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Homocysteine and arterial occlusive disease: a concise review.
Andreotti F, Burzotta F, Mazza A, Manzoli A, Robinson K, Maseri A.
Istituto di Cardiologia, Universita Cattolica del Sacro Cuore, Roma.
felicita.andreotti@iol.it
Cardiologia. 1999 Apr;44(4):341-5.
Many cross-sectional and prospective studies have shown that raised serum/plasma levels of total homocysteine increase the risk of coronary, cerebral, and peripheral artery disease. The risk associated with hyperhomocysteinemia appears to be concentration-dependent and not attributable to traditional risk factors. The odds ratio for ischemic heart disease has been estimated to be 1.4 for every 5 mumol/l increase of total plasma homocysteine. Median fasting total plasma homocysteine in adult males is approximately 10 mumol/l. Mild hyperhomocysteinemia is estimated to occur in 5-10% of the general population. Plasma concentrations are increased as a result of age, male gender, impaired renal function, low vitamin B intake, and genetically-determined defects of the enzymes involved in homocysteine metabolism. Folate supplements can reduce total homocysteine levels by approximately 25%. Studies in vitro and in vivo indicate that homocysteine can impair endothelial function. Despite increasing recognition of hyperhomocysteinemia as a risk factor for arterial occlusive disease, irrefutable proof that mild hyperhomocysteinemia contributes directly to the pathogenesis of atherothrombosis will come if interventions to lower total homocysteine reduce cardiovascular events. Family studies may also provide evidence of causality if genetic causes of hyperhomocysteinemia are found to segregate with disease.
Dietary soy protein effects on inherited polycystic kidney disease are influenced by gender and protein level.
Aukema HM, Housini I, Rawling JM.
Department of Nutrition and Food Sciences, and Center for Research on Women's Health, Texas Woman's University, Denton 76204-5888, USA. haukema@twu.edu
J Am Soc Nephrol. 1999 Feb;10(2):300-8.
The effects of dietary soy protein compared to casein were examined in male and female CD1-pcy/pcy (pcy) mice with polycystic kidney disease. Animals 10 wk of age were fed purified diets containing either soy protein isolate or casein given at a level of 17.4 or 6% protein. After 13 wk on the diets, body weights and serum concentrations of albumin and protein indicated that protein nutrition was adequate on all diets. Overall, animals fed soy protein versus casein had 28% lower (P = 0.0037) relative kidney weights (g/100 g body wt), 37% lower (P = 0.0089) cyst scores (% cyst area x relative kidney weight), and 25% less (P = 0.0144) kidney water (g). Dietary protein reduction resulted in 30% lower (P =
0.0010) relative kidney weights, 25% lower (P = 0.0327) cyst scores, and 35% less (P = 0.0001) kidney water. Analysis of interactions between main effects revealed that the effects of soy protein on kidney size were significant only in females, and that effects of soy protein on cyst score were significant only in animals on the low protein diets. In addition, differences in kidney weights and cyst score due to protein reduction were significant in animals fed soy protein, but not in those fed casein as the protein source. These results show that both dietary protein source and level significantly affect polycystic kidney disease in pcy animals, with the effects of dietary soy protein being most pronounced in
female animals fed the low protein diets and the effects of protein reduction being most pronounced in animals fed soy protein-based diets.
Recent advances in the understanding of polycystic kidney disease.
Bacallao RL; Carone FA
Division of Nephrology, Indiana University School of Medicine, Indianapolis 46236, USA.
Curr Opin Nephrol Hypertens (United States) Jul 1997, 6 (4) p377-83
Polycystic kidney disease is characterized by localized autonomous cellular proliferation, compartmentalized fluid accumulation within the cysts, and intraparenchymal fibrosis of the kidney. The clinical features include renal failure, liver cysts, and vascular and cardiac valve abnormalities. Recent developments have extended our understanding of cyst formation, fluid secretion, and the genetics of polycystic kidney disease. Two causal genes for polycystic kidney disease, PKD1 and PKD2, that are responsible for greater than 95% of cases of autosomal dominant polycystic kidney disease, have been identified and
sequenced. The mechanisms of cystogenesis are being uncovered and the phenotypic features of cystic epithelial cells are being discovered. This review describes recent advances made in the molecular biology of the genetic causes of polycystic kidney disease. The mechanistic details of cystogenesis are discussed and contrasted with the paradigms that guide current experimental approaches. (44 Refs.)
Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention.
Bagchi D, Bagchi M, Stohs SJ, Das DK, Ray SD, Kuszynski CA, Joshi SS, Pruess HG.
Department of Pharmaceutical and Administrative Sciences, Creighton University
School of Pharmacy & Allied Health Professions, 2500 California Plaza, Omaha, NE 68178, USA. debsis@bluejay.creighton.edu
Toxicology. 2000 Aug 7;148(2-3):187-97.
Free radicals have been implicated in over a hundred disease conditions in humans, including arthritis, hemorrhagic shock, atherosclerosis, advancing age, ischemia and reperfusion injury of many organs, Alzheimer and Parkinson's disease, gastrointestinal dysfunctions, tumor promotion and carcinogenesis, and AIDS. Antioxidants are potent scavengers of free radicals and serve as inhibitors of neoplastic processes. A large number of synthetic and natural antioxidants have been demonstrated to induce beneficial effects on human health and disease prevention. However, the structure-activity relationship,
bioavailability and therapeutic efficacy of the antioxidants differ extensively. Oligomeric proanthocyanidins, naturally occurring antioxidants widely available in fruits, vegetables, nuts, seeds, flowers and bark, have been reported to possess a broad spectrum of biological, pharmacological and therapeutic activities against free radicals and oxidative stress. We have assessed the concentration- or dose-dependent free radical scavenging ability of a novel IH636 grape seed proanthocyanidin extract (GSPE) both in vitro and in vivo models, and compared the free radical scavenging ability of GSPE with vitamins C, E and beta-carotene. These experiments demonstrated that GSPE is highly bioavailable and provides significantly greater protection against free radicals and free radical-induced lipid peroxidation and DNA damage than vitamins C, E and beta-carotene. GSPE was also shown to demonstrate cytotoxicity towards human breast, lung and gastric denocarcinoma cells, while enhancing the growth and viability of normal human gastric mucosal cells. The comparative protective effects of GSPE, vitamins C and E were examined on tobacco-induced oxidative stress and apoptotic cell death in human oral keratinocytes. Oxidative tissue damage was determined by lipid peroxidation and DNA fragmentation, while apoptotic cell death was assessed by flow cytometry. GSPE provided significantly better protection as compared to vitamins C and E, singly and in combination. GSPE also demonstrated excellent protection against acetaminophen overdose-induced liver and kidney damage by regulating bcl-X(L) gene, DNA damage and presumably by reducing oxidative stress. GSPE demonstrated excellent protection against myocardial ischemia-reperfusion injury and myocardial infarction in rats. GSPE was also shown to upregulate bcl(2) gene and downregulate the oncogene c-myc. Topical application of GSPE enhances sun protection factor in human volunteers, as well as supplementation of GSPE ameliorates chronic pancreatitis in humans. These results demonstrate that GSPE provides excellent protection against oxidative stress and free radical-mediated tissue injury.
Betaine, ethanol, and the liver: a review.
Barak AJ, Beckenhauer HC, Tuma DJ.
VA Alcohol Research Center, Department of Veterans Affairs Medical Center,
Omaha, NE 68105, USA.
Alcohol. 1996 Jul-Aug;13(4):395-8.
Two of the most important biochemical hepatic pathways in the liver are those that synthesize methionine and S-adenosylmethionine (SAM) through the methylation of homocysteine. This article reviews some recent findings in this laboratory, which demonstrate that ethanol feeding to rats impairs one of these pathways involving the enzyme methionine synthetase (MS), but by way of compensation increases the activity of the enzyme betaine:homocysteine methyl transferase (BHMT), which catalyzes the second pathway in methionine and SAM biosynthesis. It has been shown that despite the inhibition of MS, the enhanced BHMT pathway utilizes hepatic betaine pools to maintain levels of SAM. Subsequent to the above findings, it has been shown that minimal supplemental dietary betaine at the 0.5% level generates SAM twofold in control animals and fivefold in ethanol-fed rats. Concomitant with the betaine-generated SAM, ethanol-induced hepatic fatty infiltration was ameliorated. In view of the fact that SAM has already been used successfully in the treatment of human maladies, including liver dysfunction, betaine, shown to protect against the early stages of alcoholic liver injury as well as being a SAM generator, may become a promising therapeutic agent and a possible alternative to expensive SAM in the treatment of liver disease and other human maladies.
