Defects in B-cell function and metabolism in uremia: role of parathyroid hormone.

Patients with chronic renal failure have impaired humoral immunity, inadequate B-cell proliferation and antibody production, and elevated basal levels of cytosolic calcium ([Ca2+]i) in their B cells. Multiple mechanisms can be involved in generation of these derangements. This article reviews data suggesting that high levels of parathyroid hormone (PTH) of uremia affect the metabolism and function of B cells. We also review studies on the role of normalization of [Ca2+]i in these abnormalities. Small but well-documented studies suggest that treatment of dialysis patients with calcium channels blockers can reverse the elevation of [Ca2+]i in B cells, which was followed by improvement of B-cell function. Thus, therapy with calcium channel blockers has the potential to decrease the infectious complication of uremia.

Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy.

Transforming growth factor beta (TGF-beta) has been shown to participate in the pathophysiology of diabetic complications. As shown most recently, TGF-beta stimulates the expression of a distinct serine/threonine kinase (hSGK) which had previously been cloned as an early gene transcriptionally regulated by cell volume alterations. The present study was performed to elucidate transcription and function of hSGK in diabetic nephropathy. As shown by Northern blotting, an increase of extracellular glucose concentration increased hSGK mRNA levels in cultured cells, an effect qualitatively mimicked by osmotic cell shrinkage or treatment with TGF-beta (2 microgram/liter), phorbol 12,13-didecanoate (1 microM), or the Ca(2+) ionophore ionomycin (1 microM) and blunted by high concentrations of nifedipine (10 and 100 microM). In situ hybridization revealed that hSGK transcription was markedly enhanced in diabetic nephropathy, with particularly high expression in mesangial cells, interstitial cells, and cells in thick ascending limbs of Henle's loop and distal tubules. According to voltage clamp and tracer flux studies in Xenopus oocytes expressing the renal epithelial Na(+) channel ENaC or the mouse thick ascending limb Na(+),K(+),2Cl(-) cotransporter BSC-1, coexpression with hSGK stimulated ENaC and BSC-1 11-fold and 6-fold, respectively, effects reversed by kinase inhibitors staurosporine (1 microM) and chelerythrine (1 microM) and not elicited by inactive hSGK. In conclusion, excessive extracellular glucose concentrations enhance hSGK transcription, which in turn stimulates renal tubular Na(+) transport. These observations disclose an additional element in the pathophysiology of diabetic nephropathy.

Effect of amlodipine therapy on the monoclonal antibody 3G8-induced calcium signal in polymorphonuclear leukocytes of hemodialysis patients.

Chronic renal failure is associated with impaired phagocytosis. This was attributed to the PTH-induced elevation of basal levels of [Ca2+]i of polymorphonuclear leukocytes (PMNLs) and to the small calcium transient induced by the ligation of the Fcgamma RIII receptors of these cells with 3G8 monoclonal antibodies. The blocking of the action of PTH on the PMNLs of patients with chronic renal failure by their treatment with a calcium channel blocker normalized the basal levels of [Ca2+]i of the PMNLs and reversed the defect in their phagocytic property. It is not known whether such therapy would also restore the calcium transient in the PMNLs in response to 3G8 monoclonal antibody to normal. We examined this issue in 12 normal subjects and 18 hemodialysis patients; 9 of them were treated with the calcium channel blocker, amlodipine, and the other 9 did not receive such therapy. The treatment with amlodipine normalized [Ca2+]i of PMNLs as well as the calcium transient in response to 3G8 monoclonal antibody and reversed the defect in their phagocytosis. It is concluded that chronic renal failure is associated with deranged calcium homeostasis of PMNLs which causes abnormalities in the function of Fcgamma RIII receptors and consequently results in impaired phagocytosis. Therapy with a calcium channel blocker can reverse all these derangements in metabolism and function of PMNLs.

Jewish medicine and the University of Padua: contribution of the Padua graduate Toviah Cohen to nephrology.

During the period of the 11th to 17th century, the access of Jews to European universities was restricted and even those who were fortunate enough to be admitted to a university were not awarded a degree at the end of their studies. An exception to this situation was the University of Padua that allowed Jewish students to study and awarded them degrees; indeed 229 physicians graduated from this university between 1409 and 1721. Among these physicians there were many luminaries such as Joseph Del Medigo, Salmon Congeliano and Toviah Cohen. The latter made many contributions to the field of nephrology. In this treatise Maaseh Toviah he discussed uroscopy, kidney function, body fluid homeostasis and obstructive uropathy.

