No tumor-free waiting period after treatment of multilocular cystic renal cell carcinoma: a new case and review of the literature.

Most pretransplant malignancies require a tumor-free waiting period before transplantation. End-stage renal disease (ESRD) patients have an increased risk of renal cell carcinoma (RCC), which is mostly detected from routine screening during pre-kidney transplant evaluation. RCC must be quiescent prior to kidney transplantation. However, the tumor-free waiting period for RCC varies depending on the types of RCC. Multilocular cystic RCC (MCRCC), one subtype of clear cell RCC, has low malignant potential and may not require a tumor-free waiting period. We report a case of an ESRD patient with a newly diagnosed MCRCC that was found during routine pre-kidney transplant evaluation. A plan for kidney transplantation within 6 months of successful tumor removal by nephrectomy was made. The literature regarding MCRCC in kidney transplantation is reviewed.

Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway.

Hypertension is a leading cause of morbidity and mortality worldwide, and disordered sodium balance has long been implicated in its pathogenesis. Aldosterone is perhaps the key regulator of sodium balance and thus blood pressure. The sodium chloride cotransporter (NCC) in the distal convoluted tubule of the kidney is a major site of sodium reabsorption and plays a key role in blood pressure regulation. Chronic exposure to aldosterone increases NCC protein expression and function. However, more acute effects of aldosterone on NCC are unknown. In our salt-abundant modern society where chronic salt deprivation is rare, understanding the acute effects of aldosterone is critical. Here, we examined the acute effects (12-36 h) of aldosterone on NCC in the rodent kidney and in a mouse distal convoluted tubule cell line. Studies demonstrated that aldosterone acutely stimulated NCC activity and phosphorylation without affecting total NCC abundance or surface expression. This effect was dependent upon the presence of the mineralocorticoid receptor and serum- and glucocorticoid-regulated kinase 1 (SGK1). Furthermore, STE20/SPS-1-related proline/alanine-rich kinase (SPAK) phosphorylation also increased, and gene silencing of SPAK eliminated the effect of aldosterone on NCC activity. Aldosterone administration via a minipump in adrenalectomized rodents confirmed an increase in NCC phosphorylation without a change in NCC total protein. These data indicate that acute aldosterone-induced SPAK-dependent phosphorylation of NCC increases individual transporter activity.

Calcineurin signaling and PGC-1alpha expression are suppressed during muscle atrophy due to diabetes.

PGC-1alpha is a transcriptional coactivator that controls energy homeostasis through regulation of glucose and oxidative metabolism. Both PGC-1alpha expression and oxidative capacity are decreased in skeletal muscle of patients and animals undergoing atrophy, suggesting that PGC-1alpha participates in the regulation of muscle mass. PGC-1alpha gene expression is controlled by calcium- and cAMP-sensitive pathways. However, the mechanism regulating PGC-1alpha in skeletal muscle during atrophy remains unclear. Therefore, we examined the mechanism responsible for decreased PGC-1alpha expression using a rodent streptozotocin (STZ) model of chronic diabetes and atrophy. After 21days, the levels of PGC-1alpha protein and mRNA were decreased. We examined the activation state of CREB, a potent activator of PGC-1alpha transcription, and found that phospho-CREB was paradoxically high in muscle of STZ-rats, suggesting that the cAMP pathway was not involved in PGC-1alpha regulation. In contrast, expression of calcineurin (Cn), a calcium-dependent phosphatase, was suppressed in the same muscles. PGC-1alpha expression is regulated by two Cn substrates, MEF2 and NFATc. Therefore, we examined MEF2 and NFATc activity in muscles from STZ-rats. Target genes MRF4 and MCIP1.4 mRNAs were both significantly reduced, consistent with reduced Cn signaling. Moreover, levels of MRF4, MCIP1.4, and PGC-1alpha were also decreased in muscles of CnAalpha-/- and CnAbeta-/- mice without diabetes indicating that decreased Cn signaling, rather than changes in other calcium- or cAMP-sensitive pathways, were responsible for decreased PGC-1alpha expression. These findings demonstrate that Cn activity is a major determinant of PGC-1alpha expression in skeletal muscle during diabetes and possibly other conditions associated with loss of muscle mass.