Influence of prophylactic use of pentoxifylline on postoperative organ function in elderly cardiac surgery patients.
Boldt J, Brosch C, Piper SN, Suttner S, Lehmann A, Werling C.
Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt
Ludwigshafen, Ludwigshafen, Germany.
Crit Care Med. 2001 May;29(5):952-8.
OBJECTIVE: To study the effects of pretreatment with pentoxifylline before cardiac surgery on postoperative organ function in elderly patients (>80 yrs) undergoing cardiac surgery.
DESIGN: Prospective, randomized, placebo-controlled study.
SETTING: Two-day clinical investigation in an intensive care unit of a university-affiliated hospital.
PATIENTS: Forty elderly patients (age >80 yrs) undergoing first-time elective aortocoronary bypass grafting.
INTERVENTIONS: In 20 patients, pentoxifylline (loading bolus of 300 mg followed by a continuous infusion of 1.5 mg.kg-1.hr-1 until the second postoperative day) was given after induction of anesthesia; another 20 patients received saline solution as placebo.
MEASUREMENTS AND MAIN RESULTS: Concentrations of soluble adhesion molecules (soluble E-selectin, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecules) were measured to assess endothelial function. Liver function was evaluated by monoethylglycinexylidide test and by measuring alpha-glutathione S-transferase plasma concentrations. Renal function was assessed by measuring serum creatinine and urine concentrations of alpha-1-microglobulin. Splanchnic perfusion was assessed by monitoring intramucosal pH by using continuous tonometry. All measurements were performed before pentoxifylline infusion (T0), at the end of surgery (T1), 5 hrs after surgery (T2), and at the morning of the first (T3) and second (T4) postoperative day. Postoperative concentrations of all measured soluble adhesion molecules were significantly higher in the nontreated controls than in the pentoxifylline-treated patients. Monoethylglycinexylidide serum concentrations were significantly lower and abnormal (<50 ng/mL) postoperatively only in the untreated control patients. alpha-Glutathione S-transferase increased in both groups with a significantly higher increase in the control group (from 3.2 +/- 1.2 to 24.1 +/- 4.2 ng/mL) than in the pentoxifylline-treated patients (from 3.8 +/- 1.9 to 11.5 +/- 2.1 ng/mL). Serum creatinine was unchanged in both groups, whereas alpha-1-microglobulin increased significantly more in the control group than in the pentoxifylline-treated group. Intramucosal pH remained almost unchanged in the pentoxifylline patients (>7.35) but decreased significantly in the control group (5 hrs after surgery, intramucosal pH 7.29 +/- 0.13).
CONCLUSIONS: Pretreatment of patients aged >80 yrs undergoing cardiac surgery with pentoxifylline attenuated deterioration of endothelial, renal, and liver function as seen in an untreated control group. Splanchnic perfusion also appears to be improved in the pentoxifylline-treated group. Whether pretreatment with pentoxifylline will improve outcome in this patient population remains to be elucidated.
High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients.
Bostom AG, Shemin D, Lapane KL, Hume AL, Yoburn D, Nadeau MR, Bendich A, Selhub J, Rosenberg IH
USDA Human Nutrition Research Center on Aging, Tufts New England Medical Center, Boston, Massachusetts, USA.
Kidney Int 1996 Jan;49(1):147-52
Hyperhomocysteinemia, an arteriosclerotic risk factor, persists in 75% of dialysis patients despite routine low dose supplementation with the B-Vitamin-Co-factors/substrates for homocysteine (Hcy) metabolism, and normal or supernormal plasma status of these vitamins (Atherosclerosis 114:93, 1995). We conducted a placebo-controlled eight-week trial of the effect on plasma homocysteine of adding supraphysiologic dose folic acid (15 mg/day), B-6 (100 mg/day), and B-12 (1 mg/day) to the usual daily dosing of 1 mg folic acid, 10 mg B-6, and 12 micrograms B-12, in 27 hyperhomocysteinemic dialysis patients. Total plasma homocysteine was measured at baseline, and after four and eight weeks. Blinded analyses revealed no evidence of toxicity in the group randomized to supraphysiologic dose B-vitamin supplementation. Plasma homocysteine was significantly reduced after both four weeks (-29.8% vs. -2.0%; P = 0.0024) and eight weeks (-25.8% vs. +0.6%; P = 0.0009) of active versus placebo treatment. Also, 5 of 15 treated versus 0 of 12 placebo group patients had their plasma Hcy reduced to within the normative range (< 15 mumol/liter). Supraphysiologic doses of B-vitamins may be required to correct hyperhomocysteinemia in dialysis patients.
Renal vascular resistance in autosomal dominant polycystic kidney disease. Evaluation with color Doppler ultrasound.
Brkljacic B; Sabljar-Matovinovic M; Putarek K; Soldo D; Morovic-Vergles J ; Hauser M
Clinical Department of Radiology, University Hospital Merkur, University of Zagreb Medical School, Croatia.
Acta Radiol (Denmark) Sep 1997, 38 (5) p840-6
PURPOSE: The purpose of this study was to evaluate the performance of color duplex Doppler ultrasonography in the assessment of renal vascular resistance (RVR) by measuring resistive indices (RIs) and pulsatility indices (PIs) in patients with autosomal dominant polycystic kidney disease (ADPKD), and to correlate the measured values with renal function and the presence of arterial hypertension.
MATERIAL AND METHODS: In 42 patients with ADPKD and 65 control subjects,
RIs and PIs were measured by means of color duplex Doppler sonography and correlated with clinical and laboratory findings and with morphological abnormalities at B-mode ultrasonography.
RESULTS: Mean RI in the control subjects was 0.59 +/- 0.03 (+/-SD) and in the patients 0.71 +/- 0.11, (p < 0.01). Mean PI in the controls was 1.00 +/- 0.11 and in the patients 1.69 +/- 0.21, (p < 0.01). Elevated RIs and PIs heralded a progression of ADPKD. Doppler indices correlated significantly with renal function tests and morphological changes in the affected kidneys at ultrasound. Significantly higher RIs (p < 0.01) and PIs (p < 0.04) were measured in hypertensive ADPKD patients as compared to normotensive patients.
Correlation of patient age and Doppler indices did not reach statistical significance.
CONCLUSION: Doppler indices do reflect the increased RVR in patients with ADPKD and they correlate with renal function disturbance, with the development of systemic arterial hypertension, and with ultrasonographic abnormality of the kidney in these subjects.
Betaines: their significance for bacteria and the renal tract.
Chambers, S.T.
Clin. Sci. 1995; 88(1): 25-7.
No abstract available.
Left ventricular hypertrophy in autosomal dominant polycystic kidney disease.
Chapman AB; Johnson AM; Rainguet S; Hossack K; Gabow P; Schrier RW
Denver Health Medical Center, Colorado, USA.
J Am Soc Nephrol (United States) Aug 1997, 8 (8) p1292-7
Cardiovascular complications are the most common cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). To understand this relationship, known cardiovascular risk factors were examined in ADPKD. Left ventricular hypertrophy (LVH) is a known, important risk factor for premature cardiovascular death in patients with essential hypertension. Hypertension is known to occur frequently and early in ADPKD patients. The frequency of LVH in ADPKD patients and its relation with hypertension and other risk factors, however, is not known. In this study, echocardiographic tests were performed in 116 consecutive adult ADPKD patients and 77 healthy control subjects. There was a significantly higher frequency of LVH in ADPKD men (46 versus 20%, P < 0.05) and women (37 versus 12%, P < 0.005) compared with control subjects. LVH in ADPKD patients was associated with higher systolic and diastolic arterial BP. There also was an association between LVH, diminished renal function, and increased renal volume. When comparing ADPKD patients with and without LVH, the former were older, weighed more, had a higher prevalence of hypertension, and
had a lower hematocrit value and more renal impairment. LVH was also present in 23% of normotensive ADPKD patients and 16% of healthy control subjects (P = NS), but did not correlate with BP. The role of BP as a contributing factor to LVH in ADPKD patients may be due in part to earlier onset and inadequate treatment.
Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure.
Chauveau P, Chadefaux B, Coude M, Aupetit J, Kamoun P, Jungers P
Department of Nephrology, Necker Hospital, Paris, France.
Miner Electrolyte Metab 1996;22(1-3):106-9
Moderate hyperhomocysteinemia, a risk factor for premature atherosclerosis, is present in chronic uremic patients. We prospectively evaluated the effects of sequential supplementation with pyridoxine (70 mg/day) and folic acid (10 mg/day) for two 3-month periods in 37 nondialyzed patients (29 males) with creatinine clearance (Ccr) ranging from 10 to 80 ml/min, whose plasma vitamin B12 and folate level was in the normal range. Mean (+/- SD) baseline plasma total homocysteine (Hcy) was 14.9 +/- 5.2, 16.5 +/- 5.1 and 26.1 +/- 12.1 mumol/l (upper limit in 45 healthy controls 14.1 mumol/l) in patients with CCr 40-80, 20-40 and < 20 ml/min, respectively. Following pyridoxine Hcy did not significantly decrease whereas following folic acid Hcy decreased significantly to 9.9 +/-
2.9 (-33% vs. baseline), 10.3 +/- 3.4 (-37%) and 15.4 +/- 5.5 (-40%), respectively
(Student's paired t test, p < 0.001) in the 3 groups. We conclude that folate (but not pyridoxine) pharmacologic supplementation is effective in lowering elevated plasma Hcy in chronic renal failure patients, thus suggesting that enhancing the Hcy remethylation pathway may overcome hyperhomocysteinemia in such patients. In view of the potential atherogenic effects of hyperhomocysteinemia, long-term folate supplementation should be considered in uremic patients.
Hyperhomocysteinemia: an independent risk factor for vascular disease.
Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I.
Department of Cardiology, Adelaide Hospital, Dublin, Ireland.
N Engl J Med. 1991 Apr 25;324(17):1149-55.
BACKGROUND. Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine beta-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine beta-synthase deficiency.
METHODS. We first established a diagnostic criterion for hyperhomocysteinemia by comparing peak serum levels of homocysteine after a standard methionine-loading test in 25 obligate heterozygotes with respect to cystathionine beta-synthase deficiency (whose children were known to be homozygous for homocystinuria due to this enzyme defect) with the levels in 27 unrelated age- and sex-matched normal subjects. A level of 24.0 mumol per liter or more was 92 percent sensitive and 100 percent specific in distinguishing the two groups. The peak serum homocysteine levels in these normal subjects were then compared with those in 123 patients whose vascular disease had been diagnosed before they were 55 years of age.
RESULTS. Hyperhomocysteinemia was detected in 16 of 38 patients with cerebrovascular disease (42 percent), 7 of 25 with peripheral vascular disease (28 percent), and 18 of 60 with coronary vascular disease (30 percent), but in none of the 27 normal subjects. After adjustment for the effects of conventional risk factors, the lower 95 percent confidence limit for the odds ratio for vascular disease among the patients with hyperhomocysteinemia, as compared with the normal subjects, was 3.2. The geometric-mean peak serum homocysteine level was 1.33 times higher in the patients with vascular disease than in the normal subjects (P = 0.002). The presence of cystathionine beta-synthase deficiency was confirmed in 18 of 23 patients with vascular disease who had hyperhomocysteinemia.
CONCLUSIONS. Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency.
Alteration in plasma antioxidant capacities in chronic renal failure and hemodialysis patients: a possible explanation for the increased cardiovascular risk in these patients.
Clermont G, Lecour S, Lahet J, Siohan P, Vergely C, Chevet D, Rifle G, Rochette L.
L.P.P.C.E., Faculties of Medicine and Pharmacy, BP 87900, 21079 Cedex, Dijon,
France. gaelle.clermont@u-bourgofne.fr
Cardiovasc Res 2000 Aug 18;47(3):618-23
OBJECTIVE: The high incidence of cardiovascular diseases in chronic renal failure (CRF) and hemodialyzed (HD) patients is now well established and the involvement of oxidative stress has been hypothesized in these phenomena. The aim of our study was to evaluate the level of oxidative stress in healthy controls (CTL) compared with CRF and HD patients before (pre-HD) and after (post-HD) the dialysis session, carried out on a high biocompatible polyacrylonitrile membrane AN69.
METHODS: Several indicators of the extracellular redox status were evaluated in plasma. The ascorbyl free radica (AFR) was directly measured using electron spin resonance spectroscopy (ESR) and expressed with respect to the vitamin C level to obtain a direct index of oxidative stress. Indirect plasma parameters such as vitamin E, thiol and uric acid levels were also quantified. The plasma antioxidant status (PAS) was evaluated by the allophycocyanin test. Nitric oxide (NO) stable-end metabolites: nitrites and nitrates (NO(x)), were measured in plasma.
RESULTS: In CRF patients, vitamin C and thiol levels were low, and the AFR/vitamin C ratio high compared with the CTL. On the other hand, PAS and uric acid levels were shown to be higher in CRF patients. After the dialysis session, vitamin C level decreased and AFR/vitamin C ratio increased. The thiol levels were shown to be increased, in return PAS and uric acid levels were significantly lower after the dialysis session. NO(x) levels rose during CRF, but were significantly decreased after the dialysis procedure. No differences in vitamin E status were observed between CTL, CRF and HD patients.
CONCLUSION: Our study demonstrates that profound disturbances in the extracellular redox system occur during the course of chronic renal failure and hemodialysis, and may provide an explanation for the cardiovascular complications in these patients.
Response of hyperhomocysteinemia to folic acid supplementation in patients with end-stage renal disease.
Dierkes J, Domrose U, Ambrosch A, Bosselmann HP, Neumann KH, Luley C.
Institute of Clinical Chemistry, University Hospital, Magdeburg, Germany.
Clin Nephrol 1999 Feb;51(2):108-15
BACKGROUND: Elevated concentrations of homocysteine are associated with an increased risk for cardiovascular disease. Reasons for elevated homocysteine concentrations are folate or vitamin B12 deficiency, renal disease or genetic abnormalities. A high prevalence of hyperhomocysteinemia is found in patients with end-stage renal disease (ESRD). Since these patients are also at increased risk for vitamin deficiency, a supplementation study comparing two doses of folic acid was performed in patients with ESRD treated with maintenance hemodialysis or with peritoneal dialysis.
PATIENTS AND METHODS: Patients undergoing hemodialysis (n = 70) or peritoneal dialysis (n = 12) were supplemented with 2.5 mg or 5 mg folic acid (three times per week after each dialysis treatment) for four weeks in a parallel study design. In 20 hemodialysis patients, the effect of folic acid withdrawal was observed after four weeks.
RESULTS: Both supplementation schemes reduced homocysteine to a similar extent (35%) but did not normalize homocysteine concentrations in the majority of patients. Dialysis also had a strong homocysteine lowering effect. After supplementation, 74% of the hemodialysis patients had post-dialysis homocysteine concentrations within the reference range (<16 micromol/l). Homocysteine concentrations remained decreased in 20 patients four weeks after withdrawal of folic acid supplementation.
CONCLUSIONS: It is concluded that supplementation with 2.5 or 5 mg folic acid has a similar effect on homocysteine concentrations to supplementation regimens using 15 mg folic acid supplements. In contrast to the effect of folic acid supplementation in subjects with normal renal function, folic acid supplementation does not normalize homocysteine concentrations in ESRD patients.
Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis.
Ettinger B, Pak CY, Citron JT, Thomas C, Adams-Huet B, Vangessel A
Division of Research, Kaiser Permanente Medical Care Program, Oakland, California 94611-5714, USA.
J Urol 1997 Dec;158(6):2069-73
PURPOSE: We examined the efficacy of potassium-magnesium citrate in preventing recurrent calcium oxalate kidney calculi.
MATERIALS AND METHODS: We conducted a prospective double-blind study of 64 patients who were randomly assigned to receive placebo or potassium-magnesium citrate (42 mEq. potassium, 21 mEq. magnesium, and 63 mEq. citrate) daily for up to 3 years.
