Renal Capacity Research Articles

Sodium Glucose Co-Transporter 2 Inhibitors and Their Mechanism for Improving Glycemia in Patients with Type 2 Diabetes

Most antihyperglycemic agents available for the treatment of type 2 diabetes mellitus (T2DM) have insulin-dependent mechanisms of action; that is, they either stimulate insulin production (sulfonylureas, glinides, incretin mimetics, dipeptidyl peptidase-4 inhibitors), improve insulin sensitivity (thiazolidinediones, biguanides), or directly augment endogenous insulin (basal and prandial insulins). As β-cell function deteriorates, combination therapy is usually needed to effectively control glycemia. Moreover, some antihyperglycemic agents are associated with adverse effects, such as weight gain and hypoglycemia. A novel approach for treating T2DM is to inhibit renal glucose reabsorption through inhibition of sodium glucose co-transporter 2 (SGLT2), which is responsible for the majority of glucose reabsorption in the renal proximal tubule. By reducing the renal capacity to reabsorb filtered glucose, SGLT2 inhibitors increase excretion of excess glucose in urine, thereby decreasing plasma glucose concentration. Thus, although glucosuria is often viewed as an indicator of systemic hyperglycemia, this perception needs to be modified in patients treated with SGLT2 inhibitors where glucosuria is an indicator of the desired treatment effect. Currently, 2 SGLT2 inhibitors, canagliflozin and dapagliflozin, are approved in the United States for the treatment of patients with T2DM; other SGLT2 inhibitors are in various stages of clinical development. Clinical studies in patients with T2DM on a variety of background diabetes treatments have demonstrated the efficacy of canagliflozin and dapagliflozin in improving glycemic control and reducing body weight and blood pressure. Canagliflozin and dapagliflozin are generally well tolerated, with a low risk of hypoglycemia when not used in combination with insulin and/or sulfonylurea. Higher incidences of genital mycotic infections and adverse events related to osmotic diuresis and volume depletion were observed with both agents; they were generally mild or moderate and infrequently led to study discontinuation. Based on current evidence, SGLT2 inhibitors provide an important new treatment option for patients with T2DM.

Abstract 631: Maternal Separation (msep) Alters Baroreflex Function And Renal Blood Flow Responsiveness

An impairment of the baroreflex buffering has been shown to precede the development of hypertension. Formerly, we reported that MSep, a model of behavioral stress during early life, impairs chronic blood pressure control and renal filtration capacity. Thus, the aim of this study was to study the baroreflex function and renal blood flow regulation in MSep rats. We used 3 month-old MSep male rats, anesthetized with isoflurane. Femoral vein catheter was fitted to infuse saline (3 ml/hr, baseline), PE (phenylephrine, 1 ug/ml, 9 ml/hr) or SNP (sodium nitroprusside, 0.5 ug/ml, 9 ml/hr). Femoral artery catheter was fitted to collect blood pressure and HR data (ADInstruments). In addition, a flow probe was placed in the left renal artery for renal blood flow (RBF) assessment (Transonic). After 45 minutes of baseline, PE infusion (2 min) was performed. Following 30-minute recovery period, SNP infusion (2 min) was achieved. Delta heart rate (HR)/Delta mean arterial pressure (MAP) relationship shows a significant difference in the slopes between MSep vs. control rats (-0.5 ±0.07 vs. -1.08 ±0.08, p<0.05). PE-induced decrease in RBF was attenuated in a dose dependent manner in MSep rats (max. delta RBF -4.8±0.8 ml/min) compared to controls (max. delta RBF -7±1.5 ml/min, p<0.05, respectively). Yet, renal vascular resistance (MAP/RBF) was not different between MSep and control rats along the 2-min period (slope: 0.43±0.02 vs. 0.42±0.03 mmHg/ml/min, respectively). These data suggest that MSep rats fail to increase HR in response to a vasodilatory agent and lower HR in response to vasoactive stimulus. Furthermore, attenuated alpha-adrenergic-induced renal vascular responses support the existence of a compensatory mechanism in response to an increased sympathetic outflow to the kidney, as previously suggested. The contribution of the different components of the autonomic nervous system is the focus of ongoing studies.