Angiotensin II acts through the angiotensin 1a receptor to upregulate pendrin.

Pendrin is an anion exchanger expressed in the apical regions of B and non-A, non-B intercalated cells. Since angiotensin II increases pendrin-mediated Cl(-) absorption in vitro, we asked whether angiotensin II increases pendrin expression in vivo and whether angiotensin-induced hypertension is pendrin dependent. While blood pressure was similar in pendrin null and wild-type mice under basal conditions, following 2 wk of angiotensin II administration blood pressure was 31 mmHg lower in pendrin null than in wild-type mice. Thus pendrin null mice have a blunted pressor response to angiotensin II. Further experiments explored the effect of angiotensin on pendrin expression. Angiotensin II administration shifted pendrin label from the subapical space to the apical plasma membrane, independent of aldosterone. To explore the role of the angiotensin receptors in this response, pendrin abundance and subcellular distribution were examined in wild-type, angiotensin type 1a (Agtr1a) and type 2 receptor (Agtr2) null mice given 7 days of a NaCl-restricted diet (< 0.02% NaCl). Some mice received an Agtr1 inhibitor (candesartan) or vehicle. Both Agtr1a gene ablation and Agtr1 inhibitors shifted pendrin label from the apical plasma membrane to the subapical space, independent of the Agtr2 or nitric oxide (NO). However, Agtr1 ablation reduced pendrin protein abundance through the Agtr2 and NO. Thus angiotensin II-induced hypertension is pendrin dependent. Angiotensin II acts through the Agtr1a to shift pendrin from the subapical space to the apical plasma membrane. This Agtr1 action may be blunted by the Agtr2, which acts through NO to reduce pendrin protein abundance.

Thrombocytopenia Induced by Polysulfone Dialysis Membranes.

BACKGROUND Biocompatible hemodialysis membranes have greatly advanced the treatment of renal failure. Synthetic polysulfone dialysis membranes are considered to be very biocompatible because of their low propensity to activate complement. However, these membranes can reduce platelet count through platelet activation, although the mechanism of this activation is unknown. CASE REPORT We report the case of an 82-year-old man with a history of chronic kidney disease with recurrent gastrointestinal bleeding and worsening renal function who was initiated on renal replacement therapy with polysulfone dialysis membranes. On admission, the patient's platelet count was normal at 233×10³/µL. A significant fall in platelet count was observed following most dialysis treatments, reaching a nadir of 37×10³/µL. With occasional dialysis treatments, his platelet count did not change. This dialysis-induced thrombocytopenia resolved following substitution with Cellentia-H cellulose triacetate single-use, hollow-fiber, high-flux hemodialyzer membrane. CONCLUSIONS Polysulfone membranes are capable of activating platelets, which can result in severe thrombocytopenia. However, the magnitude of dialysis-induced thrombocytopenia varies from treatment to treatment. As such, it may not be evident when the pre- and postdialysis platelet counts are measured for a single treatment. Because the etiology of this platelet activation is unknown, substitution with cellulose triacetate membranes should be considered. These membranes have an unrelated chemical composition and a very low propensity to activate platelets.

Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure.

AIM: We have reported earlier that a high salt intake triggered an aestivation-like natriuretic-ureotelic body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure. METHODS: In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24-hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomics and selected enzyme activity measurements, body Na+ , K+ and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra-arterial blood pressure. RESULTS: 5/6 Nx rats were polyuric, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, elevated norepinephrine and copeptin levels with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic-metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein. CONCLUSION: Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under-studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.

Mediterranean diets: are they practical in the Western world?