RESULTS. New calculi formed in 63.6% of subjects receiving placebo and in 12.9% of subjects receiving potassium-magnesium citrate. When compared with placebo, the relative risk of treatment failure for potassium-magnesium citrate was 0.16 (95% confidence interval 0.05 to 0.46). Potassium-magnesium citrate had a statistically significant effect (relative risk 0.10, 95% confidence interval 0.03 to 0.36) even after adjustment for possible confounders, including age, pretreatment calculous event rate and urinary biochemical abnormalities.
CONCLUSIONS: Potassium-magnesium citrate effectively prevents recurrent calcium oxalate stones, and this treatment given for up to 3 years reduces risk of recurrence by 85%.
Acetaminophen, aspirin, and chronic renal failure.
Fored CM, Ejerblad E, Lindblad P, Fryzek JP, Dickman PW, Signorello LB, Lipworth L, Elinder CG, Blot WJ, McLaughlin JK, Zack MM, Nyren O.
Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden.
michael.fored@mep.ki.se
N Engl J Med. 2001 Dec 20;345(25):1801-8.
BACKGROUND: Several epidemiologic studies have demonstrated an association between heavy consumption of nonnarcotic analgesics and the occurrence of chronic renal failure, but it is unclear which is the cause and which is the effect
METHODS: In a nationwide, population-based, case-control study of early-stage chronic renal failure in Sweden, face-to-face interviews were conducted with 926 patients with newly diagnosed renal failure and 998 control subjects, of whom 918 and 980, respectively, had complete data. We used logistic-regression models to estimate the relative risks of disease-specific types of chronic renal failure associated with the use of various analgesics
RESULTS: Aspirin and acetaminophen were used regularly by 37 percent and 25 percent, respectively, of the patients with renal failure and by 19 percent and 12 percent, respectively, of the controls. Regular use of either drug in the absence of the other was associated with an increase by a factor of 2.5 in the risk of chronic renal failure from any cause. The relative risks rose with increasing cumulative lifetime doses, rose more consistently with acetaminophen use than with aspirin use, and were increased for most disease-specific types of chronic renal failure. When we disregarded the recent use of analgesics, which could have occurred in response to antecedents of renal disease, the
associations were only slightly attenuated
CONCLUSIONS: Our results are consistent with the existence of exacerbating effects of acetaminophen and aspirin on chronic renal failure. However, we cannot rule out the possibility of bias due to the triggering of analgesic consumption by predisposing conditions.
Plasma and platelet taurine are reduced in subjects with insulin-dependent diabetes mellitus: effects of taurine supplementation.
Franconi F, Bennardini F, Mattana A, Miceli M, Ciuti M, Mian M, Gironi A,
Anichini R, Seghieri G.
Institute of Biochemistry, University of Sassari, Italy.
Am J Clin Nutr. 1995 May;61(5):1115-9.
Plasma and platelet taurine concentrations were assayed in 39 patients with insulin-dependent diabetes mellitus (IDDM) and in 34 control subjects matched for age, sex, and both total and protein-derived daily energy intake. Platelet aggregation induced by arachidonic acid in vitro at baseline and after oral taurine supplementation (1.5 g/d) for 90 d was also studied. Plasma and platelet taurine concentrations (mean +/- SEM) were lower in diabetic patients (65.6 +/- 3.1 mumol/L, or 0.66 +/- 0.07 mol/g protein) than in control subjects (93.3 +/- 6.3 mumol/L, or 0.99 +/- 0.16 mol/g protein, P < 0.01). After oral supplementation, both plasma and platelet taurine concentrations increased
significantly in the diabetic patients, reaching the mean values of healthy control subjects. The effective dose (mean +/- SEM) of arachidonic acid required for platelets to aggregate was significantly lower in diabetic patients than in control subjects (0.44 +/- 0.07 mmol compared with 0.77 +/- 0.02 mmol, P < 0.001, whereas after taurine supplementation it equaled the mean value for healthy control subjects (0.72 +/- 0.04 mmol). In in vitro experiments, taurine reduced platelet aggregation in diabetic patients in a dose-dependent manner, whereas 10 mmol taurine/L did not modify aggregation in healthy subjects.
The kidney and homocysteine metabolism.
Friedman AN, Bostom AG, Selhub J, Levey AS, Rosenberg IH.
Vitamin Metabolism and Aging, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. afriedman@hnrc.tufts.edu
J Am Soc Nephrol. 2001 Oct;12(10):2181-9.
Homocysteine (Hcy) is an intermediate of methionine metabolism that, at elevated levels, is an independent risk factor for vascular disease and atherothrombosis. Patients with renal disease, who exhibit unusually high rates of cardiovascular morbidity and death, tend to be hyperhomocysteinemic, particularly as renal function declines. This observation and the inverse relationship between Hcy levels and GFR implicate the kidney as an important participant in Hcy handling. The normal kidney plays a major role in plasma amino acid clearance and metabolism. The existence in the kidney of specific Hcy uptake mechanisms and Hcy-metabolizing enzymes suggests that this role extends to Hcy. Dietary protein intake may affect renal Hcy handling and should be considered when measuring Hcy plasma flux and renal clearance. The underlying cause of hyperhomocysteinemia in renal disease is not entirely understood but seems to involve reduced clearance of plasma Hcy. This reduction may be attributable to defective renal clearance and/or extrarenal clearance and metabolism, the latter possibly resulting from retained uremic inhibitory substances. Although the currently available evidence is not conclusive, it seems more likely that a reduction in renal Hcy clearance and metabolism is the cause of the hyperhomocysteinemic state. Efforts to resolve this important issue will advance the search for effective Hcy-lowering therapies in patients with renal disease.
[Experimental studies of the protective effect of ginkgo biloba extract (GBE) on
cisplatin-induced toxicity in rats] [Article in Japanese]
Fukaya H, Kanno H.
Department of Otolaryngology, Fukushima Medical University School of Medicine.
Nippon Jibiinkoka Gakkai Kaiho. 1999 Jul;102(7):907-17.
Cisplatin (CDDP) is an effective antineoplastic agent in the treatment of solid malignant tumors. Its clinical use, however, is limited because of various side effects including sensorineural hearing loss. Several agents have been proposed to reduce these side effects. GBE has recently been reported to scavenge superoxide and hydroxyl radicals, resulting in a reduction of lipid peroxidation. GBE is expected to protect against CDDP-induced toxicity because its generative mechanism is thought to be associated with free-radical
formation. The purpose of the present study was to evaluate GBE's efficacy as a
protective agent against cisplatin-induced ototoxicity. Fisher rats were used in this study and were divided into three treatment groups: 1) animals administered 1.0 mg of CDDP per kg for 10 days (Group I), 2) animals receiving 100 mg of GBE per kg 90 min before administration 1.0 mg of CDDP per kg (Group II) and 3) a vehicle control (Group III). First, the protective effect of GBE on CDDP-induced ototoxicity was investigated. The auditory threshold was evaluated by means of the compound action potential (CAP) recording. After CAP recordings, cochlear sensory epithelia were observed throughout the cochlea by scanning electron microscopy. In Group II, the elevation of CAP thresholds at 12 kHz, 16 kHz, 20 kHz and the missing rate for the outer hair cells were significantly reduced as compared to those in Group I. These data suggest that GBE is effective for otoprotection against CDDP. Second, the protective effect of GBE on CDDP-induced nephrotoxicity was evaluated. Nephrotoxicity was evaluated by means of measurement of serum BUN and creatinine and histopathological examination of the kidney. These were significant differences in serum BUN and creatinine levels between Group I and Group II. Third, the influence of GBE against the antitumor effect of CDDP was researched in the rats inoculated subcutaneously with SCC-158 squamous cell carcinoma cells. There was no difference in tumor growth rate (TGR) between Group I and Group II. The result suggested that the combined administration had no influence on the antitumor activity of CDDP. In conclusion, the co-administration of CDDP with GBE is beneficial to ameliorate CDDP-induced toxicity without attenuation of CDDP antitumor activity.
The effect of oral betaine on vertebral body bone density in pyridoxine-non-responsive homocystinuria.
Gahl WA, Bernardini I, Chen S, Kurtz D, Horvath K.
Section of Human Biochemical Genetics, National Institute of Child Health and
Human Development, Bethesda, Maryland 20892.
