Age-related Decline In Renal Function Research Articles

Post-mortem toxicology in the elderly

Thearticle by Professor Byard on the ‘‘post-mortem toxicology in the elderly’’ provides timely advice on the substantial difficulties encountered in the interpretation of toxicology results in this population [1]. Aging in humans results in gradual deterioration of organ function; and particularly important when dealing with the pharmacokinetics of drugs are the heart, liver and kidney. These changes mainly affect protein binding, drug clearance and distribution; all of which may increase the sensitivity to drugs in the elderly, and in some require the use of smaller doses. However, these changes do not occur suddenly at age 65, but occur gradually, and importantly, vary significantly from one person to another. For example, in a study by Shi and Klotz one-third of elderly persons showed no decrease in renal function while in about twothirds of elderly subjects the age-related decline of renal function was associated with coexisting cardiovascular diseases and other risk factors [2]. Co-morbidity is a significant factor, if not for the effect of the diseases on drug clearance and associated clinical effects, but for the presence of a number of drugs that increase the risk of adverse effects [3]. As Prof Byard rightly points out, underlying disease will be higher in this age group, but it will be very difficult, if not impossible in most cases, to differentially separate out disease as a cause of death from drugs which have the potential (at least) to contribute to sudden death. One of the more common examples is the presence of morphine (or other opioids) in a person with terminal disease (e.g., cancer) when one or more critical organ is affected. Any concentration can be toxic depending on the established tolerance and the circumstances. While pharmacokinetic (and other) changes with age may have occurred the development of tolerance will be a far bigger factor. Unfortunately this cannot be assessed from a blood (or tissue) concentration. As with all deceased persons, young or old, the availability of relevant medical information such as dose information and vital signs such as blood pressure, pulse, breathing rate, oxygen tension are required to establish if any impending opioid toxicity was developing. This information may be available in a hospital death, but would rarely all be available in other settings. In the elderly a large inter-individual variability in drug disposition is particularly prominent [2] however this is not unique to the older population since most drugs show only a poor correlation with blood concentration and pharmacological effect. Hence it will always be difficult to ascertain what a particular concentration means, particularly if it has also changed in concentration after death [4]. These post-mortem changes are dynamic, with concentrations increasing and then decreasing as the post-mortem intervals increase, as typified by the antipsychotics [5]. While the elderly provide more difficulties in the interpretation of post-mortem toxicology results, the interpretation of drug concentrations in deceased persons provide great difficulties at all ages and as usual require a thorough appraisal of available information.

Dabigatran-Induced Gastrointestinal Bleeding in an Elderly Patient with Moderate Renal Impairment

To report a case of dabigatran-induced overanticoagulation in a patient who developed acute renal failure and to inform health care providers of the need for appropriate patient selection and periodic monitoring of renal function in the elderly. A 66-year-old woman treated with dabigatran for atrial fibrillation developed acute renal failure and upper gastrointestinal bleeding. She had been taking dabigatran 150 mg twice daily for 2 months, with intermittent renal insufficiency during the previous 6 months. On admission, laboratory values included serum creatinine 3.6 mg/dL, hematocrit 21%, and international normalized ratio greater than 10. She was treated with packed red blood cells, prothrombin complex concentrate, and multiple sessions of dialysis. There were no further bleeding events or additional transfusions for the remainder of the hospitalization. Her renal function never recovered and she remained hemodialysis-dependent. After a 47-day length of stay, she was transferred to a nursing home where she died 2 months later. Renally eliminated drugs such as dabigatran place elderly patients at increased risk of drug accumulation and adverse drug events due to age-related decline in renal function. In a recent case series, dabigatran toxicity in the elderly with renal impairment was described with 1 fatal outcome. Recent literature, including the package insert, advises intermittent monitoring of renal function in the elderly and those with moderate renal impairment. Consideration should also include the appropriateness of dabigatran therapy in patients with fluctuating renal function. In our patient, the Naranjo probability scale indicated a probable cause between the bleeding event and dabigatran use. Our case report, along with 2 other recent reports on dabigatran toxicity, illustrates the importance for appropriate patient selection and the need to periodically monitor renal function in elderly patients receiving dabigatran.

