14-3-3ζ-Mediated Stimulation of Oxidative Phosphorylation Exacerbates Oxidative Damage Under Hypothermic Oxygenated Conditions in Human Renal Tubular Cells (HK-2).

Cellular survival and death are at least partially regulated by the phosphorylation of proteins. A chaperon protein, 14-3-3ζ, regulates the activity of many proteins by covering the phosphorylation site within a 14-3-3 binding motif. Therefore, regulation of 14-3-3ζ activity may affect the fate of cells subjected to cold preservation and/or hypothermic oxygenated conditions. The present study assessed whether 14-3-3ζ protects cells from hypothermic oxygenation-induced injury and clarified its role in mitochondrial functions. Human renal tubular cell line HK-2 or 14-3-3ζ-overexpressed HK-2 (ζHK-2) cells were subjected to 72 hours of normoxic cold preservation in UW solution with or without antioxidants and hydroperoxides. Cellular death, adenosine triphosphate (ATP) content, and MTT catabolism were evaluated. Deferoxamine treatment reduced cellular death and augmented ATP content in both cell types. These indices were higher in ζHK-2, regardless of deferoxamine treatment. Exposure to hydroperoxides did not affect cellular death in either cell type, whereas hydroperoxide supplementation significantly reduced ATP content, except for low-dose hydrogen peroxide in HK-2 cells. MTT assay at normal state showed higher values in ζHK-2 cells, whereas it was impaired by hydroperoxides in both cell types. These results suggest that accumulation of hydroperoxides as a byproduct of the augmented oxidative phosphorylation by 14-3-3ζ overexpression causes mitochondrial dysfunction. In conclusion, despite possessing many potentially protective functions, 14-3-3ζ exacerbates cellular injury under hypothermic oxygenated conditions. 14-3-3ζ accelerates mitochondrial functions together with iron-dependent oxidative damage. Although further investigations are necessary, upregulation of 14-3-3ζ could be a method to maintain mitochondrial function under hypothermic oxygenated conditions, as shown in hypothermic machine preservation of renal grafts, when appropriate antioxidant treatment is administered.

Polydatin Inhibits Mitochondrial Dysfunction in the Renal Tubular Epithelial Cells of a Rat Model of Sepsis-Induced Acute Kidney Injury.

BACKGROUND: Mitochondrial injury is a major cause of sepsis-induced organ failure. Polydatin (PD), a natural polyphenol, demonstrates protective mitochondrial effects in neurons and arteriolar smooth muscle cells during severe shock. In this study, we investigated the effects of PD on renal tubular epithelial cell (RTEC) mitochondria in a rat model of sepsis-induced acute kidney injury. METHODS: Rats underwent cecal ligation and puncture (CLP) to mimic sepsis-induced acute kidney injury. Rats were randomly divided into sham, CLP + normal saline, CLP + vehicle, and CLP + PD groups. Normal saline, vehicle, and 30 mg/kg PD were administered at 6, 12, and 18 hours after CLP or sham surgery via the tail vein. Mitochondrial morphology, metabolism, and function in RTECs were then assessed. Serum cytokines, renal function, survival, and histologic changes in the kidney were also evaluated. RESULTS: CLP increased lipid peroxide content, lysosomal instability, and opening of the mitochondrial permeability transition pore and caused mitochondrial swelling. Moreover, mitochondrial membrane potential (ΔΨm) was decreased and ATP levels reduced after CLP. PD inhibited all the above effects. It also inhibited the inflammatory response, improved renal function, attenuated histologic indicators of kidney damage, and prolonged survival. CONCLUSIONS: PD protects RTECs against mitochondrial dysfunction and prolongs survival in a rat model of sepsis-induced acute kidney injury. These effects may partially result from reductions in interleukin-6 and oxidative stress.

Kidney tubular-cell secretion of osteoblast growth factor is increased by kaempferol: a scientific basis for "the kidney controlling the bone" theory of Chinese medicine.

