Is Kt/V useful in elderly dialysis patients? Pro and Con arguments.

Current guidelines for dialysis specify a minimum Kt/V. For haemodialysis (HD) patients, minimum treatment time and frequency is also specified. The guidelines allow for modification to take account of renal function. The guidelines are not specifically aimed at the elderly and may not be appropriate for all patients in this group. Increasing age is accompanied by physiological and pathological changes that may modify the patient's response to uraemia and dialysis. Frailty and multi-morbidity are likely, but to a variable extent. Elderly patients could be more susceptible to the effects of uraemia and require a higher dose of dialysis. Conversely, the generation rate of uraemic toxins is lower in elderly patients, potentially reducing the need for dialysis. In the elderly, quality of life may be more adversely affected by multimorbidity than uraemic symptoms, thus the dose of dialysis may be less relevant. Higher doses of dialysis may be more difficult to achieve in the elderly and may be less well tolerated. We conclude that the prescription of dialysis in the elderly should be individualized, taking multiple factors into account. An individualized Kt/V may be useful in controlling dialysis dose and detecting problems in delivery. However, achievement of a specified Kt/V may not result in any benefit to an elderly patient and could be counterproductive.

Glomerular filtration rate equations: a comprehensive review.

Since evaluation of glomerular filtration rate (GFR) is very important in daily medical care, and reliable methods for measuring GFR are too complicated, there has been along decades an enormous effort for developing accurate GFR equations. In the present review article, we performed a comprehensive analysis of the mainly described GFR equations, and we concluded that although MDRD, CKD-EPI, DRA and Gregori-Macías equations are valid to monitor renal function as well as to stage and follow up renal patients, the clinical nephrological evaluation still remains the best alternative for diagnosing renal health and disease.

Priority topics for European multidisciplinary guidelines on the management of chronic kidney disease in older adults.

PURPOSE: To identify and prioritize potential topics to be addressed in the development of European multidisciplinary guidelines on the management of chronic kidney disease stage 3b-5 in older patients. METHODS: We composed a list of 47 potential guideline topics by reviewing the literature, consulting online 461 nephrologists and 107 geriatricians, and obtaining expert input. A multidisciplinary panel of twelve experts then prioritized the topics during a face-to-face consensus meeting, following a nominal group technique structure with two voting rounds. Topics were rated on a 9-point scale ranging from 1 ('not at all important') to 9 ('critically important'). RESULTS: The highest rating (median; range) was assigned to 'Screening and referral' (8.5; 2.0). Eight topics shared the second highest rating with a median priority score of 8.0 (2.0) and included 'Starting dialysis or not' and 'Accurate assessment of renal function.' 'Targets for and treatment of diabetes' received the lowest rating with (3.0; 6.0). CONCLUSIONS: This joint initiative of the European Renal Association-European Dialysis Transplant Association (ERA-EDTA) and the European Union Geriatric Medicine Society (EUGMS) prioritized the development of guidance on interdisciplinary referral of older patients with chronic kidney disease stage 3b-5. Future guidance will therefore focus on identifying prognostic scores to predict death and progression to end-stage renal disease, as well as accurate tests for assessment of renal function in older kidney patients. This will contribute to more informed treatment decision making in this growing patient population.

A New Method for Individualized Digoxin Dosing in Elderly Patients.

BACKGROUND: Digoxin is a frequently prescribed drug in the elderly population. Estimated glomerular filtration rate is widely used to adjust dosages. The HUGE value is a tool for differentiating the presence or absence of chronic kidney disease in elderly patients. We aimed to investigate the usefulness of the HUGE value to predict the initial dose of digoxin in patients aged older than 70 years. METHODS: We reviewed retrospectively the medical records of patients aged older than 70 years with serum digoxin concentrations (SDCs) monitored over a 6-month period (63 patients). A linear regression relating the patient's SDC, maintenance dose of digoxin and the HUGE value was estimated to generate a dosage equation. This equation was validated retrospectively (33 patients) and prospectively (35 patients) in comparison with two existing methods based on creatinine clearance. RESULTS: An equation (HUGE_DIG) was generated to calculate the initial digoxin dose to reach a specific target SDC. Thus, to achieve a SDC of 0.8 ng/mL: Digoxin (mg/day) = 0.091 - 0.006 x HUGE. After retrospective validation, the calculated digoxin doses with this equation were administered in the prospective phase and we did not observe statistical differences between measured and desired SDCs. Moreover, the predictive performance of our equation was better than that obtained with the compared methods. CONCLUSIONS: We offer a new validated digoxin dosing equation for elderly patients. Our results support the need to perform digoxin dosing in elderly people, bearing in mind the changes in renal physiology secondary to ageing and not merely the estimated glomerular filtration rate.

