Transforming growth factor β (TGF-β ) has been shown to participate in the pathophysiology of diabetic complications. As shown most recently, TGF-β 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-β (2 μ g/liter), phorbol 12,13-didecanoate (1 μ M), or the Ca2+ionophore ionomycin (1 μ M) and blunted by high concentrations of nifedipine (10 and 100 μ M). 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 μ M) and chelerythrine (1 μ M) 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.
To examine the relations among proteinuria, prescribed and achieved blood pressure, and decline in glomerular filtration rate in the Modification of Diet in Renal Disease Study.
2 randomized trials ...in patients with chronic renal diseases of diverse cause.
15 outpatient nephrology practices at university hospitals.
840 patients, of whom 585 were in study A (glomerular filtration rate, 25 to 55 mliters/min.1.73 m2) and 255 were in study B (glomerular filtration rate, 13 to 24 mliters/min.1.73 m2). Diabetic patients who required insulin were excluded.
Patients were randomly assigned to a usual blood pressure goal (target mean arterial pressure, < or = 107 mm Hg for patients < or = 60 years of age and < or = 113 mm Hg for patients > or = 61 years of age) or a low blood pressure goal (target mean arterial pressure, < or = 92 mm Hg for patients < or = 60 years of age and < or = 98 mm Hg for patients > or = 61 years of age).
Rate of decline in glomerular filtration rate and change in proteinuria during follow-up.
The low blood pressure goal had a greater beneficial effect in persons with higher baseline proteinuria in both study A (P = 0.02) and study B (P = 0.01). Glomerular filtration rate declined faster in patients with higher achieved blood pressure during follow-up in both study A (r = -0.20; P < 0.001) and study B (r = -0.34; P < 0.001), and these correlations were stronger in persons with higher baseline proteinuria (P < 0.001 in study A; P < 0.01 in study B). In study A, the association between decline in glomerular filtration rate and achieved follow-up blood pressure was nonlinear (P = 0.011) and was stronger at higher mean arterial pressure. In both studies, the low blood pressure goal significantly reduced proteinuria during the first 4 months after randomization. This, in turn, correlated with a slower subsequent decline in glomerular filtration rate.
Our study supports the concept that proteinuria is an independent risk factor for the progression of renal disease. For patients with proteinuria of more than 1 g/d, we suggest a target blood pressure of less than 92 mm Hg (125/75 mm Hg). For patients with proteinuria of 0.25 to 1.0 g/d, a target mean arterial pressure of less than 98 mm Hg (about 130/80 mm Hg) may be advisable. The extent to which lowering blood pressure reduces proteinuria may be a measure of the effectiveness of this therapy in slowing the progression of renal disease.
Dysfunction of polymorphonuclear leukocytes in uremia: Role of parathyroid hormone. Polymorphonuclear leukocytes (PMNLs) from uremic patients have elevated basal levels of cytosolic calcium (Ca2+i), ...reduced calcium signal after activation of Fcγ RIII receptor, and impaired phagocytosis. Chronic excess of parathyroid hormone (PTH) in uremia mediates its effect on PMNL's metabolism and function through the sustained elevation of their Ca2+i. Because calcium channel blockers interfere with this effect of PTH on PMNLs, treatment of patients on hemodialysis with verapamil, nifedipine, or amlodipine was associated with an improvement in metabolism and phagocytosis of PMNLs in humans. The therapy with calcium channel blockers should be continued in order to maintain its beneficial effects.
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.
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.
To determine basal levels of cytosolic calcium (Ca2+i) and phagocytic activity in polymorphonuclear leukocytes (PMNLs) from patients with non-insulin-dependent diabetes (NIDDM).
Prospective cohort ...study.
A university-county hospital.
Cytosolic calcium levels, adenosine triphosphate (ATP) content, and phagocytosis of PMNLs from patients with NIDDM and from controls.
In patients with NIDDM, we evaluated the effect of treatment with an oral hypoglycemic agent (glyburide) on Ca2+i levels, ATP content, and the phagocytosis of PMNLs.
22 controls and 34 patients with NIDDM were examined. Fifteen patients were studied before and after 3 months of treatment with glyburide.