J Inherit Metab Dis. 1988;11(3):291-8.
Five pyridoxine-non-responsive homocystinuric patients aged 5 to 32 years were treated with oral betaine, 3 g b.i.d, in a double-blind, placebo-controlled, two-year crossover study of its effect on bone mineralization. Betaine therapy significantly reduced mean plasma homocystine (36 +/- 9 (SEM) mumol L-1 to 9 +/- 4 mumol L-1), with variable increases in plasma methionine and no adverse effects. Bone density, measured by computerized tomographic scanning of vertebral bodies, was below normal in all patients at the start of the study, and was not significantly altered by betaine therapy administered according to this protocol.
The Mosby Medical Encyclopedia, Revised Edition 1996.
Glanze, W.D.
St. Louis, MO: C.V. Mosby.
Mechanisms of progression in autosomal dominant polycystic kidney disease.
Grantham JJ
Department of Medicine, Kansas University Medical Center, Kansas City, USA.
Kidney Int Suppl (United States) Dec 1997, 63 pS93-7
Autosomal dominant polycystic kidney disease (ADPKD) progresses to end-stage renal insufficiency before the age of 73 in approximately 48% of affected individuals. Why the disease, characterized by innumerable cysts arising in proximal and distal tubules, eliminates functioning non-cystic parenchyma in some patients and spares other is a mystery. The cysts initiate in early childhood in fewer than 1% of renal tubules as a consequence of the focal expression of mutated DNA. Tubule cells proliferate, causing segmental dilation, in association with the abnormal deposition of extracellular matrix proteins. Most of the cysts separate from the parent tubules and fill with fluid by cAMP-mediated chloride secretion. Risk factors associated with accelerated loss of renal function include: genotype (PKD Type 1 progresses more rapidly than PKD Type 2); gender (males progress more rapidly than females); race (black patients progress more rapidly than whites); hypertension; proteinuria. The relation between kidney size and progression to renal failure is debated. Progressive PKD is associated with the cellular expression of proto-oncogenes (fos, myc, ras, erb), growth factors (EGF, HGF, acid and basic FGF), chemokines (MCP-1. osteopontin), metalloproteinases, and apoptotic markers, and the interstitial accumulation of Types I and IV collagen, laminin, fibronectin, macrophages and fibroblasts, the magnitudes of which increase with age. Cyst activating factor (CAF), a neutral lipid identified in cyst fluid that stimulates fluid secretion and proliferation of renal epithelial cells and monocyte chemotaxis, has recently been identified as a potential progression factor. In those patients destined to develop renal failure there is loss of non-cystic parenchyma in association with mass replacement by fluid-filled cysts in a network of interstitial fibrosis. The decline in renal function is probably the consequence of processes leading to interstitial fibrosis, as in other nephropathies, rather than due to simple mechanical displacement of parenchyma by cysts. (42 Refs.)
Cystic disease of the kidney.
Grantham, J.J., Nair, V., Winklhofer, F.
In Brenner & Rector's The Kidney, Volume 2, Sixth Edition 2000, pp. 1699-1730.
Philadelphia, PA: W.B. Saunders.
Glomerulosclerosis in the remnant kidney rat is modulated by dietary alpha-tocopherol.
Hahn S, Kuemmerle NB, Chan W, Hisano S, Saborio P, Krieg RJ Jr, Chan JC.
Department of Pediatrics, Virginia Commonwealth University's Medical College of
Virginia Campus, Richmond, USA.
J Am Soc Nephrol 1998 Nov;9(11):2089-95
Glomerulosclerosis and tubulointerstitial injury are characteristic features seen in the subtotal (5/6) nephrectomy remnant kidney model in the rat. Oxidative stress from renal mass reduction contributes to the glomerular and tubular injury. Previous studies have clearly demonstrated the prevention or inhibition of such injury by an antioxidant such as alpha-tocopherol. However, few data are available on the ability of alpha-tocopherol to modulate or arrest progression of the established disease. This study examines whether
alpha-tocopherol modulates glomerulosclerosis and tubulointerstitial injury when it is given 2 wk after renal damage has been established. The findings indicate that alpha-tocopherol has the capacity to modulate both tubulointerstitial injury and glomerulosclerosis, lower the elevated expression of transforming growth factor-beta1, and reduce plasma and kidney malondialdehyde concentration, the end product of lipid peroxidation. The results support the potential utility of alpha-tocopherol in reversing established glomerulosclerosis and tubulointerstitial injury in a remnant kidney model.
Homocysteine, cystathionine, methylmalonic acid and B-vitamins in patients with renal disease.
Herrmann W, Schorr H, Geisel J, Riegel W.
Department of Clinical Chemistry/Central Laboratory, Universitatskliniken des
Saarlandes, Homburg, Germany. kchwher@med-rz.uni-sb.de
Clin Chem Lab Med. 2001 Aug;39(8):739-46.
Moderate hyperhomocysteinemia is very frequent in renal patients. Aside from homocysteine (HCY) itself, the metabolites methylmalonic acid (MMA) and cystathionine (CYS) supply further information about disturbances in HCY metabolism. In two groups of renal patients, transplant and hemodialysis patients, we measured HCY, MMA and CYS and evaluated their diagnostic value for impaired HCY metabolism due to vitamin deficiency and renal insufficiency. We investigated serum samples from 63 transplant patients and 38 patients undergoing hemodialysis. HCY, MMA and CYS were assayed by gas chromatography-mass spectrometry, vitamin B6 by HPLC, B12 and folate by
chemiluminescence immunoassay. The determination of HCY, MMA, and CYS in renal patients provides specific information about intracellular disturbances of HCY metabolism. The frequency of increased metabolite levels in renal patients was much higher than the frequency of lowered vitamin concentrations in serum. Furthermore, the metabolite levels in transplant patients were only moderately increased, whereas they were strongly increased in patients on hemodialysis (HCY 19.2 vs. 28.8 micromol/l, MMA 292 vs. 1025 nmol/l, CYS 733 vs. 2711 nmol/l). Our findings may support the use of MMA determination in the diagnosis of vitamin B12 deficiency in renal patients. Compared to vitamin B12 deficiency, renal dysfunction itself appears to cause only a modest elevation in serum MMA. Regression analysis revealed that the moderate elevation of HCY and CYS in
transplant patients is mainly a consequence of impaired remethylation of HCY to
methionine with activated transsulfuration, whereas the mildly elevated MMA level is attributable to renal dysfunction. In patients on hemodialysis, all three metabolites were markedly elevated, indicating a strongly disturbed HCY metabolism. Based on a backward regression, we discovered that the HCY metabolism was strongly disturbed by renal insufficiency and vitamin deficiency. The markedly elevated HCY level was mainly attributable to functional vitamin B12 deficiency indicated by high MMA, and the strong CYS elevation was due to renal dysfunction and inhibition of this pathway by low levels of vitamin B6. In conclusion, besides HCY, the determination of MMA and CYS levels supports an early diagnosis of B-vitamin deficiency in renal patients. MMA is a more
sensitive indicator of intracellular vitamin B12 deficiency than vitamin B12 in serum.
Plasma reduced homocysteine concentrations are increased in end-stage renal disease.
Hoffer LJ, Robitaille L, Elian KM, Bank I, Hongsprabhas P, Mamer OA.
Lady Davis Institute for Medical Research, School of Dietetics and Human
Nutrition, The Mass Spectrometry Unit,McGill University, Montreal, Quebec,
Canada.
Kidney Int. 2001 Jan;59(1):372-7.
BACKGROUND: Plasma total homocysteine (tHcy) concentrations> 15 micromol/L are associated with an increased risk of cardiovascular disease. This is especially the case in end-stage renal disease (ESRD), in which tHcy concentrations commonly range between 20 and 30 micromol/L. Adverse vascular or prothrombotic effects associated with hyperhomocysteinemia are assumed to be mediated by the free sulfhydryl (reduced) form of the molecule (rHcy), but data based on fluorescence high-pressure liquid chromatography (HPLC) indicate that rHcy concentrations are not increased in ESRD despite two- to threefold elevations in tHcy.
METHODS: We developed a sensitive method for measuring plasma rHcy concentrations in which freshly drawn blood is incubated with sodium iodoacetate, and the resulting S-carboxymethylhomocysteine is analyzed by gas chromatography mass spectrometry.