The incidence of metabolic syndrome (MS) in renal transplant patients is unacceptably high. Dietary intake may ameliorate or worsen the potential for the development of MS. The choice of immunosuppression also plays a role. Continued effort to find beneficial dietary combinations is essential while ongoing research evolves to find newer immunosuppressive medications with less adverse metabolic side effects.

Exercise ameliorates chronic kidney disease-induced defects in muscle protein metabolism and progenitor cell function.

Chronic kidney disease (CKD) impairs muscle protein metabolism leading to muscle atrophy, and exercise can counteract this muscle wasting. Here we evaluated how resistance exercise (muscle overload) and endurance training (treadmill running) affect CKD-induced abnormalities in muscle protein metabolism and progenitor cell function using mouse plantaris muscle. Both exercise models blunted the increase in disease-induced muscle proteolysis and improved phosphorylation of Akt and the forkhead transcription factor FoxO1. Muscle overloading, but not treadmill running, corrected protein synthesis and levels of mediators of protein synthesis such as phosphorylated mTOR and p70S6K in the muscles of mice with CKD. In these mice, muscle overload, but not treadmill, running, increased muscle progenitor cell number and activity as measured by the amounts of MyoD, myogenin, and eMyHC mRNAs. Muscle overload not only increased plantaris weight and reduced muscle proteolysis but also corrected intracellular signals regulating protein and progenitor cell function in mice with CKD. Treadmill running corrects muscle proteolysis but not protein synthesis or progenitor cell function. Our results provide a basis for evaluating different types of exercise on muscle atrophy in patients with chronic kidney disease.

Getting to the meat of the matter: beyond protein supplementation in maintenance dialysis.

Until recently, patients on dialysis with low serum albumin levels were characterized as suffering from protein malnutrition suggesting that the cause of this malady was due to an inadequate intake of protein. In fact, these patients tend to suffer from a wasting syndrome similar to cachexia commonly associated with inflammation in which there is loss of lean body mass and fat mass is underutilized. The term protein energy wasting has been used to characterize this syndrome and suggests that the simple addition of protein supplements to the dietary regimen of hemodialysis patients will not cure this malady. Correction of the underlying inflammatory disorder which drives losses of body protein and fuel reserves is far more important and is the single most effective therapy. Protein supplements which may promote albumin synthesis and synthesis of liver-related proteins tend to increase muscle catabolism. Muscle growth is not fostered by increasing dietary protein above recommended goals for dialysis patients, but can be promoted by the addition of protein of high biological value that is rich in leucine and other essential amino acids in tandem with repetitive exercises. Ultimately, correction of PEW hinges on the diagnosis and treatment of co-morbid conditions in combination with strategies to replenish caloric and protein stores. A supplementary exercise program would allow recovery of lean body mass. Given the multiple co-morbidities that exist in this population, therapy would have to be individualized.

How to Successfully Train a Modern Nephrologist: Experience from US Fellowship Training Practice.

BACKGROUND: Graduate medical education varies in different countries. There is a general consensus in training methods, including residency and fellowship training systems. The graduate medical education system in western countries including the UK and the USA has been shown to be successful. The new graduate medical education training system in China was recently established and is still evolving and being implemented nationally. SUMMARY: This paper reviews the history of nephrology training programs in the USA, the role of the Accreditation Council for Graduate Medical Education (ACGME) in establishing and enforcing guidelines and curriculum for specialty training programs, the fellowship application and Match system for the recruitment of prospective fellows, and the quality control of fellowship training programs through rigorous evaluation and In-Training examination. This review specifically discusses the nephrology subspecialty fellowship and ACGME-accredited training programs in nephrology. The authors also provide several critical suggestions on the newly established postgraduate medical education training system in China, particularly in nephrology, based on experiences from successful US nephrology fellowship practices. KEY MESSAGES: The ACGME-accredited nephrology fellowship program has been shown to be effective and successful, which could provide an insight into the newly established graduate medical education training system in China. The authors are optimistic that reforms in Chinese medical training systems will be successful in the near future.

Beyond nutrition: neuropeptide signaling and muscle mass maintenance in chronic kidney disease.