OBJECTIVE: To study, at the cytological level, the basic concept of Chinese medicine that "the Kidney (Shen) controls the bone". METHODS: Kaempferol was isolated form Rhizoma Drynariae (Gu Sui Bu, GSB) and at several concentrations was incubated with opossum kidney (OK) cells, osteoblasts (MC3T3 E1) and human fibroblasts (HF) at cell concentrations of 2×10(4)/mL. Opossum kidney cell-conditioned culture media with kaempferol at 70 nmol/L (70kaeOKM) and without kaempferol (0OKM) were used to stimulate MC3T3 E1 and HF proliferation. The bone morphological protein receptors I and II (BMPR I and II) in OK cells were identified by immune-fluorescence staining and Western blot analysis. RESULTS: Kaempferol was found to increase OK cell growth (P<0.05), but alone did not promote MC3T3 E1 or HF cell proliferation. However, although OKM by itself increased MC3T3 E1 growth by 198% (P<0.01), the 70kaeOKM further increased the growth of these cells by an additional 127% (P<0.01). It indicates that the kidney cell generates a previously unknown osteoblast growth factor (OGF) and kaempferol increases kidney cell secretion of OGF. Neither of these media had any significant effect on HF growth. Kaempferol also was found to increase the level of the BMPR II in OK cells. CONCLUSIONS: This lends strong support to the original idea that the Kidney has a significant influence over bone-formation, as suggested by some long-standing Chinese medical beliefs, kaempferol may also serve to stimulate kidney repair and indirectly stimulate bone formation.

Renoprotection of Danshen Injection on streptozotocin-induced diabetic rats, associated with tubular function and structure.

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen Injection, the aqueous extracts of Radix Salvia miltiorrhiza (S. miltiorrhiza), is one of the most commonly used traditional Chinese herbs in chronic renal failure treatment. In present study, the mechanism of the renoprotective effect of Danshen Injection was analyzed on streptozocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Diabetic experimental model was established in male Sprague-Dawley (SD) rats by intraperitoneal injection of STZ. Rats with blood glucose concentration of higher than 300 mg/dl were intraperitoneally administered with Danshen Injection at a dose of 0.78 ml/kgday. The blood glucose, 24h urinary protein excretion, serum creatinine (sCr), blood urea nitrogen (BUN), advanced glycation end products (AGEs), lipid peroxide (LPO), antioxidant enzyme of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), transforming growth factor-ß1 (TGF-ß1), and histomorphological changes in kidney of diabetic rats were analyzed during the course of Danshen Injection administration, as well as the tubular function index of albumin reabsorption of fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA). RESULTS: The intraperitoneal administration of Danshen Injection could ameliorate the physiological dysfunctions of increased 24h urinary protein excretion((48.21 ± 8.04)%), sCr((39.4 ± 3.7)%), and BUN((43.37 ± 6.74)%), alleviate the ultrastructural abnormalities of hypertrophy, matrix expansion, and fibrosis in glomerulus, decrease the TGF-ß1 expression, AGEs and LPO accumulation, and increase the activity of SOD and GSH-Px in kidney of diabetic rats, but did not significantly influence the blood glucose. Besides these, the Danshen Injection administration also partly restored the decrease of megalin expression in tubules and reabsorptive function of FITC-BSA, in diabetic rats. CONCLUSION: The renoprotection of Danshen Injection on diabetic rats was associated with the preservation of tubular function and structure from the hyperglycemia induced toxicities of inappropriate cytokines secretion, oxidative stress, advanced glycation stress, and megalin expression deletion.

Na+-sulfate cotransporter SLC13A1.