RESULTS: Unlike with the earlier methodology, we found plasma rHcy concentrations two to four times higher than normal in ESRD. These concentrations were lowered by hemodialysis and were proportional to plasma tHcy over the range of tHcy concentrations that has been associated with increased cardiovascular risk (r2 = 0.39, P < 0.0001).
CONCLUSIONS: These results support the hypothesis that homocysteine could directly mediate vascular disease through mechanisms related to the reactivity of its free sulfhydryl group. It remains to be determined how much of the variability between plasma tHcy and rHcy is due to analytical variation and how much is due to biologic factors that separately influence concentrations of the disease marker, tHcy, and its presumed mediator, rHcy.
Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer's disease?
Joosten E, Lesaffre E, Riezler R, Ghekiere V, Dereymaeker L, Pelemans W, Dejaeger E.
Department of Pathophysiology, University Hospitals K. U. Leuven, Belgium.
J Gerontol A Biol Sci Med Sci. 1997 Mar;52(2):M76-9.
BACKGROUND: It is still unclear whether there is an association between Alzheimer's disease and vitamin B-12 or folate deficiency. This study was designed to investigate whether patients with Alzheimer's disease are particularly prone to metabolically significant cobalamin or folate deficiency as compared to nondemented hospitalized controls and healthy elderly controls living at home.
METHODS: Evaluation for the diagnosis of Alzheimer's disease, routine laboratory tests, serum folate and vitamin B-12, serum methylmalonic acid (MMA), total homocysteine (tHcy), and radiological tests was performed in 52 patients with Alzheimer's disease (AD), 50 nondemented hospitalized controls, and 49 healthy elderly subjects living at home.
RESULTS: Serum vitamin B-12 and folate levels are comparable between patients with AD, hospitalized control patients, and subjects living at home. Patients with AD have the highest serum MMA and tHcy levels. The MMA levels of patients with AD and hospitalized controls are not different, but the mean tHcy level is significantly higher in patients with AD as compared to nondemented patients or subjects living at home.
CONCLUSION: The interpretation of the vitamin B-12 and folate status in patients with AD depends largely on the methodology (i.e., serum vitamin vs metabolite levels) and the selection of the control group. Although patients with AD have the highest tHcy and MMA levels, metabolically significant vitamin B-12 and folate deficiency is also a substantial problem in nondemented elderly patients.
[Effects of L-carnitine on erythropoiesis and blood platelet aggregation in patients with chronic renal failure treated with hemodialysis]. [Article in Polish]
Kalinowski M, Poplawski A, Mazerska M, Daniluk A.
Kliniki Nefrologii i Chorob Wewnetrznych Akademii Medycznej w Bialymstoku.
Pol Merkuriusz Lek 1999 Feb;6(32):76-8
The aim of the work has to assess the effects of L-carnitine therapy on erythropoiesis and whole blood platelet aggregation. The studies were performed in 28 patients divided into 3 groups: I-group was given erythropoietin, II-group was given erythropoietin and L-carnitine, III-group was given L-carnitine. After 22 month of the therapy a statistically significant rise in hematocrit was observed in group III, improvement in muscle strength, a rise in free and total carnitine concentration was found in group II and III. There were no significant changes in urea concentration, platelet count and iron metabolism. Whole blood platelet aggregation induced by ADP, collagen and ristocetin was impaired relative to healthy volunteers. After 2 month of L-carnitine treatment of significant rise in collagen induced platelet aggregation was observed in group II.
Kidney stones. How to identify the cause and prevent recurrence.
LaPorte J, Baum N.
Department of Urology, Touro Infirmary, New Orleans.
Postgrad Med 1990 Apr;87(5):219-23, 226
Up to 10% of Americans will have a kidney stone at some point in life. The challenge for physicians is to reduce the high recurrence rate of this painful condition. To this end, Drs LaPorte and Baum propose an outpatient diagnostic workup that cost-effectively pinpoints the type of stone present. They also outline medical measures that help prevent recurrent stone formation.
Cardiovascular disease and the kidney. Tracking a killer in chronic kidney disease.
Levin A, Stevens L, McCullough PA.
Division of Nephrology, University of British Columbia Faculty of Medicine,
Vancouver, British Columbia, Canada. alevin@providencehealth.bc.ca
Postgrad Med. 2002 Apr;111(4):53-60.
The interlinking of CVD with CKD is undeniable. CVD accounts for more than 50% of all morbidity and mortality in patients with kidney disease who have undergone renal replacement therapy, and CVD is also prevalent in patients with mild and moderately severe kidney disease. To help address the elevated risks of these patients, primary care physicians need to maintain vigilance in (1) identifying patients who have CKD and (2) implementing strategies for reducing the prevalence of CVD in this population. It is essential that patients be screened for relatively mild kidney disease by measurement of serum creatinine and urine microalbumin and by calculation of the glomerular filtration rate in mL/min/1.73 m2 using equations based on serum creatinine. Rigorous assessment of conventional risk factors, including dyslipidemia, hypertension, and diabetes, is also necessary to prevent the poor outcomes currently observed in persons with CKD. Routine use of ACE inhibitors and aspirin is encouraged in all patients with CKD, and strict glycemic and blood pressure control is recommended for optimal outcomes. In addition, patients should be screened and treated for risk factors particularly associated with kidney disease and CVD morbidity and mortality, including anemia, hyperphosphatemia, and hyperparathyroidism. Finally, physicians should be careful to avoid therapeutic nihilism in patients with kidney disease; those at highest risk of CVD are likely to receive the greatest benefit from cardiovascular therapies.
The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection.
Licinio J, Wong ML.
Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. licinio@nih.gov
Mol Psychiatry. 1999 Jul;4(4):317-27.
Depression represents a major public health problem. It is estimated that 13-20% of the population has some depressive symptoms at any given time and about 5% of the population is assumed to suffer from major depression. Known pathological processes include ischemia, neoplasia, necrosis, apoptosis, infection, and inflammation. Of those, inflammation is the most compatible with the waxing and waning course of depression, and could explain the biology of this disorder that has a fluctuating course with severe episodes that can be followed by partial or complete remission. Over the years a body of evidence
has been accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Major depression commonly co-occurs with ischemic heart disease and decreased bone mineral density. Depressive symptoms are known to have a negative impact on cardiovascular prognosis, increasing the mortality rate of coronary artery disease. Several lines of evidence indicate that brain cytokines, principally interleukin-1beta (IL-1beta) and IL-1 receptor antagonist may have a role in the biology of major depression, and that they might additionally be involved in the pathophysiology and somatic consequences of depression as well as in the effects of antidepressant treatment. A particularly unique and novel aspect of the studies and views discussed here is their potential to lead to interventions which may reduce the morbidity and mortality risks for osteoporosis, cardiovascular disease, and behavioral symptoms in patients with major depression. We also discuss the emerging concept of peripheral and central cytokine compartments: their integration and differential regulation is a key element for the optimal functioning of the immune and nervous systems.
Ambulatory blood pressure in hypertensive patients with autosomal dominant polycystic kidney disease.
Li Kam Wa TC; Macnicol AM; Watson ML
Department of Medicine, Royal Infirmary, Edinburgh, UK.
Nephrol Dial Transplant (England) Oct 1997, 12 (10) p2075-80
BACKGROUND: Ambulatory blood pressure is more closely correlated with various indices of hypertensive target-organ damage, and is a better prognostic predictor of cardiovascular morbidity and mortality than conventional methods of blood pressure measurement. Autosomal dominant polycystic kidney disease (ADPKD) is complicated by hypertension, progressive renal failure, andan increased risk of cardiovascular mortality. This study investigated the 24-h ambulatory blood pressure profile in patients with ADPKD in view of the sparsity of such data in these patients and the possibility that abnormal diurnal blood pressure variations may have prognostic consequences.
METHODS: Ambulatory blood pressure was measured over a 24-h period by the
oscillometric method with an automatic non-invasive recorder (SpaceLabs 90207 system) in matched groups of 25 hypertensive patients with ADPKD and 25 patients with essential hypertension.
RESULTS: Both groups showed a nocturnal decrease in blood pressure, but this was significantly smaller in patients with ADPKD. There was no evidence of enhanced lability of blood pressure in ADPKD.