Mechanisms through which high glucose concentration raises [Ca2+]i in renal proximal tubular cells.

BACKGROUND: The basal levels of cytosolic calcium ([Ca2+]i) of renal proximal tubular cells of rats with streptozotocin-induced diabetes are elevated. It is possible that this phenomenon is mediated by the hyperglycemia, which may cause both increased calcium influx into and/or decreased calcium efflux out of these cells. METHODS: We examined whether high glucose concentration in vitro causes acute rise in [Ca2+]i of freshly isolated renal proximal tubular cells and explored the pathways that are involved in such an event. RESULTS: There were dose and time dependent increments in [Ca2+]i of renal proximal tubular cells exposed to high concentrations of glucose. A similar effect was observed with equimolar concentrations of mannitol or choline chloride but not urea. A substantial part of the rise in [Ca2+]i was inhibited when the media contained verapamil, nifedipine, amlodipine or ryanodine and when the cells were placed in a calcium free media. Inhibitors of G protein(s) (GDPbetaS or pertussis toxin), inhibitors of cAMP-protein kinase A pathway (RpcAMP or H-89), inhibitors of protein kinase C (staurosporine or calphostin) and inhibitor of Na+-H+ exchanger (HOE 694) blocked the rise in a dose dependent manner. High glucose concentration also caused a decrease in ATP content of these cells and a reduction in the Vmax of their Ca2+ATPase. CONCLUSIONS: The results are consistent with the formulation that the osmotic activity (cell shrinkage) of the high glucose concentration may activate a stretch receptor with subsequent stimulation of various cellular pathways including G protein(s), cAMP-protein kinase A and phospholipase C systems and calcium channels. Activation of these cellular pathways permits both calcium influx into renal tubular cells and mobilization of calcium from their intracellular stores. Further, a decrease in calcium efflux secondary to the reduction in the Vmax of Ca2+ ATPase may occur. It is possible that the rise in [Ca2+]i is critical for the stimulation of the events that lead to restoration of cell volume to normal.

Acute anuric renal failure in nonfulminant hepatitis A infection.

Acute renal failure has recently been recognized as a rare complication of nonfulminant hepatitis A infection. The availability of a specific test for IgM antibody to hepatitis A should permit prompt diagnosis of the disease and a better evaluation of its association with acute renal failure. The exact mechanism for acute renal failure in hepatitis A is uncertain but glomerulonephritis, acute tubular necrosis and hepatorenal syndrome have been postulated. We report a patient with hepatitis A infection and acute renal failure most likely due to acute tubular necrosis.

High glucose concentration causes a rise in [Ca2+]i of cardiac myocytes.

Diabetes mellitus is associated with an elevation in the basal levels of cytosolic calcium ([Ca2+]i) of cardiac myocytes. This may be due in part to a glucose-induced elevation in [Ca2+]i. The present study examined this issue and explored the cellular pathways responsible for such a phenomenon. A total of 30 mM glucose, mannitol or choline chloride, but not urea, induced a time- and dose-dependent rise in the [Ca2+]i of cardiac myocytes. G protein inhibition by GDP beta S or pertussis toxin produced significant inhibition (> or = 80%) in the rise in [Ca2+]i. Incubation of cardiac myocytes in a calcium free medium or in media containing verapamil, nifedipine or amlodipine almost completely abolished the rise in [CA2+], while ryanodine produced only small reduction (10%) in the glucose-induced rise in [Ca2+]i. Rp-cAMP or H-89, inhibitors of the cAMP-protein kinase A pathway, produced a modest decrease in the rise in [Ca2+]i, while staurosporine (an inhibitor of PKC) and HOE 694 (an inhibitor of the Na(+)-H+ exchanger) had no effect on the rise in [Ca2+]i. The results indicate that the osmotic activity of glucose (cell shrinkage) activates G protein(s), most likely through a stretch receptor, which in turn stimulates calcium channels inhibitable by verapamil, nifedipine and amlodipine, thus permitting a calcium influx into the cardiac myocytes. The increased calcium entry may stimulate a calcium release from intracellular stores by a calcium-induced calcium release process. Thus, in cardiac myocytes direct activation of calcium channels, and to a small extent activation of the cAMP-protein kinase A, and calcium-induced calcium release mediate the high glucose-induced acute rise in their [Ca2+]i.

Elevated cytosolic calcium and impaired proliferation of B lymphocytes in type II diabetes mellitus.

