Background/Aims: Progressive chronic kidney disease (CKD) is associated with worsening cardiovascular (CV) risk not explained by traditional risk factors. Left ventricular (LV) hypertrophy (LVH) is an important CV risk factor, but its progression has not been documented in early CKD. We explored whether progression of LVH in early CKD would occur despite stable kidney function. Methods: We conducted a post hoc analysis of a 12-month study of lanthanum carbonate in stage 3 CKD, which included longitudinal assessments of CV biomarkers. Primary outcome for the analysis was the change in LV mass (LVM) indexed to height in meters2.7 (LVM/Ht2.7). Secondary outcomes were changes in blood pressure (BP), pulse-wave velocity, LV systolic/diastolic function, fibroblast growth factor 23 (FGF23), klotho, and estimated glomerular filtration rate (eGFR). Results: Thirty-one of 38 original subjects had sufficient data for analysis. LVM/Ht2.7 increased (47 ± 13 vs. 53 ± 13 g/m2.7, p = 0.006) over 12 months despite stable BP, stable eGFR and normal LV systolic function. Vascular stiffness and LV diastolic dysfunction persisted throughout the study. Klotho levels decreased (748 ± 289 to 536 ± 410 pg/ml, p = 0.03) but were unrelated to changes in LVM/Ht2.7. The change in FGF23/klotho ratio was strongly correlated with changes in LVM/Ht2.7 (r2 = 0.582, p = 0.03). Conclusion: Subjects with stage 3 CKD exhibited increasing LVM, persistent LV diastolic dysfunction and vascular stiffness despite stable kidney function, BP and LV systolic function. Abnormal FGF23 signaling due to reduced klotho expression may be associated with increasing LVM. These findings deserve further evaluation in a larger population given the adverse prognostic value of these CV biomarkers.

Background/Aims: Cardiovascular disease (CVD) is increased in chronic kidney disease (CKD), and contributed to by the CKD-mineral bone disorder (CKD-MBD). CKD-MBD begins in early CKD and its vascular manifestations begin with vascular stiffness proceeding to increased carotid artery intima-media thickness (cIMT) and vascular calcification (VC). Phosphorus is associated with this progression and is considered a CVD risk factor in CKD. We hypothesized that modifying phosphorus balance with lanthanum carbonate (LaCO3) in early CKD would not produce hypophosphatemia and may affect vascular manifestations of CKD-MBD. Methods: We randomized 38 subjects with normophosphatemic stage 3 CKD to a fixed dose of LaCO3 or matching placebo without adjusting dietary phosphorus in a 12-month randomized, double-blind, pilot and feasibility study. The primary outcome was the change in serum phosphorus. Secondary outcomes were changes in measures of phosphate homeostasis and vascular stiffness assessed by carotid-femoral pulse wave velocity (PWV), cIMT and VC over 12 months. Results: There were no statistically significant differences between LaCO3 and placebo with respect to the change in serum phosphorus, urinary phosphorus, tubular reabsorption of phosphorus, PWV, cIMT, or VC. Biomarkers of the early CKD-MBD such as plasma fibroblast growth factor-23, Dickkopf-related protein 1 (DKK1), and sclerostin were increased 2- to 3-fold at baseline, but were not affected by LaCO3. Conclusion: Twelve months of LaCO3 had no effect on serum phosphorus and did not alter phosphate homeostasis, PWV, cIMT, VC, or biomarkers of CKD-MBD.

Bhutan is a country of approximately 700,000 people. It's located in the Himalayas between China and India. It is best known in the West as an exotic tourist destination because of the beautiful scenery, people, and the country's goal of “Gross National Happiness” that influences its development policy. The last decade has seen dramatic changes in Bhutan: It has gone from a monarchy to an elected democracy, and there has been an introduction of global ideas through the media, the Internet, and tourism. Despite apparent modernization, 80% of the people live in a rural setting and rely on subsistence agriculture for their livelihood. Healthcare in Bhutan is currently provided free to the people by the government. Basic healthcare and mild illnesses are managed at the local level by a network of clinics and small district hospitals with few staff. In addition, a parallel system of outpatient healthcare using traditional medical approaches is available in all hospitals. More serious health problems are referred to one of two full-service hospitals in the country. Although communicable diseases such as tuberculosis remain common, chronic non-communicable diseases (such as diabetes and hypertension) are increasingly recognized.1 Robin Owen (center) and Dr. Windus (second from right) with other healthcare professionals from the hospital in Thimphu, Bhutan. Dr. Windus has made a number of visits to Bhutan from 2005 to 2009 to evaluate chronic disease prevalence, provide nephrology consultation, and assist with continuing education. These visits were coordinated through the Ministry of Health and facilitated by several key physicians. The prevalence and causes of kidney disease are not completely understood, although risk factors for kidney disease are well known. Patients with nephrotic or nephritic presentations may be treated empirically or sent to India for a kidney biopsy and nephrology consultation. Typical diseases found on biopsy in these cases are IgA nephropathy or focal segmental glomerulosclerosis. However, in most cases presenting with chronic kidney disease (CKD), hypertension and diabetes are the most likely responsible factors. A recent WHO-Chronic Disease Risk Factors Survey of adults in Thimphu showed the prevalence of diabetes to be more than 6% and hypertension to be 36% (Bhaktaraj Giri, MD, personal communication November, 2008). It is likely that CKD will be a growing problem given the prevalence of these risk factors. In 1999, the Bhutan Health Ministry began a program to provide hemodialysis and kidney transplantation for patients with advanced kidney disease. The intent of this program was to offer hemodialysis as a bridge to a living-related donor kidney transplant in younger persons with kidney disease. A four-station dialysis unit was established at the JDW National Referral Hospital in Thimphu. Nurses were recruited and sent to Thailand for three months of training in basic dialysis techniques. As of 2005, the typical dialysis regimen was four hours twice weekly using a blood flow of 200 to 250 mL/min, dialysate flows of 500 mL/min, and 1.6 m2 polysulfone “high-efficiency” dialyzers, with an acetate bath. Most patients had