Sulfate is essential for normal physiology. The kidney plays a major role in sulfate homeostasis. Sulfate is freely filtered and strongly reabsorbed in the proximal tubule. The apical membrane Na(+)-sulfate cotransporter NaS1 (SLC13A1) mediates sulfate (re)absorption across renal proximal tubule and small intestinal epithelia. NaS1 encodes a 595-amino acid (≈ 66 kDa) protein with 13 putative transmembrane domains. Its substrate preferences are sodium and sulfate, thiosulfate, and selenate, and its activity is inhibited by molybdate, selenate, tungstate, thiosulfate, succinate, and citrate. NaS1 is primarily expressed in the kidney (proximal tubule) and intestine (duodenum to colon). NaS1 expression is down-regulated in the renal cortex by high sulfate diet, hypothyroidism, vitamin D depletion, glucocorticoids, hypokalemia, metabolic acidosis, and NSAIDs and up-regulated by low sulfate diet, thyroid hormone, vitamin D supplementation, growth hormone, chronic renal failure, and during post-natal growth. Disruption of murine NaS1 gene leads to hyposulfatemia and hypersulfaturia, as well as changes in metabolism, growth, fecundity, behavior, gut physiology, and liver detoxification. This suggests that NaS1 is an important sulfate transporter and its disruption leads to perturbed sulfate homeostasis, which contributes to numerous pathophysiological conditions.

Effects of supplemental recombinant bovine somatotropin and mist-fan cooling on the renal tubular handling of sodium in different stages of lactation in crossbred Holstein cattle.

The effect of supplementary administration of recombinant bovine somatotrophin (rbST) on the renal tubular handling of sodium in crossbred 87.5% Holstein cattle housed in normal shade (NS) or mist-fan cooled (MF) barns was evaluated. The cows were injected with 500 mg rbST at three different stages of lactation. The MF barn housed cows showed a slightly decreased ambient temperature and temperature humidity index, but an increased relative humidity. Rectal temperature and respiration rates were significantly lower in cooled cows. The rbST treated cows, housed in NS or MF barns, showed markedly increased milk yields, total body water, extracellular fluid and plasma volume levels, along with a reduced rate of urine flow and urinary excretion of sodium, potassium and chloride ions and osmolar clearance, in all three stages of lactation. Renal tubular sodium and water reabsorption were increased after rbST administration without any alteration in the renal hemodynamics. Lithium clearance data suggested that the site of response is in the proximal nephron segment, which may be mediated via increases in the plasma levels of aldosterone and IGF-1, but not vasopressin, during rbST administration.

[Renal physiology]. / Physiologie rénale.

The kidneys are responsible for the urinary excretion of uremic toxins and the regulation of several body systems such as intra and extracellular volume status, acid-base status, calcium and phosphate metabolism or erythropoiesis. They adapt quantitative and qualitative composition of the urine to keep these systems in balance. The flow of plasma is filtered in the range of 120 mL/min, and depends on the systemic and renal hemodynamics which is subject to self-regulation. The original urine will then be modified in successive segments of the nephron. The proximal nephron is to lead the massive reabsorption of water and essential elements such as sodium, bicarbonates, amino-acids and glucose. The distal nephron includes the distal convoluted tubule, the connector tube and the collecting duct. Its role is to adapt the quality composition of urine to the needs of the body.

Experimental renal preservation by normothermic resuscitation perfusion with autologous blood.

BACKGROUND: Normothermic perfusion (NP) has the potential to improve metabolic support and maintain the viability of ischaemically damaged organs. This study investigated the effects of NP compared with current methods of organ preservation in a model of controlled non-heart-beating donor (NHBD) kidneys. METHODS: Porcine kidneys (n = 6 in each group) were subjected to 10 min warm ischaemia and then preserved as follows: 2 h cold storage (CS) in ice (CS2 group), 18 h CS (CS18 group), 18 h cold machine perfusion (CP group) or 16 h CS + 2 h NP (NP group). Renal haemodynamics and function were measured during 3 h reperfusion with autologous blood using an isolated organ perfusion system. RESULTS: Increasing CS from 2 to 18 h reduced renal blood flow (mean(s.d.) area under the curve (AUC) 444(57) versus 325(70) ml per 100 g; P = 0.004), but this was restored by NP (563(119) ml per 100 g; P = 0.035 versus CS18). Renal function was also better in CS2, CP and NP groups than in the CS18 group (mean(s.d.) serum creatinine fall 92(6), 79(9) and 64(17) versus 44(13) per cent respectively; P = 0.001). The AUC for serum creatinine was significantly lower with CS for 2 h than for 18 h (mean(s.d.) 1102(2600) versus 2156(401) micromol/l.h; P = 0.001), although values in CP and NP groups were not significantly different from those in the CS2 group (1354(300) and 1756(280) micromol/l.h respectively). Two hours of NP increased the adenosine 3'-triphosphate : adenosine 3'-diphosphate ratio to a significantly higher level than the preperfusion values in all other groups (P = 0.046). CONCLUSION: NP with oxygenated blood was able to restore depleted ATP levels and reverse some of the deleterious effects of CS.