Hyponatraemia and cirrhosis.

Hyponatraemia is a common complication of advanced cirrhosis related to an impairment in the renal capacity for eliminating solute-free water, causing a retention of water that is disproportionate to the retention of sodium, thus leading to a reduction in serum sodium concentration and hypo-osmolality. The main pathogenic factor responsible for hyponatraemia is a non-osmotic hypersecretion of arginine vasopressin (AVP) or antidiuretic hormone from the neurohypophysis, related to circulatory dysfunction. Hyponatraemia in cirrhosis is associated with increased morbidity and mortality. Hyponatraemia is also associated with increased morbidity and impaired short-term survival after transplantation. The current standard of care based on restricting fluids to 1–1.5 L/day is rarely effective. Other approaches, such as albumin infusion and the use of vaptans—which act by specifically antagonizing the effects of AVP on the V2 receptors located in the kidney tubules—have been evaluated for their role in the management of hyponatraemia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatraemia; however their use in patients with end-stage liver disease is limited by hepatotoxic effects of some of these drugs. Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited.

Alterations in the metabolomics of sulfur-containing substances in rat kidney by betaine

Earlier studies have shown that betaine administration may modulate the metabolism of sulfur amino acids in the liver. In this study, we determined the changes in the metabolomics of sulfur-containing substances induced by betaine in the kidney, the other major organ actively involved in the transsulfuration reactions. Male rats received betaine (1%) in drinking water for 2 weeks before killing. Betaine intake did not affect betaine-homocysteine methyltransferase activity or its protein expression in the renal tissue. Expression of methionine synthase was also unchanged. However, methionine levels were increased significantly both in plasma and kidney. Renal methionine adenosyltransferase activity and S-adenosylmethionine concentrations were increased, but there were no changes in S-adenosylhomocysteine, homocysteine, cysteine levels or cystathionine β-synthase expression. γ-Glutamylcysteine synthetase expression or glutathione levels were not altered, but cysteine dioxygenase and taurine levels were decreased significantly. In contrast, betaine administration induced cysteine sulfinate decarboxylase and its metabolic product, hypotaurine. These results indicate that the metabolomics of sulfur-containing substances in the kidney is altered extensively by betaine, although the renal capacity for methionine synthesis is unresponsive to this substance unlike that of the liver. It is suggested that the increased methionine availability due to an enhancement of its uptake from plasma may account for the alterations in the metabolomics of sulfur-containing substances in the kidney. Further studies need to be conducted to clarify the physiological/pharmacological significance of these findings.