Frailty phenotype and chronic kidney disease: a review of the literature.

Frailty is a construct originally coined by gerontologists to describe cumulative declines across multiple physiological systems that occur with aging and lead individuals to a state of diminished physiological reserve and increased vulnerability to stressors. Fried et al. provided a standardized definition for frailty, and they created the concept of frailty phenotype which incorporates disturbances across interrelated domains (shrinking, weakness, poor endurance and energy, slowness, and low physical activity level) to indentify old people who are at risk of disability, falls, institutionalization, hospitalization, and premature death. Some authors consider the presence of lean mass reduction (sarcopenia) as part of the frailty phenotype. The frailty status has been documented in 7 % of elderly population and 14 % of not requiring dialysis CKD adult patients. Sarcopenia increases progressively along with loss of renal function in CKD patients and is high in dialysis population. It has been documented that prevalence of frailty in hemodialysis adult patients is around 42 % (35 % in young and 50 % in elderly), having a 2.60-fold higher risk of mortality and 1.43-fold higher number of hospitalization, independent of age, comorbidity, and disability. The Clinical Frailty Scale is the simplest and clinically useful and validated tool for doing a frailty phenotype, while the diagnosis of sarcopenia is based on muscle mass assessment by body imaging techniques, bioimpedance analysis, and muscle strength evaluated with a handheld dynamometer. Frailty treatment can be based on different strategies, such as exercise, nutritional interventions, drugs, vitamins, and antioxidant agents. Finally, palliative care is a very important alternative for very frail and sick patients. In conclusion, since the diagnosis and treatment of frailty and sarcopenia is crucial in geriatrics and all CKD patients, it would be very important to incorporate these evaluations in pre-dialysis, peritoneal dialysis, hemodialysis, and kidney transplant patients in order to detect and consequently treat the frailty phenotype in these groups.

Impact of renal aging on drug therapy.

Elderly patients (age ≥ 65 years old) use up to 30% of all commonly prescribed medication, and they suffer more their adverse effects than the general population. In order to minimize this risk, physicians should avoid polypharmacy, dangerous pharmacological interactions and take into account pharmacodynamic and senile pharmacokinetic changes before prescribing any medication to the elderly. The present review article originally describes how renal physiology changes secondary to aging such as dysautonomia, glomerular filtration rate reduction, tubular back-filtration, sodium, calcium and magnesium loss, potassium retention, altered dilution-concentration capability, tubular frailty, genetics, internal milieu and body composition are senile changes that when combined predispose elderly people to suffer from pharmacological adverse effects. Knowledge of these physiological modifications associated with aging and their impact on the pharmacology of particular drugs may help to optimize drug use and to avoid complications in this age group.

Effects of deferasirox on renal function and renal epithelial cell death.

Iron-chelating therapy results in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelator on the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasirox given daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24h of iron chelator treatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox-chelating therapy seems to be based on direct toxic effects of deferasirox on renal tubular cells.

Dysfunction of the thick loop of Henle and senescence: from molecular biology to clinical geriatrics.

UNLABELLED: The sodium-potassium-2 chloride bumetanide-sensitive transporter (NKCC2), a protein coded by gene SLC12A1, allows salt reabsorption in the thick ascending loop of Henle (TALH). The functional and clinical exploration of the TALH can be carried out using the Chaimowitz's test, which is based on the exploration of the tubular response to an acute overload of a hypotonic sodium chloride solution. Since this segment is normally responsible for the generation of free water clearance, its function can be assessed via the calculation of such clearance from the parameters obtained during this test. By applying the Chaimowitz's test, the presence of incompetence for sodium reabsorption in TALH in healthy old people was documented. Additionally, it was documented that in water-restricted old rats, a situation that normally induces an increase in the number of NKCC2 in young rats is absent in old ones. In the clinical setting, the increased urinary sodium loss usually found in healthy old people predisposes them to dehydration, hypotension and or hyponatremia when they are on low-sodium diet or under treatment with diuretics. These are commonly found in elderly people with geriatric syndromes such as delirium, gait disorders and incontinence. CONCLUSION: The NKCC2 transporter decrease in the thick ascending loop of Henle secondary to the ageing could explain the reduced sodium reabsorption of this segment in the healthy elderly and its potential clinical consequences of dehydration and serum sodium abnormalities.

