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.

Background: Severe secondary hyperparathyroidism, which is associated with life-threatening complications, can develop in dialysis-dependent end-stage renal disease patients. The aim of this study was to compare short- and long-term mortality in dialysis patients who underwent near-total parathyroidectomy (NTPTX) and matched nonoperated controls. Study Design: We identified 150 dialysis patients who underwent NTPTX (1993-2009) at our institution and compared them with 1,044 nonoperated control patients identified in the US Renal Data System registry, matched for age, sex, race, diabetes as cause of kidney failure, years on dialysis, and dialysis modality. Survival outcomes were estimated using multivariable Cox proportional hazards models with stratification on the matching sets, adjusted for cardiovascular comorbidities, smoking, inability to ambulate/transfer, and payor status. Results: During a follow-up of a mean of 3.6 years (range 0.1 month to 16.4 years), NTPTX patients had a significant reduction in the long-term risk of all-cause death (hazard ratio = 0.68; 95% CI, 0.52-0.89; p = 0.006) compared with controls. Thirty-day mortality rates for NTPTX patients and controls were 246 vs 105 per 1,000 person-years (p = 0.21). In adjusted analyses, NTPTX patients had a 37% reduced risk of all-cause death and a 33% reduced risk of cardiovascular death compared with controls. A durable reduction in mean parathyroid hormone was observed after NTPTX; from 1,776 ± 1,416.6 pg/mL to 301 ± 285.7 pg/mL (p < 0.0001). Conclusions: In our center, NTPTX in dialysis patients was associated with a significant reduction in long-term risk of death compared with matched control patients, without a significantly increased short-term risk.

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

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.

The elderly population in the United States continues to grow and is expected to double by 2050. With aging there are degenerative changes in many organs and the kidney is no exception. After age forty there is an increase in cortical glomerulosclerosis and a decline in both glomerular filtration rate and renal plasma flow. These changes may be associated with an inability to excrete a concentrated or a dilute urine, ammonium, sodium, or potassium. Hypernatremia and hyponatremia are the most common electrolyte abnormalities found in the elderly and both are associated with a high mortality. Under normal conditions the elderly are able to maintain water and electrolyte balance but this may be jeopardized by an illness, a decline in cognitive ability, and with certain medications. Therefore, it is important to be aware of the potential electrolyte abnormalities in the elderly that can arise under these various conditions in order to prevent adverse outcomes.

Patient: Male, 82-year-old Final Diagnosis: End stage renal disease • thrombocytopenia • co-existing disea Symptoms: Fatigue • melena • weakness Medication: — Clinical Procedure: — Specialty: Nephrology Objective: Background: Case Report: Conclusions: Unusual or unexpected effect of treatment Biocompatible hemodialysis membranes have greatly advanced the treatment of renal failure. Synthetic poly-sulfone 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. We report the case of an 82-year-old man with a history of chronic kidney disease with recurrent gastrointes-tinal 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. 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.

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.

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.

Insulin resistance is a common finding in chronic kidney disease (CKD) and is manifested by mild fasting hyperglycemia and abnormal glucose tolerance testing. Circulating levels of glucocorticoids are high. In muscle, changes in the insulin signaling pathway occur. An increase in the regulatory p85 subunit of Class I phosphatidylinositol 3-Kinase enzyme leads to decreased activation of the downstream effector protein kinase B (Akt). Mechanisms promoting muscle proteolysis and atrophy are unleashed. The link of Akt to the ubiquitin proteasome pathway, a major degradation pathway in muscle, is discussed. Another factor associated with insulin resistance in CKD is angiotensin II (Ang II) which appears to induce its intracellular effects through inflammatory cytokines or reactive oxygen species. Skeletal muscle ATP is depleted and the ability of AMP-activated protein kinase (AMPK) to replenish energy stores is blocked. How this can be reversed is discussed. Interleukin-6 (IL-6) levels are elevated in CKD and impair insulin signaling at the level of IRS-1. With exercise, IL-6 levels are reduced; glucose uptake and utilization are increased. For patients with CKD, exercise may improve insulin signaling and build up muscle. Treatment strategies for preventing muscle atrophy are discussed.

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.