an arteriovenous fistula placed in India. No evaluation of dialysis adequacy was obtained and dialysis-related laboratory testing was sporadic. Erythropoiesis stimulating agents became available in the past three years and were given at a fixed dose without adjustments. Nutrition counseling became available in the past two years, although it's not used routinely. Parathyroid hormone levels are not available and calcium supplements are used at times primarily for hypocalcemia. The traditional Bhutanese diet is very high in phosphorus and plasma phosphorus levels are typically very high. In conjunction with the development of a dialysis program, an arrangement was made with a transplant program at Christian Medical College and Hospital in Vellore, India for provision of living-related donor kidney transplants. Since 1999, more than 100 patients have undergone kidney transplant. The patients and families stay near the Vellore Medical Center for three months after the transplant for close monitoring, in case of rejection and/or complications of immunosuppression. After returning to Bhutan, they are seen periodically in the outpatient department for laboratory monitoring and renewal of immunosuppressive medications. At times, the transplant center places patients on relatively new and very costly immunosuppressive medications that are difficult to obtain. Blood monitoring of immunosuppressive drug values or viral testing are not available in Bhutan. Patients rarely return to India for follow-up unless a complication arises. In 2007, we did a dialysis nursing assessment and education program in Bhutan. The education needs for the Bhutanese dialysis nurses were found to be similar to those in the U.S., with a focus on dialysis adequacy, anemia management, bone and mineral metabolism, diet, and CKD education. When working with the nurses in Bhutan, initial relationship building and development of trust were very beneficial to a successful education process. Key first steps were to begin understanding the limits of their facility and technical resources, meeting their patients, and observing their routine approaches to dialysis. It was important during assessment that we not appear judgmental, but rather to be positive about the things being done well and to share educational opportunities with the staff. After three days of observation and discussions, we developed an educational symposium for all the dialysis nurses targeting the key issues we identified. Topics included basic principles of dialysis and how they related to adequacy, vascular access, anemia management, and CKD. Nurses were also taught the importance of diet and some basic principles of patient counseling. We also introduced the concept of quality assurance with concrete examples. In response to this symposium, the first change was to implement increased blood flow rates from 200 mL/min to 350 mL/min. With a deeper understanding of the benefits of laboratory management and trending, we helped them devise protocols for adjusting epoietin and iron therapy based on hematocrit values, and helped the staff to appreciate the complex interrelationship between adequacy, proper access, labs, medications, and nutrition. Follow-up visits by our team have shown that attention to higher blood flow rates and anemia management has been sustained. Ongoing laboratory monitoring and attention to nutrition issues still remains a challenge. The government of Bhutan currently pays for the cost of vascular-access placement, medications, and dialysis. Although a time limit for finding a living kidney donor has been set at three months, this plan has been found to be untenable in many cases. In reality, patients started on dialysis with no living-related donor stay on this treatment indefinitely, leading to the growth of the dialysis population. A limited number of dialysis machines and staff are available, due to financial constraints and space at the hospital. In order to provide dialysis to more patients, treatments schedules have been cut to once weekly in some patients, instead of twice a week. The original policy was designed to allow only living-related donors to donate kidneys. Initiation of an unrelated donor program would allow for more transplants and is under consideration. Investment in earlier detection and initiation of kidney-protective strategies in individuals with diabetes and hypertension. The close proximity to India may provide access to peritoneal dialysis supplies and fluids. Consideration should be given to starting a peritoneal dialysis program. The terrain in Bhutan is mostly mountainous, and many people live as far as a one- to two-day drive or bus ride from the nearest referral hospital, dialysis center, or specialist. Patients who need dialysis treatments are required to move closer to a dialysis unit. This disrupts family and social supports and adds a significant financial burden. Two additional dialysis units are planned but are not yet functioning. These units will further add to cost and require further nursing education. After the original nursing staff training was conducted in 1999, minimal ongoing education was available and no changes in the approach to managing the dialysis treatment had been made. Barriers include the availability of educators and time for scheduled education. Most of the advanced education is off-site and offered in India, Thailand, or elsewhere. Further on-site education is needed regarding safe dialyzer re-use and biomedical engineering/machine maintenance. Ongoing educational opportunities targeting the nursing staff and physicians. Further education could be augmented via the Internet and follow-up visits by educators. Follow-up nurse to nurse bedside observation and teaching of dialysis practices. Development of nurse-managed protocols for standard problems such as anemia and nutrition management. An ongoing program to send laboratory results and communications by e-mail to a partner facility. Nurses, physicians, and dietitians could consult between facilities on a regular basis. The prevalence and incidence of CKD in Bhutan is not known, but the risk factors for kidney disease are common and increasing. Community outreach and awareness of lifestyle issues to slow the progression of CKD. Continue to facilitate development of focused clinics for diabetes and hypertension with nurse educators, nutritional counseling, and self-care teaching to improve outcomes. This work would not have been possible without the generous support of Jack Ladenson, PhD with Pathologists Overseas, Inc.