Evaluation of oxidant-antioxidant balance in patients on maintenance haemodialysis: a comparative study of dialyzers membranes.

BACKGROUND: Haemodialysis (HD) exacerbates oxidative stress (OS). The polymethyl-methacrylate (PMMA)-BK-F membrane ameliorates OS and inflammation markers compared to polyacrylonitrile (PAN/AN69) and cellulose membranes. This may be due to the size of pore radius, high flux or other specific properties of PMMA membranes. AIM: To compare OS and inflammatory status in HD-treated end stage renal disease patients with membranes of different pore size radius and flux. METHODS: 47 patients of both sexes were studied. The HD membranes with which the patients were normally treated were changed to BK-P or B-3 membranes for 6 months. Intracellular and extracellular components of the oxidant-antioxidant balance (OAB), C-reactive protein (CRP), beta2-micro-globulin (beta2mu-globulin), albumin and transferrin were measured. RESULTS: A significant decrease in red cell membrane thiobarbituric acid reacting substances and an increase in cytosolic superoxide dismutase (SOD) and plasma total antioxidant substances were observed in all patients after 6 months of treatment with BK-P and B-3 membranes except SOD and CRP in patients previously dialysed with triacetate cellulose membranes. Albumin and transferrin remained unmodified. beta2mu-globulin significantly decreased after treatment with PMMA membranes. CONCLUSION: BK-P and B-3 HD membranes improved the OAB, beta2mu-globulin and CRP compared to PAN/AN69 and cellulose diacetate membranes.

Creatinine reabsorption by the aged kidney.

AIM: The handling of renal creatinine in human beings has classically been described as the result of two particular physiological processes: glomerular filtration and proximal tubular secretion. However, there are particular physiological situations in which tubular creatinine reabsorption has been documented, such as in the case of healthy newborns and premature babies. We performed a prospective study in order to evaluate if there is tubular creatinine reabsorption in healthy elderly people. PATIENTS AND METHOD: We studied prospectively nine healthy volunteers, four of them young (20-33 years old) and the remaining five, old (65-73 years old). Since creatinine is secreted in the proximal tubules, and its secretion can be completely blocked by cimetidine administration, a creatinine clearance with cimetidine reliably represents the glomerular filtration rate. Therefore, if the ratio creatinine clearance (Ccr)/creatinine clearance with cimetidine (CcrWC) is higher than one, this would indicate net creatinine secretion, whereas a ratio lower than one would indicate a net renal creatinine tubular reabsorption; a ratio equal to one indicates creatinine filtration. Finally, the Ccr, CcrWC, and Ccr/CcrWC ratios were compared between the young and old group. STATISTICAL TESTS: Mann-Whitney and Wilcoxon tests were used. RESULTS: As expected, creatinine clearance in the elderly was significantly lower than in the young [Ccr: 74.4 ml/min (47.9-100.9) (old) vs. 153.8 ml/min (108.3-199.2) (young), p = 0.014]. Similarly, the creatinine clearance with cimetidine (CcrWC) was significantly lower in the elderly compared to the young [CcrWC: 81.8 ml/min (69.2-94.5) (old) vs. 122.5 ml/min (82.6-162.4) (young), p = 0.028]. The ratio of Ccr/CcrWC was 0.9 in the elderly vs. 1.26 in the young (p = 0.014), indicating net creatinine reabsorption in the elderly and net creatinine secretion in the young. CONCLUSION: Our findings indicate that there seems to be a net reabsorption of creatinine in the renal tubules of healthy old persons.

Effect of different antihypertensive treatments on Ras, MAPK and Akt activation in hypertension and diabetes.

