Rebecca J. Schmidt

Gynecologic and reproductive issues in women on dialysis

Most women on dialysis are amenorrheic and do not ovulate, but little information about menstrual patterns in women on dialysis exists, especially since the introduction and use of recombinant human erythropoietin, a therapy that may improve sexual interest and function. In this study, women who were < or = 55 years of age at the start of dialysis (n = 76) completed questionnaires and form the study group. Women older than 55 years at the start of dialysis did not complete the entire questionnaire (n = 115), but their medication records were reviewed for estrogen replacement therapy. The questionnaire asked about pregnancies, menstrual periods (regularity, frequency, duration, character of flow, menopause), and menopause before beginning dialysis and currently. Women also responded to questions about sexual activity, use of birth control, contraception counseling by physicians, yearly Papanicolaou smears, and mammograms. Demographic data (age, race, age at the time dialysis started, mode of dialysis, use of recombinant human erythropoietin, and history of renal transplant) were also obtained through the questionnaires. Fifty-nine percent of the 76 women who completed the study were white and had been on dialysis a median of 3 years (range, 0.1 to 18 years). The median age was 43 years, 68% were on hemodialysis, 90% were receiving recombinant human erythropoietin, and 70% had been pregnant (a total of 179 pregnancies; four pregnancies in four women occurred after the start of dialysis). Significantly more women were menstruating before dialysis started than currently (63% v 42%; P < 0.025), but the difference could be explained by patient age: currently menstruating women were younger (37 +/- 9 v 46 +/- 11 years; P = 0.0002). More women reported menstrual regularity before beginning dialysis (75% v 42% currently; P < 0.005), but there were no differences in number of days between or number of days of menstruation before beginning dialysis and currently. Menstrual flow was reported as heavier currently by more women (64% heavy flow with clots v 38% before dialysis started; P < 0.05). The median age at menopause was 47 years; 28% of the women were postmenopausal. Fifty percent of the women were sexually active, but only 36% used birth control. Discussions between the women and their nephrologist about possible pregnancy and contraception were reported by only 13% of women. Sixty-three percent of the women reported having yearly Papanicolaou smears and 73% had had a mammogram. Only 5% of the 113 women who were older than 55 years when they began dialysis were receiving estrogen replacement therapy. Amenorrhea was reported in this study by a smaller proportion of women than in studies conducted before the introduction of recombinant human erythropoietin. The possibility that erythropoietin may restore normal hormonal cyclic function in women with end-stage renal disease requires further study. Nephrologists as well as primary care physicians and gynecologists need to focus more on the gynecologic concerns of women on dialysis, including the potential for pregnancy. The effects of estrogen replacement on atherosclerosis and osteoporosis, and consideration of such therapy in women on dialysis warrants attention.

Indices of activity of the nitric oxide system in hemodialysis patients

Arginine deficiency and/or increased levels of circulating nitric oxide (NO) synthesis (NOS) inhibitors can cause reduced NOS, which may contribute to hypertension in patients with end-stage renal disease (ESRD). To test these hypotheses, NO oxidation products (NO(2) + NO(3) = NO(x)) and cyclic guanosine monophosphate (cGMP), the vasodilatory second messenger of NO, were measured in the blood, urine, and dialysate effluent of hemodialysis (HD) patients and compared with the blood and urine of healthy subjects. The subjects ate a controlled low-nitrate diet (approximately 330 micromol/d) for 48 hours before and during blood, dialysis effluent, and 24-hour urine collection. NO(x) output was significantly reduced in HD patients versus controls (552 +/- 51 v 824 +/- 96 micromol/24 h; P < 0.001), whereas cGMP output was not low versus controls. Plasma arginine level was normal and plasma levels of citrulline and the endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA), were markedly elevated in patients with ESRD versus controls. Systolic blood pressure was greater in HD patients compared with controls despite concurrent antihypertensive therapy in most patients with ESRD. These studies suggest NO production is low in patients with ESRD undergoing HD, possibly because of the increased ratio of plasma ADMA to arginine.