Patients with diabetes mellitus have increased susceptibility to infection attributable, at least in part, to defective function of polymorphonuclear leukocytes (PMNLs) and B cells. Certain data suggest that cytosolic calcium ([Ca2+]i) is elevated in various cells in diabetes, and high [Ca2+]i adversely affects cell function. Indeed, the [Ca2+]i of PMNLs of diabetic patients is elevated, and phagocytosis of the PMNLs is impaired. The current study examines whether the [Ca2+]i of B cells is also elevated in diabetes and whether this derangement impairs B cell function. We studied 32 patients with non-insulin-dependent diabetes mellitus (NIDDM) and eight normal subjects. All patients had hyperglycemia (11.6 +/- 0.80 mmol/L) and elevated HbA1c (13.2% +/- 0.99%). The basal levels of [Ca2+]i of the B cells (113 +/- 3.3 nmol/L) were significantly (P < 0.01) higher than the values in normal subjects (85 +/- 1.7 nmol/L). There was a direct and significant correlation (r = 0.88; P < 0.01) between the [Ca2+]i of B cells and the blood levels of glucose. Proliferation of B cells in response to Staphylococcus aureus Cowan I (SAC) was significantly impaired in these patients (7.3 +/- 0.48 x 10(3) cpm v 12.5 +/- 0.61 x 10(3) cpm in normal subjects). Normalization of blood glucose with the hypoglycemic agents, glyburide, was associated with the return of both [Ca2+]i of B cells and their proliferation in response to SAC to normal. The results show that hyperglycemia in type II diabetes mellitus is associated with a significant increase in [Ca2+]i of B cells and with a decrease in their proliferation in response to mitogen. These derangements are reversed after the correction of the hyperglycemia. The data of the current study and those previously reported in PMNLs provide for a new pathogenetic process underlying the dysfunction of these cells in diabetes mellitus.

Impaired Na(+)-H+ exchanger activity of hepatocytes in chronic renal failure.

Available data indicate that cation transport is impaired in many cells in chronic renal failure (CRF). The information on the activity of the Na(+)-H+ exchanger in CRF is variable, and both increased and reduced activity have been reported. The mechanisms through which CRF may exert an effect on the Na(+)-H+ transport are not known. Data exist indicating that PTH inhibits the Na(+)-H+ exchange in kidney and liver, and this action of hormone is most likely due to its ability to raise cytosolic calcium ([Ca2+]i). Therefore, it is possible that excess PTH in CRF may adversely affect the activity of the Na(+)-H+ antiport. This study examines the activity of Na(+)-H+ antiport, intracellular pH (pHi), and buffering capacity of hepatocytes obtained from rats after 6 wk of CRF, from CRF parathyroidectomized animals, and from CRF rats and normal rats treated with verapamil. The pHi and the buffering capacity of hepatocytes were not different in all groups of animals. The activity of the Na(+)-H+ antiport of hepatocytes from CRF animals was significantly (P < 0.01) lower than in hepatocytes from normal rats, CRF parathyroidectomized rats, CRF rats treated with verapamil, and normal rats treated with verapamil, and the values in the latter four groups of animals were not different. This impaired activity of Na(+)-H+ antiport in CRF was observed in all external concentrations of sodium (25, 50, 75, 100, 125, and 150 mM). Thus, CRF altered the kinetics of the transporter in that its Vmax decreased and its K(m) increased. The data show that: (1) CRF is associated with reduction in the activity of Na(+)-H+ antiport in hepatocytes; (2) this defect is due to the state of secondary hyperparathyroidism of CRF; and (3) excess PTH mediates its effect by elevating [Ca2+]i of hepatocytes because treatment of CRF animals with verapamil, which blocks the PTH-induced rise in [Ca2+]i of these cells, prevented the impairment in the activity of the Na(+)-H+ antiport.

Elevation of [Ca2+]i of renal proximal tubular cells and down-regulation of mRNA of PTH-PTHrP, V1a and AT1 receptors in kidney of diabetic rats.