Maternal Over-Hydration in Labor can Cause Dilutional Hyponatremia in Neonates

A term baby was born by semi-elective cesarean section for maternal prolonged rupture of membranes and nonprogression of labor. His mother had received 2 L of intravenous fluids prior to delivery. The baby was well at birth and establishing breast feeds. He underwent blood investigations for risk of sepsis and intravenous antibiotics were started. At 4 h of age, the baby developed brief (<2 min) seizures, and was admitted to the neonatal unit. Cerebral function monitoring did not reveal any abnormality. Blood glucose was normal, while the blood investigations conducted previously, revealed serum sodium of 124 mmol/L (normal range 135–145 mmol/L), with other electrolytes and inflammatory markers being normal. He was successfully treated with a bolus of 3 % sodium chloride and no further seizures were noted. Further history revealed that his mother had ingested 2.5 L of water during the 8 h prior to delivery, which had not been recorded in obstetric charts. A diagnosis of dilutional hyponatremia secondary to maternal overhydration was made. Pediatricians should consider potential mechanisms and differential diagnoses in newborn babies presenting with hyponatremia within the first 24 h of life.Most cases in neonates will be of dilutional hyponatremia, with imbalance between fluid intake and urine output, and low levels of urine sodium. Oliguria with a risk of dilutional hyponatremia can occur in the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which is typically associated with infection e.g., congenital pneumonia, in birth asphyxia (with hypoxic renal injury) and in preterm infants who have impaired ability to concentrate urine [1–4]. Dilutional hyponatremia with apparently normal urine output occurs with excess administration of hypotonic fluids to an infant (as revealed by assessing fluid balance, input/output charts and weight). Situations where that administration has occurred in utero as a result of maternal over-hydration, it may not be evident immediately [3]. It is worth noting that these conditions may co-exist, such as an infant with disrupted tubular function due to birth asphyxia will be more vulnerable to incautious intravenous fluid management. Non-dilutional hyponatremia is most typically associated with renal salt-wasting, for example in congenital adrenal hyperplasia (CAH). The source of sodium loss can be confirmed by an inappropriately high urinary sodium in the presence of low serum sodium, and other clinical and biochemical abnormalities may be evident (e.g., hyperkalemia, poor glycemic control and ambiguous genitalia in CAH). There are multiple reports of dilutional hyponatremia in infants due to maternal water intoxication [5]. It occurs due to excess transfer of free water across the placenta following excessive administration of fluids to the mother in labor [4, 5]. Pregnant women have lower serum sodium (by ~3–5 mmol/L) than non-pregnant women, while the sodium concentration in the fetus is about 3 mmol/L lower than that of the mother [5]. Thus, maternal hyponatremia (due to iatrogenic fluid overload and/or drinking hypotonic fluids), results in the fetus becoming hyponatremic [3]. Anti-diuretic hormone (ADH) levels in the fetus rise before the onset of labor and remain elevated. High ADH and limited renal capacity in neonates makes them vulnerable to water overload causing hyponatremia [5]. S. P. Paul (*) Department of Pediatric Gastroenterology, Bristol Royal Hospital for Children, Paul O’Gorman Building, Upper Maudlin Street, Bristol BS2 8BJ, UK e-mail: siba@doctors.org.uk

Activation of adenosine receptors improves renal antioxidant status in diabetic Wistar but not SHR rats

Background. Diabetes and hypertension independently contribute to renal injury, and the major mechanisms involved are increased reactive oxygen species (ROS) bioavailability and renin-angiotensin system (RAS) activation. We investigated the role of adenosine in controlling ROS production and RAS activation associated with renal dysfunction in hypertension and diabetes.Methods. Fourteen days after induction of diabetes with streptozotocin in 12-week-old male Wistar and spontaneously hypertensive (SHR) rats, animals were treated during 7 days with 2-chloroadenosine (CADO group, 5 mg/kg/d), a stable analogue of adenosine, or underwent a sham operation procedure. At the end of the study (day 21), intra-arterial systolic blood pressure (SBP) was measured, and 24-h urine and plasma samples and renal tissue were collected.Results. CADO treatment decreased the plasma glucose concentration and glucose and protein excretion by more than 30% in both strains. CADO treatment decreased SBP in diabetic SHR rats (143 ± 8 versus 114 ± 4 mmHg, p < 0.05), but not in diabetic Wistar rats. The hypotensive effect of CADO was associated to a ∼70% increase in plasma angiotensinogen (AGT) concentration and a ∼50% decrease in urinary AGT excretion. CADO also caused a decrease in medullary and cortical hydrogen peroxide production of about 40%, which was associated with a proportional increase in glutathione peroxidase (GPx) activity in diabetic Wistar but not in diabetic SHR animals.Conclusions. These results suggest that activation of adenosine receptors improves renal antioxidant capacity in diabetic Wistar but not SHR rats, although it improves glucose metabolism in both strains. Furthermore, activation of adenosine receptors does not seem to be directly influencing AGT production.

Effect of early life Ca and P restriction on renal transporters gene expression in post weaning piglets