Incretin Therapies in the Management of Patients with Type 2 Diabetes Mellitus and Renal Impairment

Renal impairment (RI) is common among patients with type 2 diabetes mellitus (T2DM), and these patients also experience an age-related decline in renal function. At the same time, treatment options are more limited and treatment is more complex, particularly in patients with moderate or severe RI due to contraindications, need for dose adjustment and/or regular monitoring, and side effects, such as fluid retention and hypoglycemia, which are a more serious concern in this patient population. Incretin therapies, consisting of the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are a promising new class of antihyperglycemic drugs. In the overall population, they improve glycemic control in a glucose-dependent manner and are not likely to cause hypoglycemia, representing a clear advantage in at-risk populations. Data regarding use of these agents in renally impaired patients have started to emerge, and the objective of this article is to provide an overview of the currently available data and the potential role of these novel agents in the management of patients with T2DM and RI. Data for the GLP-1 receptor agonists in patients with moderate or severe RI are still limited, with no trials dedicated to these populations currently published. In addition, their potential to cause gastrointestinal side effects may limit use in patients with RI due to the risk of dehydration and hypovolemia. The use of GLP-1 receptor agonists in patients with moderate or severe RI is therefore, at present, underlying caution and/or restrictions. On the other hand, data from specific trials in patients with moderate or severe RI are now becoming available for most of the DPP-4 inhibitors. These studies demonstrate good efficacy and tolerability of the DPP-4 inhibitors in patients with moderate or severe RI, thus opening a place for these therapies in the treatment of populations with T2DM and RI. Several of the DPP-4 inhibitors are already approved for use in patients with moderate or severe RI, including for those with end-stage renal disease. While discussing the advantages related to their common mechanism of action, this article also describes differences among the DPP-4 inhibitors (eg, related to their pharmacokinetic properties and the available clinical data). In conclusion, while initial data for these new therapies are promising, further experience is needed to fully assess the risk-benefit balance and clinical positioning of these agents in RI populations.

Age-Related Changes in Pharmacokinetics

Ageing is characterized by a progressive decline in the functional reserve of multiple organs and systems, which can influence drug disposition. In addition, comorbidity and polypharmacy are highly prevalent in the elderly. As ageing is associated with some reduction in first-pass metabolism, bioavailability of a few drugs can be increased. With ageing body fat increases and total body water as well as lean body mass decrease. Consequently, hydrophilic drugs have a smaller apparent volume of distribution (V) and lipophilic drugs have an increased V with a prolonged half-life. Drugs with a high hepatic extraction ratio display some age-related decrease in systemic clearance (CL), but for most drugs with a low hepatic extraction ratio, CL is not reduced with advancing age. In general, activities of cytochrome P450 enzymes are preserved in normal ageing and the genetic influence is much more striking than age effects. Drug transporters play an important role in pharmacokinetic processes, but their function and pharmacology have not yet been fully examined for agerelated effects. One third of elderly persons show no decrease in renal function (GFR > 70 mL/min/1.73 m2). In about two thirds of elderly subjects, the age-related decline of renal function was associated with coexisting cardiovascular diseases and other risk factors. In the elderly a large interindividual variability in drug disposition is particularly prominent. In conclusion, the complexity of interactions between comorbidity, polypharmacy, and age-related changes in pharmacokinetics (and pharmacodynamics) justify the old and well-known dosing aphorism " start low, go slow" for aged individuals.

Should Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) be Prescribed to the Older Adult?

The prevalence of chronic pain increases with age, exceeding 50% in individuals aged ≥65 years. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay of chronic pain management but carry significant dose-related risks of cardiovascular, renal, haematological and other systemic adverse events (AEs). Older patients have an increased risk of these AEs and are more likely to take multiple medications that can potentially interact with NSAIDs. In particular, older patients are more likely to have cardiovascular disease and a natural age-related decline in renal function, increasing the risks of cardiovascular, haematological and renal AEs. Given these risks, recent guidelines for the management of chronic pain in the elderly recommend using NSAIDs rarely and only in carefully selected patients. NSAIDs currently available in the US fall into three categories: nonselective NSAIDs that act via inhibition of cyclo-oxygenase (COX)-1 and COX-2; celecoxib, a selective inhibitor of COX-2; and topical NSAIDs that inhibit both COX-1 and COX-2 but result in much less systemic NSAID exposure than oral formulations. Topical NSAIDs have demonstrated efficacy similar to oral NSAIDs, with an incidence of AEs similar to placebo; however, these agents are an option only in patients with localized pain in superficial joints. Safe pain management in older patients therefore requires cautious choice of selective and nonselective oral NSAIDs, topical NSAIDs or non-NSAID analgesics. This article discusses the risks and benefits of NSAID therapy, reviews its mechanism of action as the source of adverse effects and provides recommendations for maximizing NSAID safety, particularly in older patients. Articles cited in this review were identified via a search of PubMed (January 2005 to November 2009) and a manual search of reference lists from the articles identified in that search. Priority was given to articles discussing NSAID use in older populations, clinical trials of high quality, reports on NSAID safety and AEs, and treatment guidelines.