The effect of trophic factor supplementation on cold ischemia-induced early apoptotic changes.

We have previously shown that trophic factor supplementation (TFS) of University of Wisconsin (UW) solution enhanced kidney viability after cold storage. Here, we use an in vitro model to study the effect of TFS on early apoptotic changes after cold ischemic storage. Mitochondrial membrane potential was determined by fluorescence intensity in primary canine kidney tubule cells, Madin-Darby canine kidney cells, and human umbilical vein endothelial cells. In addition, caspase 3 enzyme activity assay and immunofluorescence staining were performed to evaluate apoptosis. There was a 15% increase in mitochondrial membrane potential in human umbilical vein endothelial cells stored in trophic factor supplemented University of Wisconsin solution after four-hour rewarming (P<0.05). TFS suppressed caspase 3 enzyme activity and activation in human umbilical vein endothelial cells. We confirmed that the presence of TFS in UW solution has a beneficial effect by protecting mitochondrial function and reducing early apoptotic changes in vascular endothelial cells.

A computer program for single-injection tracer clearance from one, two, or many blood samples

A computer program based on a Bayesian statistical model has been developed for calculating tracer clearance from any number of plasma samples drawn at arbitrary time intervals. Bayesian prior parameters were calculated from clinical data for Tc99m-MAG3, Tc99m-EC, I131-OIH, Tc99m-DTPA, and Yb169-DTPA and then used to calculate clearance from prospective data. Clearance estimates using only one or two plasma samples were found to closely approximate the results of using multiple samples. When only one or a few samples are available, the program supplements the observed data by a Bayesian prior probability distribution (based on prior clinical measurements) to achieve agreement with multisample clearance. When many points are available, the observed data overwhelm the prior probability, and results approach those of conventional curve fitting but with less sensitivity to bad data points and less risk of fitting failure.

Tempol reduces oxidative stress and restores renal dopamine D1-like receptor- G protein coupling and function in hyperglycemic rats.

Dopamine via activation of renal D1-like receptors inhibits the activities of Na-K-ATPase and Na/H exchanger and subsequently increases sodium excretion. Decreased renal dopamine production and sodium excretion are associated with hyperglycemic conditions. We have earlier reported D1-like receptor-G protein uncoupling and reduced response to D1-like receptor activation in streptozotocin (STZ)-treated hyperglycemic rats (Marwaha A, Banday AA, and Lokhandwala MF. Am J Physiol Renal Physiol 286: F451-F457, 2004). The present study was designed to test the hypothesis that oxidative stress associated with hyperglycemia increases basal D1-like receptor serine phosphorylation via activation of the PKC-G protein receptor kinase (GRK) pathway, resulting in loss of D1-like receptor-G protein coupling and function. We observed that STZ-treated rats exhibited oxidative stress as evidenced by increased lipid peroxidation. Furthermore, PKC activity and expression of PKC-betaI- and -delta-isoforms were increased in STZ-treated rats. In addition, in STZ-treated rats there was increased GRK2 translocation to proximal tubular membrane and increased basal serine D1-like receptor phosphorylation. Supplementation with the antioxidant tempol lowered oxidative stress in STZ-treated rats, led to normalization of PKC activity, and prevented GRK2 translocation. Furthermore, tempol supplementation in STZ-treated rats restored D1-like receptor-G protein coupling and inhibition of Na-K-ATPase activity on D1-like receptor agonist stimulation. The functional consequence was the restoration of the natriuretic response to D1-like receptor activation. We conclude that oxidative stress associated with hyperglycemia causes an increase in activity and expression of PKC. This leads to translocation of GRK2, subsequent phosphorylation of the D1-like receptor, its uncoupling from G proteins and loss of responsiveness to agonist stimulation.

Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes.

OBJECTIVE: The present study was designed to assess the effect of magnesium plus zinc, vitamins C plus E, and a combination of these micronutrients on nephropathy indexes in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled clinical trial, 69 type 2 diabetic patients were randomly divided into four groups, each group receiving one of the following daily supplement for 3 months: group M (n = 16), 200 mg Mg and 30 mg Zn; group V (n = 18), 200 mg vitamin C and 100 IU vitamin E; group MV (n = 17), minerals plus vitamins; and group P (n = 18), placebo. Urinary albumin excretion and N-acetyl-beta-d-glucosaminidase activity (NAG) in urine were determined at the beginning and at the end of the trial. Treatment effects were analyzed by general linear modeling. RESULTS: Results indicate that after 3 months of supplementation, levels of urinary albumin excretion decreased in the V and MV groups (P = 0.034 and P = 0.005, respectively). Urinary NAG activity did not significantly change in any treatment groups. Levels of systolic, diastolic, and mean blood pressure significantly decreased in the MV group (P = 0.008, P = 0.017, and P = 0.009, respectively). Also, combination of vitamin and mineral supplementation had significant effects in decreasing fasting serum glucose (P = 0.035) and malondialdehyde concentrations (P = 0.004) and in increasing HDL cholesterol and apolipoprotein A1 levels (P = 0.019). There was no significant change in the levels of these parameters in the other three groups. CONCLUSIONS: In conclusion, the results of the present study provide evidence for the effects of vitamins C and E and also combination of magnesium, zinc, and vitamins C and E supplementation on improvement of glomerular but not tubular renal function in type 2 diabetic patients.

A new renal mitochondrial carrier, KMCP1, is up-regulated during tubular cell regeneration and induction of antioxidant enzymes.

The mitochondrial carrier family transports a variety of metabolites across the inner mitochondrial membrane. We identified and cloned a new member of this family, KMCP1 (kidney mitochondrial carrier protein-1), that is highly homologous to the previously identified protein BMCP1 (brain mitochondrial carrier protein-1). Western blotting and in situ experiments showed that this carrier is expressed predominantly within the kidney cortex in the proximal and distal tubules. KMCP1 was increased during fasting and during the regenerative phase of glycerol-induced renal failure. We show that both situations are associated with transiently increased expression of superoxide-generating enzymes, followed by increased mitochondrial metabolism and antioxidant defenses. Given that KMCP1 expression occurs simultaneously with these latter events, we propose that KMCP1 is involved in situations in which mitochondrial metabolism is increased, in particular when the cellular redox balance tends toward a pro-oxidant status.

Comparison of acute and chronic antioxidant interventions in experimental renovascular disease.