Ras GTPases function as transducers of extracellular signals regulating many cell functions, and they appear to be involved in the development of hypertension. In the present study, we have investigated whether antihypertensive treatment with ARBs (angiotensin II receptor blockers), ACEi (angiotensin-converting enzyme inhibitors) and diuretics induce changes in Ras activation and in some of its effectors [ERK (extracellular-signal-regulated kinase) and Akt] in lymphocytes from patients with hypertension without or with diabetes. ACEi treatment transiently reduced Ras activation in the first month of treatment, but diuretics induced a sustained increase in Ras activation throughout the 3 months of the study. In patients with hypertension and diabetes, ARB, ACEi and diuretic treatment increased Ras activation only during the first week. ACEi treatment increased phospho-ERK expression during the first week and also in the last 2 months of the study; however, diuretic treatment reduced phospho-ERK expression during the last 2 months of the study. In patients with hypertension and diabetes, antihypertensive treatments did not induce changes in phospho-ERK expression in lymphocytes. ACEi treatment reduced phospho-Akt expression in patients with hypertension and diabetes only in the first month of treatment. In conclusion, these findings show that antihypertensive treatments with ACEi, and diuretics to a lesser extent, modify Ras activation and some of its signalling pathways, although in different directions, whereas ARBs do not appear to have any influence on Ras signalling pathways.

Physiological similarities and differences between renal aging and chronic renal disease.

Even though there are some functional similarities between the aged kidney and the chronically damaged one, such as the reduction in glomerular filtration rate and in the sodium-water reabsorption capability, there are many physiological differences between these two groups, as is the case of erythropoietin, urea, potassium, calcium, phosphorus and magnesium renal handling. Thus, the data presented demonstrate that renal aging and chronic kidney disease constitute different clinical scenes.

Effect of adenosine in extracellular matrix synthesis in human and rat mesangial cells.

Adenosine (ADO) is an intermediary metabolite of adenosine trisphosphate degradation and a vasoactive mediator. We showed previously that ADO induces contraction and proliferation in rat mesangial cells by a mechanism involving A1 and A2 receptors. The studies concerning the effect of ADO on extracellular matrix (ECM) accumulation in mesangial cells are scarce. The purpose of our study was to evaluate the effect of ADO and the effect of the selective stimulation of A1 and A2 ADO receptors on the expression of ECM components fibronectin and collagen type I, in human and rat renal mesangial cells. Cultured human and rat renal mesangial cells were subjected to selective stimulation of A1 and A2 ADO receptors for 24 and 48 h. Fibronectin and collagen type I expression was evaluated by Western blot; total collagen synthesis was measured by [3H]-proline incorporation into collagen proteins. ADO, A1 and A2 receptor stimulation induce increases in fibronectin expression in rat mesangial cells, and A1 receptor stimulation partially inhibits fibronectin expression in serum-stimulated rat mesangial cells, without any effect in human mesangial cells. A2 receptor stimulation reduces collagen type I expression in serum-stimulated mesangial cells. Neither ADO nor A1 or A2 receptor stimulation induce significant changes in total collagen synthesis. These data suggest that ADO is not a major regulator of ECM synthesis in rat and human mesangial cells.

Verapamil reverts acute renal functional impairment induced by angiotensin II converting enzyme inhibitors.

Angiotensin converting enzyme inhibitors (ACEI) reduce blood pressure (BP) and provide end-organ protection, but may induce renal function deterioration. In these cases, serum creatinine (SCr) can be normalized by ACEI withdrawn. In some patients, it could be desirable to maintain the ACEI for the protection of the kidney and heart. The objective of the study was to evaluate the effect of Verapamil (V) on renal function added to patients with elevated SCr due to ACEI treatment. In 46 hypertensive patients without previous renal failure, in which ACEI treatment induced an acute increase in SCr (> or = 20% or 0.5 mg/dL), ACEI treatment was maintained and 180 mg/day of V was added for 12 weeks. Those patients showing further SCr increase or no BP control at four weeks were withdrawn. Patients under BP control were moved on the combination V 180 + Trandolapril 2 mg/day for eight weeks more. SCr decreased from 136 +/- 49 micromol/L at baseline to 126 +/- 49 at 12 weeks after adding V (p < 0.001) and to 111 +/- 31 micromol/L at 20 weeks (p < 0.01). Creatinine clearance increased from 62 +/- 22 mL/min at baseline to 68 +/- 28 after 12 weeks of V (p < 0.001). This article demonstrates than in patients with acute renal function impairment secondary to ACEI treatment, the addition of 180 mg/day of verapamil to ACEI reverses SCr towards previous values.