Nitric oxide production is low in end-stage renal disease patients on peritoneal dialysis

To test the hypothesis that nitric oxide (NO) deficiency occurs in end-stage renal disease (ESRD), NO oxidation products (NO2 + NO3 = NOx) and cGMP were measured in blood, urine, and dialysate effluent of peritoneal dialysis (PD) patients and compared with blood and urine of healthy subjects. All subjects were on a controlled low-nitrate diet (approximately 330 micromol/day). NOx and cGMP outputs were significantly reduced in PD patients (334 +/- 50 micromol/24 h and 55 +/- 13 nmol/24 h, respectively) vs. controls (823 +/- 101 micromol/24 h and 149 +/- 46 nmol/24 h). Plasma arginine was borderline low, plasma citrulline was elevated and plasma levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine were approximately five time higher in PD patients (2.2 +/- 0.3 microM) vs. controls (0.4 +/- 0.1 microM). Although blood pressure (BP) was not different between groups at the time of study, 10 of 11 PD patients were on medication for hypertension. These studies demonstrate that total NO production is low in ESRD, and with appropriate caution, we conclude that this NO deficiency may contribute to the increased BP that occurs in ESRD.To test the hypothesis that nitric oxide (NO) deficiency occurs in end-stage renal disease (ESRD), NO oxidation products (NO2 + NO3 = NOx) and cGMP were measured in blood, urine, and dialysate effluent of peritoneal dialysis (PD) patients and compared with blood and urine of healthy subjects. All subjects were on a controlled low-nitrate diet (∼330 μmol/day). NOx and cGMP outputs were significantly reduced in PD patients (334 ± 50 μmol/24 h and 55 ± 13 nmol/24 h, respectively) vs. controls (823 ± 101 μmol/24 h and 149 ± 46 nmol/24 h). Plasma arginine was borderline low, plasma citrulline was elevated and plasma levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine were approximately five time higher in PD patients (2.2 ± 0.3 μM) vs. controls (0.4 ± 0.1 μM). Although blood pressure (BP) was not different between groups at the time of study, 10 of 11 PD patients were on medication for hypertension. These studies demonstrate that total NO production is low in ESRD, and with appropriate caution, we conclude that this NO deficiency may contribute to the increased BP that occurs in ESRD.

Peginesatide for Anemia in Patients with Chronic Kidney Disease Not Receiving Dialysis

BACKGROUND Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peginesatide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis. METHODS In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.025 mg or 0.04 mg per kilogram of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 μg per kilogram. Doses of both drugs were adjusted to achieve and maintain hemoglobin levels between 11.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was -1.0 g per deciliter or higher. Cardiovascular safety was evaluated on the basis of an adjudicated composite end point. RESULTS In both studies and at both starting doses, peginesatide was noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], -0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, -0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide. CONCLUSIONS The efficacy of peginesatide (administered monthly) was similar to that of darbepoetin (administered every 2 weeks) in increasing and maintaining hemoglobin levels. However, cardiovascular events and mortality were increased with peginesatide in patients with chronic kidney disease who were not undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00598273 [PEARL 1], NCT00598442 [PEARL 2], NCT00597753 [EMERALD 1], and NCT00597584 [EMERALD 2].).

Fertility and contraception in end-stage renal disease

The hormonal aberrations that occur with end-stage renal disease (ESRD) are presented in this review in relation to fertility and conception among women on dialysis. The imbalance in gonadotropin production in dialysis-dependent men and women is characterized by elevations in luteinizing hormone (LH). In women dialysis patients, the normal estradiol-stimulated LH surge does not occur, resulting in anovulation. In men dialysis patients spermatogenesis is impaired, and low testosterone levels cause elevated LH. Infertility in those with ESRD is a culmination of many factors, including impotence and loss of libido, anovulation, and an altered hormonal milieu. Despite these inhibitors of conception, women on dialysis can conceive; pregnancy has been reported in 1% to 7% of women on dialysis in survey studies. The influence of dialysis mode (hemodialysis v peritoneal dialysis), recombinant human erythropoietin (EPO), and dialysis adequacy on the likelihood of conception among patients of either sex on dialysis is unknown. Reduced sexual activity and interest has consistently been reported in the ESRD population. The reasons for this are complex and likely involve the effects of comorbid illnesses, overall health status, body image factors, and hormonal alterations. Nephrologists rarely discuss conception and contraception with their women dialysis patients. Greater attention to these issues is needed.