Muscle wasting is a hallmark of uremic cachexia and has frequently been attributed to malnutrition that manifests as anorexia in chronic kidney disease. However, recent evidence indicates that proteolytic mechanisms are responsible for atrophy. Cheung and colleagues have reexamined the links between loss of lean body mass and nutrition. They demonstrate that neuropeptide signaling pathways, which regulate appetite and energy expenditure, also affect expression of key proteins involved in muscle mass maintenance.

Insomnia on dialysis nights: the beneficial effects of cool dialysate.

BACKGROUND: Hemodialysis (HD) induces physiological changes that may affect the ability to dissipate heat and adversely affect sleep on the nights following treatment. We studied the effects of altering dialysate temperature on polysomnographic measures of nocturnal sleep and the time course of proximal skin temperature. METHODS: The sample included seven stable HD patients. The three-phase randomized trial was conducted in a research facility. After one acclimatization night, subjects were readmitted in the evening on two additional occasions for 42 hours and received HD the next morning in the warm condition (dialysate--37 degrees C) and cool condition (dialysate--35 degrees C) in random order. Continuous proximal skin temperature (axillary, Tax) and polysomnographic measures of sleep were recorded the nights before and after HD was administered. RESULTS: Highly significant findings included that the course of Tax was markedly affected by the interaction of time and condition. In addition, there was a greater drop of Tax in the early morning following the warm condition than during the baseline nights or in the cool condition. Logistic regression indicated that the odds for the occurrence of sleep and its deeper stages were strongly and positively associated with Tax. Time of sleep onset was earlier in the cool condition (p = 0.032) with trends toward longer total sleep times (p = 0.090) and shorter REM latencies (p = 0.088). CONCLUSIONS: These observations suggest that the use of cool dialysate during HD may improve nocturnal sleep the night following treatment by decreasing sympathetic activation and sustaining the normally elevated nocturnal skin temperature until later into the morning hours.

Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions.

With trauma, sepsis, cancer, or uremia, animals or patients experience accelerated degradation of muscle protein in the ATP-ubiquitin-proteasome (Ub-P'some) system. The initial step in myofibrillar proteolysis is unknown because this proteolytic system does not break down actomyosin complexes or myofibrils, even though it degrades monomeric actin or myosin. Since cytokines or insulin resistance are common in catabolic states and will activate caspases, we examined whether caspase-3 would break down actomyosin. We found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P'some. In fact, limited actomyosin cleavage by caspase-3 yields a 125% increase in protein degradation by the Ub-P'some system. Serum deprivation of L6 muscle cells stimulates actin cleavage and proteolysis; insulin blocks these responses by a mechanism requiring PI3K. Cleaved actin fragments are present in muscles of rats with muscle atrophy from diabetes or chronic uremia. Accumulation of actin fragments and the rate of proteolysis in muscle stimulated by diabetes are suppressed by a caspase-3 inhibitor. Thus, in catabolic conditions, an initial step resulting in loss of muscle protein is activation of caspase-3, yielding proteins that are degraded by the Ub-P'some system. Therapeutic strategies could be designed to prevent these events.

Chlorhexidine-impregnated transparent dressings decrease catheter-related infections in hemodialysis patients: a quality improvement project.