CONCLUSIONS: The nocturnal fall in blood pressure was attenuated in patients with ADPKD. Further studies are required to assess the importance of this finding and its possible contribution to the progression of renal failure or increased cardiovascular mortality in these patients.
Circadian blood pressure changes in untreated children with kidney disease and
conserved renal function.
Lingens N, Freund M, Seeman T, Witte K, Lemmer B, Scharer K.
Division of Paediatric Nephrology, University Children's Hospital, Heidelberg,
Germany.
Acta Paediatr 1997 Jul;86(7):719-23
Ambulatory blood pressure monitoring over 24 h was applied in 31 children with kidney disease, aged 3-19 (median 11) years, in the absence of renal insufficiency and without antihypertensive therapy. Median creatinine clearance was 112 ml/min/1.73m2. Ambulatory blood pressure monitoring revealed that eight patients (26%) were hypertensive during the daytime, compared to 62% through casual recordings obtained in the office and 38% when blood pressure was taken at home. Nocturnal hypertension was detected by ambulatory monitoring in six patients, two of whom had normal blood pressure in the daytime. Median nocturnal dipping was 13% for systolic and 21% for diastolic blood pressure, i.e. similar to healthy children. Rhythm analysis recognized a distorted circadian pattern for systolic and/or diastolic blood pressure in eight patients. In conclusion, ambulatory blood pressure monitoring allows the evaluation of hypertension more reliably than casual recordings in the office. Nocturnal hypertension, as a major risk factor for renal deterioration, is detected in a similar proportion as daytime hypertension in almost 20% of untreated children with kidney disease and normal renal function.
Validation of an immunoassay for measurement of plasma total homocysteine.
Marangon K, O'Byrne D, Devaraj S, Jialal I.
Department of Pathology, University of Texas Southwestern Medical Center at
Dallas 75235-9073, USA.
Am J Clin Pathol. 1999 Dec;112(6):757-62.
Hyperhomocysteinemia is an evolving cardiovascular risk factor. It is imperative that a simple, precise, and accurate assay be available in the clinical laboratory. The aim of this study was to evaluate an automated fluorescence polarization immunoassay for homocysteine. The assay had excellent precision at normal and high levels (intra-assay and interassay coefficients of variation < 5%). The method was linear from 0.24 to 50 mumol/L and displayed good correlation with a high-performance liquid chromatography (HPLC) method. There was no significant interference detectable in icteric and hyperlipidemic
samples, but hemolysis resulted in a significant negative bias. While homocysteine levels were not increased in smokers, patients with renal failure had significantly higher levels compared with control subjects. This automated assay requires no sample preparation, displays excellent precision, shows good correlation with HPLC, and, thus, is favored over HPLC for use in the clinical laboratory. The main indications for measuring plasma homocysteine levels will be in the early diagnosis of cobalamin deficiency, patients with cardiovascular disease and few or no established risk factors, and patients with unexplained venous thromboembolic disease.
Total serum homocysteine in senile dementia of Alzheimer type.
McCaddon A, Davies G, Hudson P, Tandy S, Cattell H.
Wrexham Maelor Hospital, North Wales, UK. andrew@mccaddon.demon.co.uk
Int J Geriatr Psychiatry. 1998 Apr;13(4):235-9.
OBJECTIVE: The main hypothesis was that subtle vitamin B12 deficiencies occur more commonly in senile dementia of Alzheimer type (SDAT) that in healthy elderly individuals, and may be revealed by elevated total serum homocysteine (tHcy). A subsidiary hypothesis was that such deficiencies would be nutritionally independent as determined by retinol binding protein (RBP).
DESIGN: A prospective case-controlled survey. SETTING: A Welsh urban psychogeriatric assessment centre and local general practice. PATIENTS: Thirty patients, aged 65 or over, seen consecutively in 1994 with features compatible with DSM-III-R criteria for primary degenerative dementia of Alzheimer type and 30 cognitively intact age-matched control subjects. MEASURES: Diagnosis was assessed using the CAMDEX. Cognitive scores were evaluated with the CAMCOG scale for patients and MMSE scores for control subjects. THcy was measured using high performance liquid chromatography (HPLC), and RBP assayed by a radial immunodiffusion method.
RESULTS: Patients had a highly significant elevation of tHcy compared with control (p < 0.0001). Multiple regression highlighted the interrelated effects of tHcy and total serum cobalamin on cognitive scores. RBP did not differ between groups. Macrocytosis was absent, and neutrophil hypersegmentation uncommon, in hyperhomocysteinaemic patients.
CONCLUSIONS: SDAT patients have significantly elevated tHcy. This is independent of RBP determined nutritional status. 'Classical' haematological changes of cobalamin or folate deficiency are poor predictors of tHcy in these patients. Aberrant cobalamin tissue delivery appears to contribute to SDAT cognitive decline. Relative contributions of other tHcy determinants require further investigation.
Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.
McCully, KS.
Am. J. Pathol. 1969 Jul; 56(1): 111-28.
No abstract available.
A controlled trial of the effect of folate supplements on homocysteine, lipids and hemorheology in end-stage renal disease.
McGregor D, Shand B, Lynn K.
Department of Nephrology, Christchurch Hospital, Christchurch, New Zealand.
davidm2@chhlth.govt.nz
Nephron. 2000 Jul;85(3):215-20.
Elevated plasma homocysteine (Hcy), dyslipidemia and hemorheological abnormalities all occur commonly in end-stage renal disease (ESRD) and are recognized risk factors for arteriosclerosis. To study the effect of folate supplementation on these factors we conducted a randomized controlled trial. Thirteen hemodialysis (HD) and 8 continuous ambulatory peritoneal dialysis (CAPD) patients received either 5 mg folic acid daily or placebo for 3 months. After 1 and 3 months, fasting blood samples were taken for Hcy, lipid profile, blood and plasma viscosity, red blood cell (RBC) osmotic fragility, plasma
fibrinogen concentration and in vivo platelet aggregability. At baseline, the CAPD patients had a higher mean plasma fibrinogen concentration than the HD patients and they also tended to have higher mean plasma viscosity. Folate-treated patients showed marked increases in RBC folate and an average decrease in plasma Hcy concentration of 33%. Mean total cholesterol, LDL cholesterol and triglyceride concentrations decreased significantly in the CAPD patients who took folate. Folate had no significant effect on hemorheology. In conclusion, folate supplements in ESRD reduce plasma Hcy concentrations and may improve lipid profiles. In our patients, hemorheological abnormalities were more marked in patients on CAPD than in those on HD and were not improved by folate supplementation. Copyright 2000 S. Karger AG, Basel
DNA diagnosis and clinical manifestations of autosomal dominant polycystic kidney disease.
Merta M; Stekrova J; Zidovska J; Vorsilkova M; Walterova J; Kapras J; Alanova M; Raskova D; Gaillyova R; Archmanova E; Rysava R
1st Medical Department, 1st Medical Faculty, Charles University, Prague, Czech
Republic.
Folia Biol (Praha) (Czech Republic) 1997, 43 (5) p201-4
At least 2 genes, detectable by DNA methods, encode autosomal dominant polycystic kidney disease (ADPKD), which remains the most frequent and serious hereditary renal disease. PKD1 gene, localized on chromosome 16, responds for the clinical course in the majority of ADPKD patients, whereas PKD2 gene, localized on chromosome 4, is responsible for less than 10-15% of cases, with presumed milder phenotypic manifestations. To start the clinical and genetic correlation in patients with different genotypes (PKD1 vs. PKD2) in the Czech population, a pilot group of 88 patients with ADPKD was analysed. Families with PKD1 (n = 44) represented 95.6% and families with PKD2 (n = 2) 4.4% of all families investigated (n = 46). Our clinical analysis, yet based only on a limited number of PKD2 subjects, does not definitely support the concept
of a milder phenotype and prognosis in PKD2 versus PKD1 patients, in terms of mean age of diagnosis (29 vs. 29 years), mean age at function or ultrasound findings.
Polycystic kidney disease: an unrecognized emerging infectious disease?