Polymorphonuclear leukocytes from patients with NIDDM showed significantly elevated basal levels of Ca2+i (68 +/- 9.6 compared with 43 +/- 4.9 nmol/L; P < 0.01); reduced ATP content (1.30 +/- 0.58 compared with 2.35 +/- 0.45 nmol/10(6) PMNLs; P < 0.01); and impaired phagocytosis (117 +/- 21.0 compared with 145 +/- 17.4 micrograms oil/10(7) PMNLs per minute; P < 0.01) compared with controls. There was a direct and significant correlation (P < 0.01, r = 0.80) between Ca2+i levels in PMNLs and serum glucose levels and an inverse correlation between phagocytic ability and Ca2+i levels (P < 0.01; r = 0.62) as well as between phagocytic activity and fasting serum glucose levels (P < 0.01, r = 0.54) in patients with NIDDM. Glyburide therapy resulted in significant reduction in fasting serum glucose levels; in PMNLs, this treatment resulted in a significant reduction in Ca2+i levels, a significant increase in ATP content, and a significant improvement of phagocytosis.
Patients with NIDDM have elevated Ca2+i levels in PMNLs. This abnormality is probably induced by hyperglycemia and is primarily responsible for the imparied phagocytosis seen in these patients.
Post-heparin hepatic lipase activity is reduced in chronic renal failure (CRF). This could be due to reduced synthesis, decreased activity, and/or impaired secretion of the enzyme. Further, the ...factor(s) responsible for such derangements are not elucidated. We examined hepatic lipase metabolism in normal, 6-wk-old CRF rats, CRF-PTX (parathyroidectomized) rats, and CRF and normal rats treated with verapamil (CRF-V, normal-V) using liver homogenate, hepatic cell culture for 8 h, and in vitro liver perfusion. The Vmax of hepatic lipase in liver homogenate was significantly (P < 0.01) reduced and the Km was significantly (P < 0.01) increased in CRF rats, but the values were normal in CRF-PTX, CRF-V, and normal-V rats. Culture of hepatic cells for 8 h was associated with an increase in hepatic lipase activity but the increment in CRF rats was significantly (P < 0.01) lower than that of normal, CRF-PTX, CRF-V, and normal-V rats. Both parathyroid hormone (PTH)-(1-84) and 1-34 inhibited the production of hepatic lipase in cultured cells from normal, CRF-PTX, CRF-V, and normal-V rats. The expression of the mRNA of the hepatic lipase was significantly reduced in CRF animals with the ratio between it and that of house keeping gene G3DPH being 15 +/-3% compared to 40 +/- 1.3% in normal, 44+/-2.9% CRF-PTX, 44 +/- 5.4% in CRF-V, and 39 +/- 3.9% in normal-V rats. Infusion of heparin to the in vitro hepatic perfusion system increased the activity of hepatic lipase in the effluent in all groups of rat except in CRF animals. Infusion of PTH-(1-34) in dose of 10(-6) M into the liver perfusion system inhibited the increase in post-heparin hepatic lipase activity. The data show that in CRF (a) the mRNA of hepatic lipase is downregulated, and hepatic lipase production, activity and release are impaired, (b) that this is due to the state of secondary hyperparathyroidism of CRF since both acute and chronic excess of PTH were associated with these abnormalities, (c) and that prevention of excess PTH by PTX of CRF rats or blocking the effect of PTH by treatment with verapamil corrected the derangement in hepatic lipase metabolism.
The heart is a target organ for parathyroid hormone (PTH), and the action of this hormone on the myocardium may be mediated through the ability of PTH to increase cytosolic calcium (Ca2+i) in the ...myocardial cells. However, direct evidence for such an effect of PTH is lacking, and the mechanism(s) through which the hormone can potentially exert such an effect have not been elucidated. In the present study these questions were examined using cardiac myocytes isolated from adult rats. Both PTH-(1-34) and PTH-(1-84) produced a dose-dependent increase in Ca2+i of myocytes, but the effect of the latter was significantly (P < 0.01) greater than the former. This action of PTH was abolished by the inactivation of the hormone, the use of a PTH antagonist, or by verapamil. The G protein activator, guanosine 5'-O-(3-thiothriphosphate) (GTP gamma S), mimicked the effect of PTH, whereas pertussis toxin, the G protein inhibitor, guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), or ryanodine significantly reduced the PTH-induced rise in Ca2+i. Dibutyryl- and 8-bromoadenosine-3',5'-cyclic monophosphate, forskolin, 12-O-tetradecanoylphorbol 13-acetate, and staurosporine did not increase Ca2+i in myocytes, and staurosporine did not alter the PTH-induced rise in Ca2+i. BAY K 8644 augmented the effect of PTH on Ca2+i. These data demonstrate that 1) PTH increases Ca2+i of cardiac myocytes, 2) this action is receptor mediated and is produced by activation of the L-type calcium channels following stimulation of G protein(s), and 3) the rise in Ca2+i is due to both augmented entry of calcium into the myocytes and mobilization of calcium from sarcoplasmic reticulum by a calcium-induced calcium release mechanism.
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