PURPOSE: Central venous catheters (CVC) are associated with increased infection rates, morbidity and mortality compared to other hemodialysis vascular access. Chlorhexidine-impregnated transparent (CHG-transparent) dressings allow for continuous antimicrobial exposure and easy visibility of the CVC insertion site. We conducted a quality improvement project to compare catheter-related infection (CRI) rates in two dressing regimens - CHG-transparent dressings and adhesive dry gauze dressing in hemodialysis patients with tunneled CVCs. METHODS: The study was conducted in two phases. In phase 1, CHG-transparent dressing was introduced to EDC hemodialysis unit, while EDG and EDN hemodialysis units, served as the control sites and maintained adhesive dry gauze dressing. Phase 2 of the study involved replacing the adhesive dry gauze dressing with CHG-transparent dressing at EDG and EDN and maintaining CHG-transparent dressing at EDC. CRI rates at each hemodialysis unit during the 12-month intervention were compared to CRI rates for the 12-month pre-intervention period for each study phase. CRI rates were also compared between all three hemodialysis units. RESULTS: In phase 1, CRI rates (per 1000 days) in EDC (intervention site) decreased by 52% (1.69 vs. 0.82, p<0.05) and increased by 12% (1.80 vs. 2.02, p = 0.75) at EDG, and 35% (0.91 vs. 1.23, p = 0.40) at EDN. In phase 2, CRI rates at EDG and EDN (intervention sites) decreased by 86% (1.86 vs. 0.26 p<0.05), and 53% (1.89 vs. 0.88, p<0.05), respectively, and decreased by 20% at EDC (0.73 vs. 0.58, p = 0.65). CONCLUSIONS: Replacing adhesive dry gauze dressing with CHG-transparent dressing for hemodialysis patients with tunneled CVC was associated with decreased CRI rates.

Urea transporters and sweat response to uremia.

In humans, urea is excreted in sweat, largely through the eccrine sweat gland. The urea concentration in human sweat is elevated when compared to blood urea nitrogen. The sweat urea nitrogen (UN) of patients with end-stage kidney disease (ESRD) is increased when compared with healthy humans. The ability to produce sweat is maintained in the overwhelming majority of ESRD patients. A comprehensive literature review found no reports of sweat UN neither in healthy rodents nor in rodent models of chronic kidney disease (CKD). Therefore, this study measured sweat UN concentrations in healthy and uremic rats. Uninephrectomy followed by renal artery ligation was used to remove 5/6 of renal function. Rats were then fed a high-protein diet to induce uremia. Pilocarpine was used to induce sweating. Sweat droplets were collected under oil. Sweat UN was measured with a urease assay. Serum UN was measured using a fluorescent ortho-pthalaldehyde reaction. Immunohistochemistry (IHC) was accomplished with a horseradish peroxidase and diaminobenzidine technique. Sweat UN in uremic rats was elevated greater than two times compared to healthy pair-fed controls (220 ± 17 and 91 ± 15 mmol/L, respectively). Post hoc analysis showed a significant difference between male and female uremic sweat UN (279 ± 38 and 177 ± 11 mmol/L, respectively.) IHC shows, for the first time, the presence of the urea transporters UT-B and UT-A2 in both healthy and uremic rat cutaneous structures. Future studies will use this model to elucidate how rat sweat UN and other solute excretion is altered by commonly prescribed diuretics.

Metabolic acidosis: an unrecognized cause of morbidity in the patient with chronic kidney disease.

In patients with chronic kidney disease, metabolic acidosis can occur as a result of insufficient ammoniagenesis within the damaged kidney. This, in turn, can bring about a variety of sequella that have their basis in hormonal and cellular abnormalities that effect stunted growth, loss of muscle and bone mass, and negative nitrogen balance. Cellular mechanisms accounting for these findings are reviewed. In bone, metabolic acidosis causes direct dissolution of bone; ostoeclastic activity is increased while osteoblastic activity is suppressed. In muscle, branched-chain amino acid oxidation is increased and the ubiquitin-proteasome pathway is activated: muscle wasting results. Even a modest degree of metabolic acidosis can be harmful and can initiate a series of maladaptive responses that are not easily reversed, although there is evidence that alkali therapy can be beneficial in reversing these responses.

Daytime sleepiness in stable hemodialysis patients.