Reactive oxygen species (ROS) can modulate renal hemodynamics and function both directly, by leading to vasoconstriction, and indirectly, by inducing renal inflammation and tissue growth. The involvement of oxidative stress in the pathogenesis of renovascular disease (RVD) is increasingly recognized, but the relative contribution of long-term tissue injury to renal dysfunction remains unclear. We hypothesized that functional and structural alterations elicited by oxidative stress in RVD would be more effectively modulated by chronic than by acute antioxidant intervention. Renal hemodynamics and function were quantified in vivo in pigs using electron-beam computed tomography at baseline and after vasoactive challenge (ACh and sodium nitroprusside); after 12 wk of RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7); RVD acutely infused with the SOD-mimetic tempol (RVD+tempol, n = 7); RVD chronically supplemented with antioxidant vitamins C (1 g) and E (100 IU/kg; RVD+vitamins, n = 7); or control (normal, n = 7). Renal tissue was studied ex vivo using immunoblotting and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate were similarly decreased in all RVD groups. ACh-stimulated RBF remained unchanged in RVD, increased in RVD+tempol, but further increased (similarly to normal) in RVD+vitamins (P < 0.05 vs. RVD). Furthermore, RVD+vitamins also showed a decreased presence of superoxide anion, decreased NAD(P)H-oxidase and nitrotyrosine expression, increased endothelial nitric oxide synthase expression, and attenuated renal fibrosis. Chronic antioxidant intervention in early RVD improved renal hemodynamic responses more effectively than acute intervention, likely due to increased nitric oxide bioavailability and decreased structural injury. These suggest that chronic tissue changes play an important role in renal compromise mediated by oxidative stress in RVD.

Renal tubule sodium transporter abundance profiling in rat kidney: response to aldosterone and variations in NaCl intake.

Based on extensive physiological study of sodium transport mechanisms along the renal tubule, complementary DNAs for all of the major transporters and channels responsible for renal tubular sodium reabsorption have been cloned over the past decade. There is now a comprehensive set of cDNA and antibody probes that can be used to investigate physiological mechanisms on a molecular level. Using rabbit polyclonal antibodies to all of the major renal Na transport proteins, we have developed profiling methods allowing comprehensive, integrated analysis of sodium transporter protein abundance changes along the renal tubule in response to physiological and pathophysiological perturbations. Here, we review some of our recent findings with this approach, focusing on renal responses to aldosterone and to variations in NaCl intake.

Novel action of lignans isolated from Hernandia nymphaeifolia on Ca(2+) signaling in renal tubular cells.

The effect of five lignans, epi-aschantin, epi-magnolin, epi-yangambin, deoxypodophyllotoxin and yatein, isolated from Hernandia nymphaeifolia on Ca(2+) signaling in Madin-Darby canine kidney cells was examined using fura-2 as a Ca(2+) indicator. These lignans at concentrations between 10 and 100 microM increased [Ca(2+)](i) in a concentration-dependent manner. Removal of extracellular Ca(2+) abolished the Ca(2+) signals evoked by 50 microM of the lignans. La(3+)(50 microM) abolished the Ca(2+) signals induced by 100 microM of epi-aschantin, epi-magnolin and epi-yangambin, and 20 microM deoxypodophyllotoxin, but inhibited by 60% 50 microM yatein-induced responses. All five lignans (50-100 microM) inhibited by 42-65% thapsigargin-induced capacitative Ca(2+) entry, and inhibited by 23-61% thapsigargin-induced intracellular Ca(2+) release. Epi-yangambin (100 microM), epi-magnolin (100 microM), and epi-aschantin (100 microM) inhibited by 8-38% 10 microM ATP-induced Ca(2+) release. Trypan blue exclusion revealed that incubation with deoxypodophyllotoxin or yatein (but not the other lignans) decreased cell viability in a concentration-dependent manner. Together, the results suggest that, in renal tubular cells, these lignans exert multiple actions on Ca(2+) signaling. They caused Ca(2+) influx but reduced thapsigargin-induced capacitative Ca(2+) entry and also thapsigargin- and ATP-induced Ca(2+) release. Additionally, deoxypodophyllotoxin and yatein may be cytotoxic.

Membranes and their constituents as promoters of calcium oxalate crystal formation in human urine.