SIRTing out the link between autophagy and ageing

Population-based studies of chronic kidney disease (CKD) paint a dismal picture. A recently conducted overview of 26 different studies of diverse populations concluded that the median prevalence of CKD was 7.2% in persons aged 30 years and older; in those aged 64 and older, the prevalence ranged from 23.4 to 35.8% [1]. In conglomerate, these data indicate not only the high prevalence of CKD in the general population but also emphasize the sharp increase in CKD among the ageing population—truly a major health care problem.

Low cardiopulmonary bypass perfusion temperatures are associated with acute kidney injury following coronary artery bypass surgery

Acute kidney injury (AKI) is a common complication after coronary artery bypass surgery (CABG). The role of hypothermia in postoperative renal function remains controversial. We set out to examine the effect of varying cardiopulmonary bypass (CPB) temperatures on early postoperative renal function. Patients undergoing first-time CABG between 2002 and 2006 and without evidence of preoperative renal insufficiency (estimated creatinine clearance >or=50 ml min(-1), calculated by the Cockcroft-Gault formula) were studied. Medical history and intra-operative variables, including lowest nasopharyngeal and arterial CPB perfusion temperatures, were collected prospectively. Primary endpoint was the development of early postoperative AKI (defined as creatinine clearance <50 ml min(-1)), which was assessed using multivariate and propensity score analyses. This study included 1072 patients. AKI occurred in 175 (16%). Univariate analysis demonstrated that lower arterial CPB perfusion temperatures, and not nasopharyngeal ones, were significantly associated with renal dysfunction following CABG. Multivariate regression analysis identified reduced arterial perfusion temperature as an independent risk factor for AKI (odds ratio (OR) 0.92, 95% confidence interval (CI): 0.86-0.98, p=0.012), along with age (OR 1.07, 95% CI: 1.04-1.10, p<0.001) and depressed preoperative creatinine clearance (OR 0.89, 95% CI: 0.87-0.91, p<0.001). Propensity score adjustment confirmed that lower CPB perfusion temperatures (<27 degrees C) were associated with postoperative AKI (OR 1.66, 95% CI: 1.16-2.39, p=0.0056). Lower CPB perfusion temperatures are significantly associated with AKI following CABG. In addition to the known age-related decline in renal function, it appears that hypothermia may contribute to renal injury during cardiac surgery.

Development of cardiovascular disease due to renal insufficiency in male sheep following fetal unilateral nephrectomy

Renal insufficiency is associated with the development of cardiovascular disease. This study investigated whether reduced fetal renal mass resulted in renal insufficiency, hypertension, cardiac dysfunction and whether these changes progressed with age. Fetal uninephrectomy was performed at 100-day gestation (term, 150 days) and studies performed in male sheep from 6 weeks to 24 months of age. Renal function declined with age in sham animals as demonstrated by increasing plasma creatinine levels and urinary excretion of albumin. The age-related decline in renal function was exacerbated in animals that had undergone fetal uninephrectomy. Evidence of renal insufficiency was indicated from as early as 6 weeks of age with elevations in plasma creatinine (Ptreatment < 0.001), urea (Ptreatment < 0.001) and sodium (Ptreatment < 0.05) levels in uninephrectomized lambs as compared with sham animals. At 6 months, urinary albumin excretion (P < 0.001) was increased and urinary sodium excretion (P < 0.001) decreased in the uninephrectomized animals. By 24 months, renal function had deteriorated further with significant progression of albuminuria (P(treatment x age) < 0.001). Elevation of mean arterial pressure (approximately 15 mmHg) was associated with significantly increased cardiac output, stroke volume and plasma volume at 6 months; arterial pressure (approximately 27 mmHg) had increased further in uninephrectomized animals at 24 months and was driven by increased total peripheral resistance. Cardiac functional reserve (dobutamine challenge) was reduced in uninephrectomized animals at 6 and 24 months of age (Ptreatment < 0.001), and this was associated with left ventricular enlargement (P < 0.001) and reduced fractional shortening (P < 0.01). Fetal uninephrectomy causing a reduction in nephron endowment results in an accelerated age-related decline in renal function. This is associated with an early onset of elevated blood pressure and impairments in cardiac structure and function.