The objective of this study was to evaluate the effect of Ca and P restriction during the post‐weaning period in pigs. Piglets (n=5/treatment) were assigned to one of 4 treatments: Control (100% NRC requirements), or 7‐d, 14‐d or 21‐d postweaning Ca and P restriction (33% of NRC requirements). After restriction periods, piglets were fed 100% of NRC requirements. Performance was measured until d 35, at which time kidney gene expression of renal transporters was measured using qPCR relative to the control group. Performance did not differ between treatments. However, during d 21–35 the gain‐to‐feed ratio was greater (P &lt; 0.05) in piglets restricted for 21 d (0.692 G:F) or 14 d (0.672 G:F) compared with 7 d (0.583 G:F). Relative mRNA level of the solute carrier family 34 member 1(SLC34A1) was up‐regulated (P &lt; 0.05) in piglets restricted for 21 d (1.16‐fold) or 14 d (1.18‐fold), consistent with improved gain‐to‐feed ratio and indicating improved active phosphate transport into cells. The solute carrier family 8 member 1 (SLC8A1) was down‐regulated (P &lt; 0.05) in piglets restricted for 7 d (−1.78‐fold), demonstrating a long‐term effect of early life nutrition on Ca metabolism. No differences were observed in ATP2B1, SLC22A and SLC34A2 mRNA levels. These results suggest performance and renal capacity benefits in response to 14 to 21 d post‐weaning Ca and P restriction.Grant Funding Source: Alltech, Inc.

Proximal tubular angiotensinogen in renal biopsy suggests nondipper BP rhythm accompanied by enhanced tubular sodium reabsorption

The renal capacity for sodium excretion is impaired by a reduction in the glomerular ultrafiltration coefficient and by enhancement of the fractional tubular sodium reabsorption (FRNa), leading to a nondipper circadian blood pressure (BP) rhythm. Angiotensin II in the systemic circulation can be easily filtered across the glomerular capillary walls and stimulates renal proximal tubular angiotensinogen (PT-AGT) production, leading to the activation of intrarenal angiotensin II, which is known to augment the FRNa in animal models. We performed an immunohistochemical investigation to determine the contribution of PT-AGT to enhancement of FRNa and the nondipper circadian BP rhythm in 40 consecutive patients with primary IgA nephropathy (IgAN). Immunostaining for PT-AGT was increased in the IgAN patients compared with control individuals (P = 0.04), and correlated directly with the FRNa (r = 0.39, P = 0.01) and the night/day ratio of BP (r = 0.38, P = 0.02), but not creatinine clearance (r = -0.008, P = 0.9). The night/day ratio of BP was determined by both creatinine clearance (r = -0.36, P = 0.03) and FRNa (r = 0.47, P = 0.006). Tubular sodium reabsorption is stimulated by intrarenal angiotensin II, as indicated by PT-AGT, and contributes to the genesis of the nondipper BP rhythm. Further studies are needed to evaluate whether or not treatment to prevent sodium retention is useful for patients who exhibit increased PT-AGT in renal biopsies.

Defective renal maintenance of the vitamin D endocrine system impairs vitamin D renoprotection: a downward spiral in kidney disease

In kidney disease, the progressive loss of renal capacity to produce calcitriol, the vitamin D hormone, is a key contributor to elevations in parathyroid hormone (PTH) and mineral and skeletal disorders predisposing to renal and cardiovascular damage, ectopic calcifications, and high mortality rates. Thus, the safe correction of calcitriol deficiency to suppress PTH has been the treatment of choice for decades. However, recent epidemiological and experimental data suggest that calcitriol replacement may improve outcomes through renal and cardioprotective actions unrelated to PTH suppression. Furthermore, a striking incidence of vitamin D deficiency occurs in kidney disease and associates more strongly than calcitriol deficiency with a higher risk for kidney disease progression and death. Despite the translational relevance of these findings, no prospective trials are currently available in support of the efficacy of vitamin D supplementation and/or calcitriol replacement to safely halt/moderate renal disease progression. This review updates the pathophysiology behind the vicious cycle by which kidney injury impairs the maintenance of normal vitamin D and calcitriol levels, which in turn impedes vitamin D/calcitriol renoprotective actions, a requirement for the design of prospective trials to improve current recommendations for vitamin D interventions at all stages of kidney disease.