We have proposed that membranes of cellular degradation products are a suitable substrate for the nucleation of calcium oxalate (CaOx) crystals in human urine. Human urine is generally metastable with respect to CaOx. To demonstrate that cellular membranes present in the urine promote nucleation of CaOx we removed these substrates by filtration or centrifugation and induced crystallization by adding sodium oxalate, before and after filtration or centrifugation. In a separate experiment, membrane vesicles isolated from rat renal tubular brush border were added into the filtered or centrifuged urine before crystal induction. Crystals were counted using a particle counter. Urine, the pellet, and retentate were analyzed for the presence of membranes, lipids, and proteins. Lipids were further separated into different classes, identified, and quantified. Both filtration and centrifugation removed lipids, proteins, and membrane vesicles, causing a reduction in lipid and protein contents of the urine. More crystals formed in whole than in filtered or centrifuged urine. The number of crystals significantly increased when filtered urine was supplemented with various urinary components such as the retentate and phospholipids, which are removed during filtration. We also determined the urinary metastable limit with respect to CaOx. Filtration and centrifugation were associated with increased metastable limit which was reduced by the addition of membrane vesicles. These results support our hypothesis that urine normally contains promoters of CaOx crystal formation and that membranes and their constituents are the most likely substrate for crystal nucleation in the urine.

Long-term oral creatine supplementation does not impair renal function in healthy athletes.

PURPOSE: Oral creatine supplementation is widely used in sportsmen and women. Side effects have been postulated, but no thorough investigations have been conducted to support these assertions. It is important to know whether long-term oral creatine supplementation has any detrimental effects on kidney function in healthy population. METHODS: Creatinine, urea, and plasma albumin clearances have been determined in oral creatine consumers (10 months to 5 yr) and in a control group. RESULTS: There were no statistical differences between the control group and the creatine consumer group for plasma contents and urine excretion rates for creatinine, urea, and albumin. Clearance of these compounds did not differ between the two groups. Thus, glomerular filtration rate, tubular reabsorption, and glomerular membrane permeability were normal in both groups. CONCLUSIONS: Neither short-term, medium-term, nor long-term oral creatine supplements induce detrimental effects on the kidney of healthy individuals.

Divergent effects of calcium channel and angiotensin converting enzyme blockade on glomerulotubular function in cyclosporine-treated renal allograft recipients.

The effects of amlodipine and perindopril on renal hemodynamics and tubular function in cyclosporine-treated hypertensive renal allograft recipients were evaluated in a randomized, double-blind crossover fashion. Ten patients were studied after a 2-week placebo run-in and, after 8 weeks of active treatment, allowing a 2-week placebo washout between treatments. At the end of each period, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured as 51Cr-EDTA and 123I-hippuran clearance, respectively, and tubular function evaluated by the lithium clearance technique was determined. Both drugs maintained GFR and ERPF and lowered mean arterial pressure (MAP, mm Hg) to a similar extent (time x treatment, P = 0.466): amlodipine from 126.9 +/- 2.5 to 115.9 +/- 2.2; perindopril from 126.9 +/- 2.5 to 117.9 +/- 3.9 (time effect of all treatments together, P = 0.003). Accordingly, renal vascular resistance (RVR, mm Hg/mL/min/1.73 m2) was equally reduced (time x treatment, P = 0.955): amlodipine from 0.36 +/- 0.03 to 0.30 +/- 0.02; perindopril from 0.36 +/- 0.03 to 0.32 +/- 0.01 (time effect all treatments together, P = 0.043). Sodium clearance and fractional excretion of sodium were not affected by either drug. Output of fluid from the proximal tubules measured as clearance of lithium (CLi, mL/min) and uric acid (CUr, mL/min) was higher after amlodipine than after perindopril (CLi 19.1 +/- 2.1 v 16.5 +/- 1.7, P =0.036 and CUr 7.0 +/- 0.6 v 5.9 +/- 0.4, P = 0.007). As a consequence, after amlodipine, distal absolute reabsorption of sodium was higher (DARNa 2.57 +/- 0.28 v 2.19 +/- 0.22 mEq/min, P = 0.027) and serum uric acid was lower (5.9 +/- 0.3 v 6.7 +/- 0.4 mg/dL, P = 0.001) in comparison with perindopril. In cyclosporine-treated renal allograft hypertensives, amlodipine and perindopril lower blood pressure equally and reduce RVR to the same extent. Overall sodium excretion is not affected by either agent. Urate clearance is higher and serum uric acid lower on amlodipine as compared with perindopril.