BACKGROUND: Patients frequently sleep during hemodialysis (HD), a behavior often attributed to treatment-related fatigue and/or simple boredom. The possibility that this behavior reflects a more pervasive underlying increase in daytime sleepiness has never been systematically examined. Thus, we studied a sample of HD patients on an off-dialysis day to establish the presence or absence of daytime sleepiness independent of effects of treatment, quantify its severity, and identify associated demographic, metabolic, and sleep-related variables. METHODS: Forty-six stable HD patients underwent polysomnography, followed the next day (a nondialysis day) by the Multiple Sleep Latency Test (MSLT; low score = greater sleepiness), a measure of physiological daytime sleepiness. Subjects also completed the Epworth Sleepiness Scale (ESS; high score = greater sleepiness), a measure of subjective daytime sleepiness. RESULTS: One third (n = 15) of subjects had MSLT scores suggesting abnormal levels of physiological daytime sleepiness, and six subjects had scores consistent with severe, pathological sleepiness. Thirty percent (n = 14) had significant subjective daytime sleepiness as measured by the ESS. However, MSLT and ESS scores were unrelated. Higher indices of sleep apnea (r = -0.324; P = 0.028) and brief arousals (r = -0.370; P = 0.009) correlated significantly with increased physiological, but not subjective, sleepiness. Longer nocturnal sleep latencies (r = 0.350; P = 0.017) and greater percentage of rapid-eye-movement sleep (r = 0.302; P = 0.042) were associated with decreased physiological sleepiness. Other major demographic, metabolic, and sleep-related variables did not correlate with MSLT scores, and none of the variables examined were related to ESS scores. CONCLUSION: Daytime sleepiness is common in HD patients and may be severe despite the absence of obvious clinical risk factors for the condition. Thus, research designed to identify cost-effective indicators of daytime sleepiness and evaluate the detrimental effects of sleepiness on clinical outcomes in HD patients is warranted.

Nocturnal sleep, daytime sleepiness, and quality of life in stable patients on hemodialysis.

BACKGROUND: Although considerable progress has been made in the treatment of chronic kidney disease, compromised quality of life continues to be a significant problem for patients receiving hemodialysis (HD). However, in spite of the high prevalence of sleep complaints and disorders in this population, the relationship between these problems and quality of life remains to be well characterized. Thus, we studied a sample of stable HD patients to explore relationships between quality of life and both subjective and objective measures of nocturnal sleep and daytime sleepiness METHODS: The sample included forty-six HD patients, 24 men and 22 women, with a mean age of 51.6 (10.8) years. Subjects underwent one night of polysomnography followed the next morning by a Multiple Sleep Latency Test (MSLT), an objective measure of daytime sleepiness. Subjects also completed: 1) a brief nocturnal sleep questionnaire; 2) the Epworth Sleepiness Scale; and, 3) the Quality of Life Index (QLI, Dialysis Version) which provides an overall QLI score and four subscale scores for Health & Functioning (H&F), Social & Economic (S&E), Psychological & Spiritual (P&S), and Family (F). (The range of scores is 0 to 30 with higher scores indicating better quality of life.) RESULTS: The mean (standard deviation; SD) of the overall QLI was 22.8 (4.0). The mean (SD) of the four subscales were as follows: H&F - 21.1 (4.7); S&E - 22.0 (4.8); P&S - 24.5 (4.4); and, F - 26.8 (3.5). H&F (rs = -0.326, p = 0.013) and F (rs = -0.248, p = 0.048) subscale scores were negatively correlated with periodic limb movement index but not other polysomnographic measures. The H&F subscale score were positively correlated with nocturnal sleep latency (rs = 0.248, p = 0.048) while the H&F (rs = 0.278, p = 0.030) and total QLI (rs = 0.263, p = 0.038) scores were positively associated with MSLT scores. Both of these latter findings indicate that higher life quality is associated with lower sleepiness levels. ESS scores were unrelated to overall QLI scores or the subscale scores. Subjective reports of difficulty falling asleep and waking up too early were significantly correlated with all four subscale scores and overall QLI. Feeling rested in the morning was positively associated with S&E, P&S, and Total QLI scores. CONCLUSION: Selected measures of both poor nocturnal sleep and increased daytime sleepiness are associated with decreased quality of life in HD patients, underscoring the importance of recognizing and treating these patients' sleep problems.