Nocturnal Hypertension and Chronic Kidney Disease

The importance of the kidneys, as well as the renal function curve, in determining the arterial pressure (BP) has been widely-accepted (long-term BP regulation). Our recent studies have suggested that kidneys may participate in the pathogenesis of a circadian BP rhythm (short-term BP regulation). We have postulated that sodium sensitivity of BP is increased by both reduced glomerular ultrafiltration coefficient and by enhancement of tubular sodium reabsorption in chronic kidney disease (CKD). Glomerular filtration rate (GFR) is reduced in the former condition and is augmented in the latter. In patients with high-sodium sensitivity, the nocturnal BP dip is diminished, resulting in non-dipper pattern of circadian BP rhythm irrespectively of the mechanisms causing sodium sensitivity. We have found that in patients with more severe renal dysfunction it took longer “dipping time” for their nocturnal mean arterial pressure to fall below 90% of their daytime mean value and showed non-dipper circadian rhythms for BP and natriuresis. These findings encourage us to postulate that reduced renal capacity to excrete sodium into urine causes nocturnal elevation of BP (i.e. non-dipper) in order to compensate for diminished daytime natriuresis by enhancing night-time pressure-natriuresis. Both high sodiumsensitivity and non-dippers are risks for cardiovascular disease. Investigation on the renal mechanisms of non-dipper and nocturnal hypertension may be the shortest way to solve cardio-renal connection.

Oral Colchicine (Colcrys®) in the Treatment and Prophylaxis of Gout†

Gout is a disease with a descriptive history dating back to the time of Hippocrates. It is a well known type of arthritis associated with impaired metabolism of purines, resulting in hyperuricaemia and an accumulation of the metabolic end product urate, in the form of monosodium urate crystals, in joints. The build-up of these crystals induces an acute inflammatory response that involves leukocyte recruitment, in particular that of neutrophils. Hyperuricaemia is the most important risk factor in the development of gout, and is caused more commonly by decreased renal capacity to clear urate (in »90% of patients) than by over production of urate (»10%). Hyperuricaemia is physiochemically defined as urate levels >6.8mg/dL (408 mmol/L) in men and women, as urate saturation leading to crystal formation occurs at 6.8mg/dL at 37 C. Although the risk of acute gout increases with serum urate concentration, not all patients with hyperuricaemia will develop gout. Other common risk factors for gout include excessive intake of certain purine-rich foods (e.g. meat and seafood), alcohol and fructose, obesity and the use of medications that affect urate levels (such as diuretics, furosemide and ciclosporin). In addition, some common chronic disorders, such as diabetes mellitus, the metabolic syndrome, renal disease, hypertension, cardiovascular disease and hyperlipidaemia, are associated with gout. Furthermore, hyperuricaemia may increase the risk of hypertension and chronic renal disease. The prevalence of gout is difficult to quantify, but is estimated to be »1% in adults in Western countries. The incidence of gout increases with age, and is particularly high among elderly men (aged >65 years). In recent years, increases in the prevalence and incidence of gout have been reported, which are attributed in part to the aging population, who have a higher likelihood than younger individuals of co-morbidities and concurrent medication requirements that contribute to an increase in risk factors or gout-associated disorders. Although the symptoms of an acute gout flare are self limiting, they usually include extreme pain and can take ‡1 week to resolve. Aside from pain, patients are most concerned with the loss of mobility, as well as emotional stress, interrupted sleep, work and social limitations, and joint swelling and deformities. Therefore, treatment

Renal Clearance of Cobalt in Relation to the Use of Metal-on-Metal Bearings in Hip Arthroplasty

A concern regarding the use of metal-on-metal bearings in hip arthroplasty has been that the high levels of metal ions that are released overwhelm the renal threshold for metal excretion, leading to systemic buildup of metals. The purpose of this investigation was to determine if the physiological renal capacity for cobalt clearance and cobalt concentrating efficiency is overwhelmed by the elevation in metal ion levels seen in patients with metal-on-metal-bearing hip devices. Concurrent specimens of urine and plasma were obtained from a group of 461 patients (346 men and 115 women) at various intervals after either a unilateral (296) or a bilateral (130) metal-on-metal hip arthroplasty or preoperatively (thirty-five patients; the control specimens). Metal ion analyses were performed with high-resolution inductively coupled mass spectrometry. Renal efficiency was measured as the ratio of urine cobalt concentration to plasma cobalt concentration. Cobalt clearance was calculated by dividing the urine cobalt output in twenty-four hours by the plasma cobalt concentration. Dividing the quotient by 1440 adjusts it to clearance per minute. The median renal efficiency was found to be 0.9 in the analysis of the preoperative specimens, indicating that there was renal conservation of cobalt. In patients with metal-on-metal bearings, the median renal efficiency was 3.2, indicating that, as a result of cobalt excretion, the cobalt concentration in urine was threefold higher than the concentration in plasma. Linear regression analysis showed that renal efficiency progressively increased at a rate of 9% for every microg/24 hr increase in cobalt release. Cobalt clearance showed a similar trend, increasing from 1.3 mL/min in the preoperative group to 3.7 mL/min in the follow-up group. In the follow-up group, renal cobalt clearance progressively increased from 1.9 to 7.1 mL/min with increasing daily cobalt output, which indicates that with increasing in vivo metal ion release there was a progressive increase in the rate at which the kidneys cleared the plasma of cobalt. In subjects with no prosthetic device, the kidneys tend to conserve cobalt in the body. We found that, in patients with a metal-on-metal hip prosthesis, there is a progressive increase in cobalt clearance with increasing in vivo wear at the levels of cobalt release expected in patients with an array of metal-on-metal-bearing total joint arthroplasties. We found no threshold beyond which renal capacity to excrete these ions is overwhelmed.

Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality

In the course of kidney disease, the progressive loss of renal capacity to maintain normal serum levels of 1,25-dihydroxyvitamin D (1,25(OH) 2D) is a main contributor to parathyroid hyperplasia and high serum PTH. High PTH causes mineral and skeletal abnormalities predisposing to ectopic calcifications and increased mortality. Intriguingly, replacement therapy with 1,25(OH) 2D or its less calcemic analogs was recently shown to improve survival in kidney disease patients through renal and cardiovascular protective actions that are independent of PTH suppression. This work presents preliminary evidence that 1,25(OH) 2D inhibition of TACE (Tumor necrosis factor Alpha Converting Enzyme) is a potential common mechanism underlying the efficacy of therapy with 1,25(OH) 2D or its analogs to improve outcomes in chronic kidney disease. 1,25(OH) 2D prevents/moderates not only the onset and progression of parathyroid TACE/TGFα-driven secondary hyperparathyroidism, but, more significantly, renal TACE/TGFα-driven fibrotic and inflammatory lesions to the renal parenchyma, and TACE/TNFα-driven systemic inflammation, which is known to aggravate renal and cardiovascular lesions and enhance the risk of vascular calcification and cardiovascular mortality.

Therapie von Aszites, Hyponatriämie und hepatorenalem Syndrom bei der Leberzirrhose

Ascites and hyponatremia are frequent complications of advanced liver cirrhosis. Over 50 % of cirrhotic patients develop ascites and about one third gets hyponatremic. The development of ascites is due to an increased sodium retention in the kidneys, leading to expansion of extracellular volume and accumulation of fluid in the peritoneum. Hyponatremia is related to an impairment in the renal capacity to eliminate solute-free water that causes water retention that is disproportionate to the sodium retention, thus causing a reduction in serum sodium concentration. The exact pathogenesis of sodium retention is not clear, yet. The main pathogenic factor responsible for hyponatremia is a nonosmotic hypersecretion of vasopressin from the neurohypophysis. There is evidence suggesting that hyponatremia predisposes to hepatic encephalopathy. Impairment in glomerular filtration rate in hepatorenal syndrome is due to renal vasoconstriction. Treatment of ascites consists of potassium sparing diuretics, loop diuretics, and/or paracentesis. The current standard of care of hyponatremia based on fluid restriction is unsatisfactory. Currently, a new family of drugs, known as vaptans, which act by specifically antagonizing the effects of vasopressin on the V2 receptors located in the kidney, is evaluated for their role in the management of hyponatremia. Because data on long-term administration are still incomplete, they cannot be used routinely, yet. Liver transplantation is the treatment of choice for hepatorenal syndrome. As bridge to transplantation long-term administration of intravenous albumin and vasoconstrictors can be used.