Miller-Hjelle MA, Hjelle JT, Jones M, Mayberry WR, Dombrink-Kurtzman MA,
Peterson SW, Nowak DM, Darras FS
Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine at Peoria 61656, USA. Marcia.A.Miller@uic.edu
Emerg Infect Dis 1997 Apr-Jun;3(2):113-27
Polycystic kidney disease (PKD) is one of the most common genetic diseases in humans. We contend that it may be an emerging infectious disease and/or microbial toxicosis in a vulnerable human subpopulation. Use of a differential activation protocol for the Limulus amebocyte lysate (LAL) assay showed bacterial endotoxin and fungal (1-->3)-beta-D-glucans in cyst fluids from human kidneys with PKD. Fatty acid analysis of cyst fluid confirmed the presence of 3-hydroxy fatty acids characteristic of endotoxin. Tissue and cyst fluid from three PKD patients were examined for fungal components. Serologic tests showed Fusarium, Aspergillus, and Candida antigens. IgE, but not IgG, reactive with Fusarium and Candida were also detected in cyst fluid. Fungal DNA was detected in kidney tissue and cyst fluid from these three PKD patients, but not in healthy human kidney tissue. We examine the intertwined nature of the actions of endotoxin and fungal components, sphingolipid biology in PKD, the structure of PKD gene products, infections, and integrity of gut function to establish a mechanistic hypothesis for microbial provocation of human cystic disease. Proof of this hypothesis will require identification of the microbes and microbial components involved and multifaceted studies of PKD cell biology.
Inhibition of rotavirus and enterovirus infections by tea extracts.
Mukoyama A, Ushijima H, Nishimura S, Koike H, Toda M, Hara Y, Shimamura T.
Department of Enteroviruses, National Institute of Health, Tokyo, Japan.
Jpn J Med Sci Biol. 1991 Aug;44(4):181-6.
Epigallocatechin gallate from green tea and theaflavin digallate from black tea inhibited infections of cultured rhesus monkey kidney MA 104 cells with rotaviruses and enteroviruses. Their antiviral effects were maximally induced when directly added to virus, and their pre- and post-treatment of the cells produced much weak antiviral activity. Antiviral activity of the extracts therefore seems to be attributable to interference with virus adsorption.
Ginkgo biloba extract ameliorates gentamicin-induced nephrotoxicity in rats.
Naidu MU, Shifow AA, Kumar KV, Ratnakar KS.
Central Research Laboratory, Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India.
Phytomedicine. 2000 Jun;7(3):191-7.
The effect of Ginkgo biloba (EGb), a plant extract with an antioxidant effect, has been studied on gentamicin-induced nephrotoxicity in male wistar rats. Ginkgo biloba extract (300 mg/kg BW) was administered orally 2 days before and 8 days concurrently with gentamicin (80 mg/kg BW). Saline treated animals served as control. Estimations of urine creatinine, glucose, blood urea, serum creatinine, plasma and kidney tissue MDA were carried out after 8 days of gentamicin treatment. Kidneys were examined using histological techniques. Blood urea and serum creatinine were increased by 896% and 461% respectively, with gentamicin, compared to saline treated group. Creatinine clearance was significantly decreased with gentamicin. Ginkgo biloba extract protected rats from gentamicin-induced nephrotoxicity. Changes in blood urea, serum creatinine and creatinine clearance induced by gentamicin were significantly prevented by Ginkgo biloba extract. There was a 177% and 374% rise in plasma and kidney tissue MDA with gentamicin, which were significantly reduced to normal with Ginkgo biloba extract. Histomorphology showed necrosis and desquamation of tubular epithelial cells in renal cortex with gentamicin, while it was normal and comparable to control with Ginkgo biloba extract. These data suggest that supplementation of Ginkgo biloba extract may be helpful to reduce gentamicin nephrotoxicity.
Millions of Americans May Be at Risk for Kidney Disease: Simple Blood Tests Can Detect Your Risk 2001a Feb 26.
National Kidney Foundation.
New York: National Kidney Foundation (www.kidney.org).
Nutrition and Chronic Kidney Disease 2001b.
National Kidney Foundation.
New York: National Kidney Foundation.
Phosphorous and Renal Diet 2001c.
National Kidney Foundation.
New York: National Kidney Foundation.
Potassium and Renal Diet 2001d.
National Kidney Foundation.
New York: National Kidney Foundation.
Vitamins and Minerals in Kidney Disease 2001e.
National Kidney Foundation.
New York: National Kidney Foundation.
What Are Kidney Stones? 1998.
National Kidney and Urologic Diseases Information Clearinghouse.
Bethesda, MD: National Kidney and Urologic Diseases Information Clearinghouse/ National Institute of Diabetes & Digestive & Kidney Diseases.
Urinary protein excretion and serum tumor necrosis factor in diabetic patients
with advanced renal failure: effects of pentoxifylline administration.
Navarro JF, Mora C, Rivero A, Gallego E, Chahin J, Macia M, Mendez ML, Garcia J.
Department of Nephrology, Hospital Ntra. Sra. de Candelaria, Santa Cruz de
Tenerife, Spain. jgperez@arrakis.es
Am J Kidney Dis. 1999 Mar;33(3):458-63.
In 24 diabetic patients with advanced renal failure (creatinine clearance [C(Cr)] < 35 mL/min), we prospectively studied serum tumor necrosis factor-alpha (TNF-alpha) levels, the possible relationship with urinary protein excretion, and the effects of pentoxifylline (PTF) administration. PTF (400 mg daily) was administered for 6 months to 14 patients, and the results were compared with data from a control group (n = 10). Baseline parameters were similar in both groups. At the end of the study, urinary protein excretion and serum TNF-alpha decreased in the active group from 2.7 (1.2 to 5.8) g/d and 569 +/- 285 pg/mL to 1.1 (0.3 to 4.0) g/d and 329 +/- 232 pg/mL, respectively (P < 0.001). By
contrast, proteinuria and TNF-alpha did not change in the control group. Regression analysis showed a significant correlation between proteinuria and serum TNF-alpha both at basal (r = 0.55) and at the sixth month (r = 0.57). Furthermore, the reduction of urinary protein excretion was strongly correlated with the decrease of TNF-alpha (r = 0.72, P < 0.01). Serum Cr and C(Cr) remained stable in both groups during the study. Our findings suggest that cytokines might play a role in renal damage in diabetic nephropathy. PTF is effective in reducing proteinuria in diabetic patients with advanced renal failure. The anticytokine activity of PTF may be a further explanation for this antiproteinuric effect.
Effects of pentoxifylline on the haematologic status in anaemic patients with advanced renal failure.
Navarro JF, Mora C, Garcia J, Rivero A, Macia M, Gallego E, Mendez ML, Chahin J.
Department of Nephrology, Hospital Ntra. Sra. de Candelaria, Santa Cruz de
Tenerife, Spain.
Scand J Urol Nephrol. 1999 Apr;33(2):121-5.
OBJECTIVE: Erythropoietin (EPO) deficiency is the main cause of renal anaemia. However, inhibition of erythropoiesis by cytokines such as tumour necrosis factor alpha (TNF-a) may play an important role. The aim of this work was to study the effects of pentoxifylline, an agent with anti-TNF-a properties, on the haematologic status in anaemic patients with advanced renal failure.
MATERIAL AND METHODS: In a prospective study, 7 anaemic patients with advanced renal disease (creatinine clearance <30 ml/min) were treated with pentoxifylline (400 mg orally daily) for 6 months. The evolution of haemoglobin, haematocrit, creatinine clearance and serum EPO and TNF-a a concentrations were compared with those obtained from an untreated control group.
RESULTS: Haemoglobin and haematocrit significantly increased in the pentoxifylline-treated patients (9.9+/-0.5 g/dl and 27.9+/-1.6% at baseline; 10.6+/-0.6 g/dl and 31.3+/-1.9% at the 6th month, respectively, p < 0.01), whereas no variation was seen in the control group. Serum EPO levels remained stable in all patients. However, the serum TNF-a concentration decreased significantly in patients receiving pentoxifylline (basal 623+/-366 pg/ml; 6th month 562+/-358 pg/ml, p < 0.01), but not in the control group.
CONCLUSIONS: Our findings suggest that the inhibition of erythropoiesis by cytokines may play a significant role in renal anaemia. The administration of agents with anti-cytokine properties, such as pentoxifylline, can improve the haematologic status in anaemic patients with advanced renal failure. |