Nephrology Potpourri

Background: Oral sodium phosphate solution (OSPS) preparations are preferred cleansing agents for colonoscopy because of ease of use and excellent preparation quality. Besides causing acute renal failure in some patients, the high phosphorus content can potentially cause chronic kidney damage to patients undergoing colonoscopy. Methods: We carried out a retrospective study on patients with creatinine levels in the normal range who had undergone colonoscopy or flexible sigmoidoscopy using OSPS preparation from January 1998 to February 2005 and followed them for 1 year to determine its effects on their renal function. A control group of patients with similar comorbidities during this period were chosen to assess agerelated decline in renal function in this population. Results: A total of 286 patients were selected in the study group, and 125 patients were selected in the control group. Both groups had similar baseline characteristics. The baseline glomerular filtration rate (GFR) in the study group was 79 mL/min/1.73 m 2 , which declined to 73 mL/min/ 1.73 m 2 at 6 months after exposure to OSPS preparation. This finding was significantly different from the control group, in whom the baseline GFR was 76 mL/min/ 1.73 m 2 and remained stable at 6 months. Linear regression analysis showed that use of angiotensinconverting enzyme inhibitors and/or angiotensin receptor blockers and the presence of diabetes were significant determinants of the fall in GFR after use of OSPS preparation. Conclusions: Oral sodium phosphate solution preparation is associated with decline in GFR in elderly patients with creatinine levels in the normal range. Its routine use for elective and screening procedures should be discouraged in the elderly population. Arch Intern Med. 2008;168(6):593-597

The Effect of Oral Sodium Phosphate Drug Products on Renal Function in Adults Undergoing Bowel Endoscopy

Oral sodium phosphate solution (OSPS) preparations are preferred cleansing agents for colonoscopy because of ease of use and excellent preparation quality. Besides causing acute renal failure in some patients, the high phosphorus content can potentially cause chronic kidney damage to patients undergoing colonoscopy. We carried out a retrospective study on patients with creatinine levels in the normal range who had undergone colonoscopy or flexible sigmoidoscopy using OSPS preparation from January 1998 to February 2005 and followed them for 1 year to determine its effects on their renal function. A control group of patients with similar comorbidities during this period were chosen to assess age-related decline in renal function in this population. A total of 286 patients were selected in the study group, and 125 patients were selected in the control group. Both groups had similar baseline characteristics. The baseline glomerular filtration rate (GFR) in the study group was 79 mL/min/1.73 m(2), which declined to 73 mL/min/1.73 m(2) at 6 months after exposure to OSPS preparation. This finding was significantly different from the control group, in whom the baseline GFR was 76 mL/min/1.73 m(2) and remained stable at 6 months. Linear regression analysis showed that use of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers and the presence of diabetes were significant determinants of the fall in GFR after use of OSPS preparation. Oral sodium phosphate solution preparation is associated with decline in GFR in elderly patients with creatinine levels in the normal range. Its routine use for elective and screening procedures should be discouraged in the elderly population.

Exercise Stimulates Transcription Factors (Nrf2 &amp; NFkB), Increases Antioxidant Defenses, Decreases Oxidative Stress, and Restores Renal Dopamine D1 Receptor Function in Aging

We reported that oxidative stress associated with aging contributes to diminished natriuretic response to dopamine in old (24‐month) Fischer 344 rats. Here, we explored whether 3‐month exercise in old rats reduces oxidative stress and restores natriuretic response to D1 receptor activation. In old rats, 3‐month treadmill exercise decreased oxidative stress marker malondialdehyde in renal proximal tubules (RPTs) compared to sedentary controls. In the exercised animals, western blotting analyses showed an increase in the expression of antioxidant enzymes, hemeoxygenase 1 and superoxide dismutase. Moreover, nuclear expression of transcription factors, NFkB and Nrf2, was higher in exercised compared to sedentary rats. Electrophoretic mobility shift assay (EMSA) showed an increased nuclear NFkB‐DNA binding in exercised rats. Also, exercise improved D1 receptor expression as evidenced by increased receptor protein content and receptor numbers and restored D1 receptor agonist (SKF 38393) induced natriuresis and diuresis compared to controls. These results suggest that long‐term exercise increases antioxidant defenses involving NFkB and Nrf2 in RPTs, which contributes to decrease in oxidative stress and restores D1 receptor function in old rats. We conclude that exercise as an intervention may be beneficial in attenuating age‐related decline in renal function. [NIH/NIA, AG25056 funded the study].