Präoperative Betreuung des nierenkranken Patienten

The preoperative evaluation of patients with renal disease does not begin with the anaesthesiologist's visit, but with the evaluation and care given by the primary physician. To decrease postoperative morbidity and mortality, an optimal preoperative preparation is essential. The kidney is highly sensitive to perioperative hypoperfusion. Basically the medullary oxygenation with its high rate of oxygen extraction (about 79% of the delivered oxygen) is vulnerable to hypoxia, which may lead to acute tubular necrosis. The main goal of perioperative care is to avoid hypoperfusion and therefore hypoxia of the kidney. A perioperative equalized intravascular fluid balance (normovolaemia) seems to be the most effective strategy to prevent postoperative renal dysfunction. On the other side, the anaesthesia management depends on the renal function. The dosage of anaesthetics must be adapted to an impaired renal capacity. Accurate assessment of the renal function relies on laboratory determinations. The most useful laboratory tests are those related to the glomerular filtration rate (GFR), which represents the renal function. The measurement of the creatinine clearance is the most precise method available for clinically assessing overall renal function (really GFR). Measurement of creatinine clearance by 24-hour urine collection is uncomfortable and highly error-prone. For the estimation of GFR, the use of the Cockroft-Gault or the MDRD (Modification of Diet in Renal Disease) formula is recommended. The renal impairment is grouped according to the glomerular function, estimated by the named formula. Other important parameters to estimate the effects of an advanced renal dysfunction are the haemoglobin and the serum concentration of potassium and sodium. If possible, elective operative interventions should be carried out during a stable phase of the disease. Appropriate treatment of concomitant symptoms, such as hypertonia, is essential and contributes to a reduction of post operative renal dysfunction. Timely consultation with the responsible anaesthesist can prevent unnecessary delay of the intervention.

CFTR structure and function: is there a role in the kidney?

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutations in the CFTR gene may result in a defective protein processing that leads to changes in function and regulation of this chloride channel. Despite of the expression of CFTR in the kidney, patients with CF do not present major renal dysfunction, but it is known that both the urinary excretion of proteins and renal capacity to concentrate and dilute urine are altered in these patients. CFTR mRNA is expressed in all nephron segments of rat and human, and this abundance is more prominent in renal cortex and outer medulla renal areas. CFTR protein was detected in apical surface of both proximal and distal tubules of rat kidney but not in the outer medullary collecting ducts. Studies have demonstrated that CFTR does not only transport Cl- but also ATP. ATP transport by CFTR could be involved in the control of other ion transporters such as Na+ (ENaC) and K+ (renal outer medullary potassium) channels, especially in TAL and CCD. In the kidney, CFTR also might be involved in the endocytosis of low-molecular-weight proteins by proximal tubules. This review is focused on the CFTR function and structure, its role in the renal physiology, and its modulation by hormones involved in the control of extracellular fluid volume.

Use Of Daptomycin In The Treatment Of Prosthetic Joint Infections: A Prospective Observational Study Of 30 Patients With Infected Prosthetic Joint Infections

This prospective, observational study evaluated daptomycin, a lipopeptide antibiotic active against most Gram-positive bacteria, in prosthetic joint infections. Thirty patients received daptomycin for a mean of 37 days. Most patients received daptomycin 4 or 6 mg/kg/day as secondor third-line therapy after failing prior therapy; three patients with reduced renal capacity at baseline received 4 mg/kg q48h. At 6 to 12 months' posttreatment follow-up, 20 patients (66%) had no clinical, laboratory, or radiographic signs of recurrent infection. Ten patients (33%), all of whom were infected with methicillin-resistant Staphylococcus aureus, failed therapy with daptomycin. Daptomycin was discontinued in one patient due to an elevated level of creatinine phosphokinase. These results suggest daptomycin is a viable alternative to vancomycin or vancomyin-containing combination regimens for prosthetic joint infections. Sources of support: Suresh J. Antony, MD: Travel Grant from Cubist Pharmaceuticals, Inc. Editorial assistance was provided by Phase Five Communications, Inc. New York, supported by Cubist Pharmaceuticals, Inc.