An elevation in intracellular calcium ([Ca2+]i) in rats with chronic renal failure and elevated blood levels of PTH is associated with down-regulation of the mRNA of many proteins. Similarly, in phosphate depleted animals that have normal renal function and low blood levels of PTH, [Ca2+]i is elevated and the mRNA of PTH-PTHrP receptor is down-regulated. The effect of elevation in [Ca2+]i on molecular machinery of many proteins may represent a generalized phenomenon. Diabetes mellitus may also be associated with a rise in [Ca2+]i and therefore down-regulation of the mRNA of proteins may also occur. The present study examined the effect of streptozotocin-induced diabetes mellitus in rats on the [Ca2+]i of the renal proximal tubular cells and on their mRNAs of the PTH-PTHrP, V1a and AT1 receptors. The basal levels of [Ca2+]i of these cells increased significantly (P < 0.01) after one day of diabetes and remained elevated thereafter. There was a significant (r = 0.67, P < 0.01) direct correlation between the [Ca2+]i of the cells and blood levels of glucose up to 350 mg/dl, and the value of [Ca2+]i plateaued with higher concentrations of glucose. Three days of amlodipine therapy prevented and reversed the elevated levels of [Ca2+]i despite marked hyperglycemia. The mRNA of all three receptors in the kidney were down-regulated and this defect was prevented by amlodipine which normalized the [Ca2+]i of the cells. The results show that: (1) the hyperglycemia of IDDM in rats causes a significant elevation in the basal levels of [Ca2+]i of the renal proximal tubular cells and down-regulation of their mRNA of PTH-PTHrP, V1a and AT1 receptors; (2) normalization of the [Ca2+]i of these cells by treatment of the diabetic rats with amlodipine prevented the elevation of [Ca2+]i and the down-regulation of the mRNA of these receptors; (3) these effects occurred in the presence of normal renal function and normal blood of PTH and phosphorus.

Short-term effects of blood pressure control and antihypertensive drug regimen on glomerular filtration rate: the African-American Study of Kidney Disease and Hypertension Pilot Study.

The African-American Study of Kidney Disease and Hypertension pilot study randomized 94 nondiabetic black men and women (mean age, 53 years; 75% male) with presumed hypertensive nephrosclerosis and a baseline glomerular filtration rate (GFR) of 25 to 70 mL/min/1.73 m2 (mean, 52.3 mL/min/1.73 m2) to blood pressure control at either a low mean arterial pressure (MAP) goal of < or = 92 mm Hg or a usual MAP goal of 102 to 107 mm Hg and an antihypertensive drug regimen that included either a calcium antagonist (amlodipine), a beta-blocker (atenolol), or an angiotensin-converting enzyme (ACE) inhibitor (enalapril). After 3 months of follow-up (n = 90), the mean GFR was similar (53.0 mL/min/1.73 m2 v 53.7 mL/min/1.73 m2) to the baseline levels in participants randomized to the low MAP group (n = 44), whereas the mean GFR increased by 3.9 mL/min/1.73 m2 (P = 0.02) in participants randomized to the usual MAP group (n = 46). During the same period of time, the mean GFR increased significantly in participants randomized to the calcium channel blocker regimen (n = 28) (5.7 mL/min/ 1.73 m2; P = 0.01) but not in participants randomized to the beta-blocker regimen (n = 31) (1.7 mL/min/1.73 m2; P = 0.10) or the ACE inhibitor regimen (n = 31) (1.1 mL/min/1.73 m2; P = 0.52). Changes in GFR at 3 months were significantly different among the three treatment groups (P = 0.04). We conclude that the magnitude of short-term effects of blood pressure control and antihypertensive drug regimens on GFR should be considered when estimating sample size for clinical trials designed to evaluate the effects of these interventions on long-term changes in GFR slope.

A longitudinal study on the effect of nifedipine therapy and its discontinuation on [Ca2+]i and proliferation of B lymphocytes of dialysis patients.

The abnormalities in cytosolic calcium ([Ca2+]i) and proliferation of B cells in uremic patients are significantly improved by treatment with nifedipine. The rapidity with which this agent induces its beneficial effect and whether these derangements reemerge after cessation of therapy are not known. We studied six hemodialysis patients before, during, and after treatment with nifedipine. Before treatment, [Ca2+]i of B cells was markedly elevated (125 +/- 4.3 nmol/L) and their proliferation markedly reduced (5.2 +/- 0.36 x 10(3) cpm). After 1 month of therapy, [Ca2+]i fell significantly (P < 0.01) to 95 +/- 1.7 nmol/L and to a normal value of 84 +/- 1.6 after 2 months. The levels of [Ca2+]i rose significantly (P < 0.01) to 95 +/- 2.3 nmol/L after 1 month of cessation of therapy and were 115 +/- 2.8 nmol/L by 2 months. Proliferation of B cells improved significantly (P < 0.01) after 1 month of therapy (9.4 +/- 1.1 x 10(3) cpm) with further improvement during the subsequent month, reaching a normal value (12.2 +/- 1.1 x 10(3) cpm) by the end of the 2 months. Proliferation of B cells decreased after cessation of therapy and was 5.2 +/- 0.17 x 10(3) cpm after 2 months, a value similar to the pretreatment level. The blunted inhibitory effect of PTH-(1-84) on B cell proliferation was reversed by nifedipine treatment and reappeared after discontinuation of therapy. Also, serum globulin levels increased after administration of nifedipine and decreased again after cessation of treatment. The results show that nifedipine rapidly reversed the elevation in [Ca2+]i of B cells, the impairment in their proliferation, and the blunted inhibitory effect of PTH on B cell proliferation, and was associated with increased serum globulin levels. These derangements reemerged after cessation of therapy. These data indicate that nifedipine therapy is effective in the management of the abnormalities in B cell metabolism and function in hemodialysis patients. The treatment with this drug must be maintained to sustain its beneficial effects. Other calcium channel blockers may also be effective, but their effects were not examined in the current study.