Sex Steroids and Renal Disease

Epidemiological studies have shown that male sex is an independent risk factor for the development and progression of renal disease, and men progress to end stage renal disease (ESRD) faster than premenopausal women in such diseases as autoimmune glomerulonephritis, hypertensive glomerulosclerosis, and polycystic kidney disease.1–3 Although the age-related decline in renal function is also faster in men, women become more susceptible to renal diseases after menopause.4 Insight from in vitro studies and animal models suggest that sex steroids play pivotal roles in modifying the progression to ESRD. Because there is a paucity of data in humans showing the mechanisms by which sex steroids impact renal disease, most of the studies discussed this review will be in animals, mainly rats. Furthermore, determining the roles of sex steroids in various diseases has been done using gonedectomized animals; however, although gonadectomy removes more than sex steroids and most studies only replace the sex steroid of interest, these are still the best studies in which to evaluate mechanisms responsible for sex differences in renal disease. Studies in postmenopausal women will also be kept to a minimum in this review because it is likely that sex steroids change action with aging, as suggested by the Women’s Health Initiative study. Estrogen receptors (ER) are present in the kidney, although their localization in nephron segments has not been fully elucidated. Mesangial cells contain both ERα and ERβ,5 as do endothelium and vascular smooth muscle cells.5–7 Whether the newly described transmembrane estrogen receptor, GPR30,8 is present in kidneys has not been determined. Ovariectomy (ovx) of Dahl salt sensitive rats (DS) caused decreases in ERα but increases in ERβ expression in the renal cortex and medulla,9 whereas ovx in salt resistant (DR) rats caused decreases in cortical and increases in medullary ERα, and …

Fasting insulin modifies the relation between age and renal function

The worldwide increase in end-stage renal disease has been alleged to be associated with insulin resistance-related conditions. Insulin resistance and the concomitant compensatory hyperinsulinaemia may accelerate age-related decline in renal function through inducing glomerular hyperfiltration, even in non-diabetic subjects. This population-based study is the first to investigate whether fasting insulin concentrations modify the relationship between age and renal function in a general non-diabetic population. Fasting insulin was measured in 3432 subjects, representing the general population. Cross-sectional analyses of the association between age, renal function and its modification by insulin were performed by means of linear regression. Renal function was assessed as 24-h creatinine clearance (CrCl) and 24-h urinary albumine excretion (UAE). Age was 48 +/- 12 (range: 28-75) years, 44% were male, CrCl was 100 +/- 26 ml/min and UAE was 7.0 (5.4-10.7)] mg/24 h. The results confirmed a parabolic relation between age and renal function. Fasting insulin modified these parabolic relationships of age with CrCl and UAE (P < 0.001 for both interaction terms), in such a way that hyperinsulinaemia is associated with a stronger inverse parabolic relation between age and CrCl, and stronger positive parabolic relation between age and UAE at an older age than lower insulin concentrations. Our results are consistent with the hypothesis that insulin accelerates the age-related decline of renal function in the general non-diabetic population. This indicates that insulin resistance, and the concomitant compensatory hyperinsulinaemia could contribute to the increased incidence in end-stage renal disease.

Gonadal steroids, salt-sensitivity and renal function

The aim of this article is to discuss the impact of male and female sex hormones on renal function and to develop the concept that salt-sensitivity of renal function behaves independently of the systemic blood pressure response to salt and may contribute to renal sex-specific differences. Men exhibit a more rapid age-related decline in renal function than women and some renal diseases are clearly sex dependent. Recent studies have shown that gonadal steroids have an important influence on sodium handling and renal hemodynamics that may offer a key for understanding the sexual dimorphism of the renal function. It has been found that androgens increase proximal sodium reabsorption and intraglomerular pressure by modulating afferent and efferent arteriolar tonus via angiotensin II, endothelin and oxidative stress. In contrast, female sex hormones lead to a renal vasodilation and decrease filtration fraction. Some newly discovered mechanisms triggering the salt-sensitivity of the renal function and the interaction between gonadal steroids and components of the renin cascade may play an important role in the dimorphism of renal response to salt.