Patients With Renal Dysfunction Require a Longer Duration Until Blood Pressure Dips During the Night

We have postulated that the diminished renal capacity to excrete sodium causes nocturnal blood pressure (BP) elevation, which enhances pressure natriuresis in compensation for impaired daytime natriuresis. If such a mechanism holds, high BP during sleep at night may continue until excess sodium is sufficiently excreted into urine. This study examined whether the duration, defined as "dipping time," until nocturnal mean arterial pressure began to fall to <90% of daytime average became longer as renal function deteriorated. Ambulatory BP measurements and urinary sodium excretion rates were evaluated for daytime and nighttime to estimate their circadian rhythms in 65 subjects with chronic kidney disease. Dipping time showed an inverse relationship with creatinine clearance (C(cr); rho=-0.61; P<0.0001) and positive relationships with night/day ratios of mean arterial pressure (rho=0.84; P<0.0001) and natriuresis (rho=0.61; P<0.0001), both of which were also inversely correlated with C(cr) (mean arterial pressure: r=-0.58, P<0.0001; natriuresis: r=-0.69, P<0.0001). When divided into tertiles by C(cr) (mL/min), hazard ratios of nocturnal BP dip adjusted for age, gender, and body mass index were 0.37 (95% CI: 0.17 to 0.79; P=0.01) for the second tertile (C(cr): 50 to 90) and 0.20 (95% CI: 0.08 to 0.55; P=0.002) for the third tertile (C(cr): 5 to 41) compared with the first tertile (C(cr): 91 to 164). These findings demonstrate that patients with renal dysfunction require a longer duration until BP falls during the night. The prolonged duration until BP dip during sleep seems an essential component of the nondipper pattern of the circadian BP rhythm.

Hyponatremia in cirrhosis: Pathogenesis, clinical significance, and management

Hyponatremia is a frequent complication of advanced cirrhosis related to an impairment in the renal capacity to eliminate solute-free water that causes a retention of water that is disproportionate to the retention of sodium, thus causing a reduction in serum sodium concentration and hypo-osmolality. The main pathogenic factor responsible for hyponatremia is a nonosmotic hypersecretion of arginine vasopressin (or antidiuretic hormone) from the neurohypophysis related to circulatory dysfunction. Hyponatremia in cirrhosis is associated with increased morbidity and mortality. There is evidence suggesting that hyponatremia may affect brain function and predispose to hepatic encephalopathy. Hyponatremia also represents a risk factor for liver transplantation as it is associated with increased frequency of complications and impaired short-term survival after transplantation. The current standard of care based on fluid restriction is unsatisfactory. Currently, a new family of drugs, known as vaptans, which act by antagonizing specifically the effects of arginine vasopressin on the V2 receptors located in the kidney tubules, is being evaluated for their role in the management of hyponatremia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatremia. Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited. Treatment with vaptans represents a novel approach to improving serum sodium concentration in cirrhosis.

Kidney and Circadian Blood Pressure Rhythm

Association between nondipper pattern of circadian rhythm of blood pressure (BP) and impaired renal capacity to excrete sodium into urine was confirmed by Bankir et al1 in this issue of Hypertension based on a large number of subjects. Although this association has been observed in small studies,2,3 their study1 is the first to show it in a large-scale setting, and, therefore, is highly welcomed. Because there is a tight link between kidney and hypertension, renal dysfunction causes hypertension, whereas hypertension accelerates renal damage. It is well appreciated that the kidneys play an important role in the long-term regulation of BP. Usually it takes almost 1 week for kidneys to achieve a new steady-state balance of sodium, when sodium intake is altered. Therefore, renal participation in the short-term BP regulation, such as circadian rhythm, has been overlooked. However, the findings of Bankir et al1 strongly suggest that nocturnal hypertension and nondipper pattern of circadian BP rhythm are because of impaired renal capacity to excrete sodium, and circadian BP rhythm is at least in part regulated by kidneys. Sodium sensitivity of BP is also determined by renal capacity to excrete sodium and is regulated by glomerulotubular balance between glomerular ultrafiltration capability and rate of tubular sodium reabsorption.4 Thus, sodium sensitivity is increased in chronic kidney disease (CKD) where glomerular filtration rate (GFR) is reduced and also in disorders with enhanced tubular sodium reabsorption, including primary aldosteronism, diabetes mellitus, and metabolic syndrome, where GFR is augmented. When sodium sensitivity is increased, glomerular capillary pressure is usually elevated, resulting in albuminuria and renal damage. It becomes evident that, in patients with high-sodium sensitivity, the nocturnal dip in …