Amlodipine prevents and reverses the elevation in [Ca2+]i and the impaired phagocytosis of PMNL of diabetic rats.

BACKGROUND: High glucose concentration, through the activation of calcium channels, augments in vitro calcium entry into cells and leads to elevation in the basal levels of [Ca2+]i, the latter causes cell dysfunction. DESIGN OF STUDY: The present study examined whether streptozotocin-induced diabetes mellitus in rats causes a rise in [Ca2+]i of PMNL and impairs their phagocytosis and whether treatment of these rats with the calcium channel blocker, amlodipine, prevents and/or reverses these derangements. Amlodipine was given either from day one of diabetes or after 3 or 12 days of established diabetes. RESULTS: The [Ca2+]i of PMNL was elevated and their phagocytosis was reduced after one day of diabetes. These derangements were present and became more marked with longer duration of diabetes. There was a direct and significant correlation (r = 0.88) between [Ca2+]i of PMNL and blood glucose and an inverse relationship between phagocytosis and blood glucose (r = 0.83) or [Ca2+]i (r = 0.67). Three days of amlodipine therapy were required to completely prevent or reverse the elevation in [Ca2+]i of PMNL. This action of the drug occurred despite the hyperglycaemia. Amlodipine produced marked and significant improvements in phagocytosis but the values remained modestly below normal. Amlodipine given to normal rats did not affect [Ca2+]i or phagocytosis of PMNL. CONCLUSION: The results show that (i) [Ca2+]i of PMNL increases and phagocytosis decreases rapidly after the induction of diabetes; (ii) treatment of diabetic rats with amlodipine normalizes [Ca2+]i of PMNL and markedly improves their phagocytosis, despite hyperglycemia; (iii) high [Ca2+]i is responsible, in major part, for the impaired phagocytosis but other factors are also operative; and (iv) calcium channel blockers could prove useful in the treatment of the metabolic and functional derangements of PMNL in patients with poorly controlled diabetes.

Influence of Judaism and Jewish physicians on Greek and Byzantine medicine and their contribution to nephrology.

Both the Old Testament and the Talmud contain a great deal of information on medicine, nephrology, health and disease. The basic premise of early Jewish medicine is based on the notion that disease is due to structural changes in internal organs. This is in contrast to the mythical dogma of humoralism as the basis of health and disease espoused by Hippocrates and Galen. The Old Testament and the Mosaic Codes provided the basis for modern public health and for the hygienic rules practised in our times. The Talmudists laid the foundations for the science of pathology as we know it today. These issues are discussed in detail and the contributions of three prominent medieval physicians (Asaph Judaeus, Isaac Judaeus and Maimonides) are presented.

Role of elevated cytosolic calcium in the pathogenesis of complications in diabetes mellitus.

Both type I and type II diabetes mellitus are associated with derangements in the regulation of intracellular calcium. Hyperglycemia causes an acute rise in cytosolic calcium ([Ca2+]i) due to increased calcium influx and in certain cells to mobilization of intracellular calcium stores as well. The increase in calcium entry is secondary to the activation of calcium channels inhibitable by verapamil, nifedipine, or amlodipine. The stimulation of these calcium channels is mediated by the activation of G protein(s), leading to stimulation of various cellular pathways. Chronic hyperglycemia is also associated with decreased calcium exit from cells. The combination of increased calcium influx and decreased calcium efflux leads to sustained elevation in basal levels of [Ca2+]i. The latter abnormality may adversely affect cell function. Treatment of diabetic animals with calcium channel blockers normalizes cell [Ca2+]i and prevents and/or reverses the derangements in cellular function.