Pharmacokinetics of Oseltamivir in Young and Very Elderly Subjects

Pharmacokinetic studies of oseltamivir in very elderly patients (> or = 80 y) have not previously been performed. To compare the pharmacokinetics of oseltamivir and the active carboxylate metabolite in healthy young and very elderly Japanese subjects. Young (20-35 y, fasting, n = 7) and very elderly subjects (> or = 80 y, fed, n = 5) were enrolled in single-center studies and received a single oral dose of oseltamivir 75 mg. Plasma and urine samples were collected (24 h) for pharmacokinetic analysis, and safety was assessed. The time to maximum plasma concentration (tmax) for oseltamivir was delayed in the very elderly compared with the young subjects (2.30 vs 0.71 h, respectively). Furthermore, oseltamivir maximum plasma concentration (Cmax) and AUC(inf) were 52% and 80% higher, respectively, in the very elderly compared with the young subjects. Oral clearance was 45% lower in elderly patients, possibly due to the effects of administration of oseltamivir with a meal. For the active metabolite, oseltamivir carboxylate, Cmax and AUC(inf) values were, respectively, 22% and 91% higher in the very elderly subjects than in the young subjects, while oral clearance was 50% lower in the elderly population. The increased exposure of the active metabolite is likely to correlate with an age-related decline in renal function. For both oseltamivir and the active metabolite, there was large interpatient variability in the Cmax values. The data reported here indicate that oseltamivir would be effective in both of these populations, as trough concentrations for the active metabolite at 12 and 24 hours exceeded the 50% inhibitory concentration against the neuraminidase of influenza A and B isolates by more than 50-fold. Oseltamivir was well tolerated in both groups. Exposures (AUC(inf)) to both the parent drug and active metabolite were increased by more than 80% in the small number of very elderly subjects presented here. However, oseltamivir was well tolerated by these subjects.

Good News and Bad News: Blood Lead Levels in the US Go Down, but Higher Levels Are Still Associated with a Higher Burden of CKD: Continued Decline in Blood Lead Levels among Adults in the United States: The National Health and Nutrition Examination Survey. Arch Intern Med 165: 2155-2161, 2005.

Good News and Bad News: Blood Lead Levels in the US Go Down, but Higher Levels Are Still Associated with a Higher Burden of CKD: Continued Decline in Blood Lead Levels among Adults in the United States: The National Health and Nutrition Examination Survey. Arch Intern Med 165: 2155-2161, 2005.

Renal Function, Erythropoietin, and Anemia of Older Persons

In the older population, anemia has been associated with poor outcomes including disability and mortality. Understanding the mechanisms leading to anemia is essential to plan better treatment and prevention strategies. We tested the hypothesis that the age-related decline in kidney function is associated with an increased prevalence of anemia and that such an increase is accompanied by a concomitant decrement in erythropoietin levels. Data were from the InCHIANTI study, a population-based study performed in a sample of community-dwelling older (> or = 65 years) persons living in Italy. This analysis included 1005 participants with complete data on hemoglobin and erythropoietin levels and markers of renal function. The prevalence of anemia according to the World Health Organization criteria (hemoglobin level < 12 g/dL for women and < 13 g/dL for men) was 12.0% and increased with age in both sexes. After adjusting for age, diseases, and other confounders, only participants with a creatinine clearance (CrCl) of 30 mL/min or lower (< or = 0.50 mL/s) had a higher prevalence of anemia compared with those with a CrCl higher than 90 mL/min (> 1.50 mL/s) (P<.01). Consistently, participants with a CrCl of 30 mL/min or lower (< or = 0.50 mL/s) had significantly lower age- and hemoglobin-adjusted erythropoietin endogenous levels. After excluding men and women with CrCl of 30 mL/min or lower (< or = 0.50 mL/s) and adjusting for confounders, we found a trend toward an increase in prevalence of anemia with decreasing renal function; however, it was not statistically significant. Severe age-related decline in renal function is associated with a reduced erythropoietin secretion and anemia. Whether moderate kidney impairment in older persons is associated with a progressively increasing risk of anemia remains to be determined.

