abraham in the book of Genesis. Although some claim that there are medical advantages to being circumcised, available data do not support a medical benefit for circumcision.

Efficacious response with low-dose indapamide therapy in the treatment of type II diabetic patients with normal renal function or moderate renal insufficiency and moderate hypertension.

We examined the efficacy of low daily dose (1.25 mg/day) of indapamide in the treatment of high blood pressure in patients with diabetes mellitus with normal renal function and those with moderate renal insufficiency (serum creatinine <1.5 mg/dl). The study was an open label one of four months duration. Twenty-eight patients were enrolled in the study and only 15 completed it. Within 2 weeks of therapy, systolic blood pressure fell from 173 +/- 4.5 to 144 +/- 2.0 mm Hg and diastolic blood pressure from 96 +/- 2.1 to 80 +/- 1.8 mm Hg (p < 0.01) and blood pressure remained at these levels throughout the study. The results show that low dose indapamide is effective in the treatment of moderate hypertension in patients with diabetes mellitus who have normal renal function or moderate renal insufficiency. Therefore, this dose of 1.25 mg/day is recommended for the treatment of such patients.

Amlodipine reverses the elevation in [Ca2+]i and the impairment of phagocytosis in PMNLs of NIDDM patients.

BACKGROUND: Patients with diabetes mellitus display an elevation in the basal levels of [Ca2+]i of polymorphonuclear leukocytes (PMNLs) and impaired phagocytosis. These derangements are due to the hyperglycemia of diabetes. Calcium channel blockers reverse these abnormalities both in in vitro studies and in diabetic rats. These observations suggest that calcium channel blockers may be useful in the treatment of patients with uncontrolled diabetes. The present study examined this issue. METHODS: A total of 32 normal subjects and 36 patients with uncontrolled noninsulin-dependent diabetes mellitus (NIDDM) were studied with and without treatment with amlodipine both in a cross-sectional and longitudinal design approach. RESULTS: In addition to the elevation in basal levels of [Ca2+]i and the impaired phagocytosis, there was also down-regulation of the mRNA of Fc gamma RIII receptors in the PMNLs of the diabetic patients. Treatment of the patients with a small dose of amlodipine (5 mg/day) corrected these abnormalities despite persistent hypoglycemia. This beneficial effect of nifedipine was noted as long as the therapy with the drug was maintained. CONCLUSION: The results show that the elevation in [Ca2+]i of the PMNLs is associated with down-regulation of the mRNA of their Fc gamma RIII receptors, which is at least, in part, responsible for the impaired phagocytosis. These derangements in the metabolism and function of the PMNLs are most likely responsible for the increased susceptibility of the diabetic patients to infection. Calcium channel blockers may be a beneficial adjunct therapy in patients with uncontrolled diabetes.

Fibrinolysis defect in long-term hemodialysis patients with type 2 diabetes mellitus and its relation to metabolic disorders.

BACKGROUND/AIMS: Patients with chronic renal failure (CRF) secondary to diabetes mellitus show a high incidence of atherosclerosis with its thrombotic complications. Both CRF and type 2 diabetes mellitus (DM2) results in fibrinolysis defects causally related to atherogenesis and thrombogenesis. It is not well known whether or not and, if so, how fibrinolysis is altered in patients with both CRF and DM2. Our study was designed (1) to identify the fibrinolysis defect present in patients with DM2-mediated CRF and treated by long-term hemodialysis (DM2HD), and (2) to establish whether the fibrinolysis defect is related to the metabolic abnormalities observed in CRF or DM2. METHODS: Sixteen DM2HD patients and 23 healthy individuals (HI) had their euglobulin clot lysis time (ECLT), and tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) activities (act) and concentrations (ag) assessed before and after standard fibrinolytic stimulus (i.v. administration of 0.4 microg/kg BW 1-deamino-8-D-arginine vasopressin, DDAVP) along with metabolic status markers. RESULTS: DDAVP caused a significant shortening of ECLT, rises in tPA act and ag, and a significant decrease in PAI-1 act. PAI-1 ag declined significantly in HI, but not in DM2HD. A comparison of responses to DDAVP revealed the groups differed significantly in the change in PAI-1 ag. Whereas, in HI, PAI-1 ag decreased by 11.8 ng/ml, no decrease was seen in DM2HD (0.0 ng/ml) (p < 0.0001; medians given; unpaired Wilcoxon's test). Stepwise regression analysis showed the change in PAI-1 ag was highly group-specific (DM2HD vs. HI, regression coefficient 21.22; partial correlation 0.58; p < 0.0001) and, also dependent on the serum concentrations of apolipoprotein A-I (-32.41; -0.46; p < 0.01) and homocysteine (0.35; 0.36; p < 0.05). CONCLUSIONS: Patients with type 2 DM and CRF on long-term hemodialysis have a fibrinolysis defect manifesting itself after standard fibrinolytic stimulus by an insufficient decrease in PAI-1 concentrations. The defect is related to decreased serum levels of apolipoprotein A-I and increased serum levels of homocysteine. The defect might be a factor contributing to accelerated atherosclerosis and thrombotic complications in these patients.