Reduced alpha adrenergic mediated contraction of renal preglomerular blood vessels as a function of gender and aging

As human males age, a decline in baroreflex-mediated elevation of blood pressure occurs due, at least in part, to a reduction in alpha-1 adrenergic vasoconstrictor function. Alpha adrenergic constriction is mediated by guanosine triphosphate binding Protein (G Protein) coupled signaling pathways. Alpha-1 A/C, B, and D adrenergic receptor expressions, measured by GeneChip array, are not reduced during aging in renal blood vessels of male or female rats. Alpha-1 A GeneChip expression is greater, at all ages studied, in females than in males. Prazosin binding by alpha-1 adrenergic receptors is greater in young adult female rats than in young adult male rats; however, it is reduced with aging in both male and female rats. G alpha q GeneChip expression declines while expression of adrenergic receptor kinase (GRK2) and tyrosine phosphatases (TyrP) increase with aging in male rats. The declines in alpha-1 adrenergic receptor binding and G alpha q expression and also the increases in GRK2 and TyrP expression likely relate to the age-related decline of vasoconstriction in male rats. The information that the expression of alpha-1 A adrenergic receptors is greater in female rats and (GRK2) expression does not increase during aging could relate to the gender differences in vasoconstrictor function with aging. Gene therapy to ameliorate the age-related decline in renal function could possibly reduce the need for renal dialysis. Signaling pathways such as those reviewed herein may provide an outline of the molecular pathways needed to move toward successful renal gene therapy for aging individuals.

Effects of chronic chromium picolinate treatment in uninephrectomized rat

Chromium picolinate [Cr(pic)3] is a nutritional supplement that is advocated as an adjuvant therapy for impaired glucose tolerance/type 2 diabetes because it improves glucose homeostasis. Because renal dysfunction is a major complication of type 2 diabetes, the potential impact of Cr(pic)3 on kidney function requires due consideration. This investigation takes added importance because the kidney is not only the principal route of elimination for chromium but also an organ that preferentially accumulates it. To avoid the confounding influence of chronic hyperglycemia, and its associated complications, we used the unilaterally nephrectomized (UNX) rat that shows impaired kidney function with age. We tested the hypothesis that chronic treatment of the UNX rat with Cr(pic)3 exacerbates the age-related decline in renal function. Accordingly, UNX rats were fed a diet lacking (eg, control; n = 5) or containing 5 mg/kg of Cr(pic)3 (n = 7) for 60 days. The treatment did not affect glucose tolerance as reflected by lack of any effect on changes in blood glucose concentration during glucose tolerance testing. Although nonfasting blood glucose concentrations were similar between the 2 groups, plasma insulin concentration was lower in the Cr(pic)3-treated group ( P < .05), suggesting improved insulin sensitivity. Body weight, blood pressure, heart rate, daily food and fluid consumption, daily urinary fluid and electrolyte excretions, urine osmolality, and daily protein excretion were similar between the 2 groups before and during Cr(pic)3 treatment. Although renal excretory responses to acute administration of a 5% isotonic saline volume load were similar between the 2 groups, the Cr(pic)3-treated group displayed a more robust ability to excrete a 10% isotonic saline volume load, an effect primarily related to reduced tubular reabsorption of the filtered fluid and sodium loads. In conclusion, chronic Cr(pic)3 did not adversely affect renal function. Rather, the treatment improved the ability of the animal to dispose of an acute isotonic saline volume load, suggesting preservation of renal function in the UNX rat.

Selecting Nonprescription Analgesics

Worldwide, there has been an emerging patient demand for access to efficient drugs without consulting a doctor and obtaining a prescription. As a result, there has been an expanding movement of prescription-only drugs to over-the-counter (OTC) status. An increasing number of drugs are becoming available OTC, empowering patients to treat themselves. Where the principle of empowering individuals to treat themselves can fail is when consumers lack the knowledge to do so safely. This potentially applies to the self-selection of analgesic drugs by consumers. When used inappropriately, these drugs pose significant risks. The nonsteroidal antiinflammatory drugs (NSAIDs) are associated with many adverse reactions, interactions, and contraindications in a number of patient groups, even at OTC doses. In particular, in the elderly, the high incidence of cardiovascular and gastrointestinal disease, coupled with age-related decline in renal function and multiple medication use, all warrant extra caution with the use of NSAIDs and make paracetamol the simple analgesic drug of first choice. Despite the possibility of hepatotoxicity in overdose, paracetamol represents a better all-round option for most patients requiring OTC analgesic therapy.