Effects of aging and alterations in dietary sodium intake on total nitric oxide production

Animal studies suggest that nitric oxide (NO) deficiency is linked to salt-sensitive hypertension and that NO activity decreases during normal aging. This study investigates the impact of increasing age and manipulations in dietary salt intake on biochemical indices of the NO system in healthy humans. We measured NO(2) + NO(3) (NO(X); stable oxidation products of NO) and cyclic guanosine monophosphate (cGMP; major second messenger) in plasma and urine of 30 healthy subjects aged 22 to 77 years. Subjects were maintained on controlled low NO(X) and low-, normal-, or high-salt diets for 3 days. Salt sensitivity of blood pressure was seen only in the oldest subjects. Plasma renin activity was suppressed by a high salt intake in all age groups, and baseline values declined with advancing age. Neither age nor salt intake correlated with indices of NO activity over the third 24-hour period of controlled salt intake. In a subgroup of subjects aged 33 +/- 4 years challenged with ultrahigh sodium intake (400 mEq/24 h), again there was no increase in NO(2) + NO(3) or cGMP measures. In contrast to animal studies, there is no correlation in humans between either salt intake or age and total NO production and activity, indicated by NO(2) + NO(3) and cGMP measures. This does not preclude undetected alterations occurring in NO production and/or activity in strategic locations in the kidney and cardiovascular system. Limitations of blood and urine measurements of NO(2) + NO(3) and cGMP as indices of NO activity are discussed.

Re-envisioning Fistula First in a patient-centered culture.

The main options for vascular access in hemodialysis patients are arteriovenous fistulas (AVFs), arteriovenous grafts, and tunneled cuffed central venous catheters. AVFs have the lowest complication rate and require the fewest interventions and lowest cost to maintain. There has been a dramatic national increase in prevalent AVFs among patients with ESRD in the United States driven, in part, by the Fistula First Breakthrough Initiative. The Fistula First Breakthrough Initiative has engaged stakeholders in the dialysis community to disseminate best practices and quality improvement activities to increase AVF prevalence in suitable candidates. In the pursuit of maximizing AVF placement and prevalence, less emphasis has been placed on the individual patient context. An AVF may not be the best access choice in a subset of patients, particularly those with poor long-term prognoses or comorbid chronic diseases with a short life expectancy, those patients more likely to die than to have their CKD progress to ESRD requiring dialysis, and those with vascular anatomy not amenable to successful AVF placement. Placement of an AVF in these patients subjects them to uncomfortable and likely unnecessary and/or unsuccessful surgeries at an expense, while doing little to improve their clinical outcome or their individual experience of care. AVF prevalence as a pay-for-performance measure without the appropriate case-mix adjustment may penalize providers for accepting higher-risk patients. Although a functioning AVF that provides reliable hemodialysis remains the gold standard for vascular access for most patients, it may not be the most suitable option for every patient.

Treating anemia of chronic kidney disease in the primary care setting: cardiovascular outcomes and management recommendations

Anemia is an underrecognized but characteristic feature of chronic kidney disease (CKD), associated with significant cardiovascular morbidity, hospitalization, and mortality. Since their inception nearly two decades ago, erythropoiesis-stimulating agents (ESAs) have revolutionized the care of patients with renal anemia, and their use has been associated with improved quality of life and reduced hospitalizations, inpatient costs, and mortality. Hemoglobin targets ≥13 g/dL have been linked with adverse events in recent randomized trials, raising concerns over the proper hemoglobin range for ESA treatment. This review appraises observational and randomized studies of the outcomes of erythropoietic treatment and offers recommendations for managing renal anemia in the primary care setting.

Informing Our Elders About Dialysis: Is an Age-Attuned Approach Warranted?

As the fastest growing sector of the incident ESRD population, older patients constitute a group for which renal replacement therapy has special implications. Older CKD patients have unique needs by virtue of advanced age, high prevalence of comorbid conditions, slower progression of renal disease, and reduced survival. Burdens and risks attendant to dialysis may be amplified in the older patient and patients with impaired functional status or comorbid conditions, and therefore, dialysis may confer little to no survival benefit. Rates of dialysis withdrawal are highest among the oldest patients, raising the possibility that the standard content of informed consent for dialysis warrants an age-sensitive approach that is attuned to the very different balance of pros and cons of dialysis for older patients with multiple comorbidities and younger patients with limited comorbidity. Informed consent for older patients should include presentation of risks, benefits, and burdens associated with dialysis, age-specific estimates of prognosis with and without dialysis, and potential for loss of independence and decline in functional status with initiation of dialysis. In this article, medical evidence and clinical practice guidelines relevant to advance care planning for the older patient with CKD are reviewed, issues to consider in the dialogue with older patients contemplating dialysis are presented, and recommendations for an age-attuned approach to informed consent for older CKD patients are made.

Hormone Replacement Therapy in Postmenopausal Women with End‐Stage Renal Disease: A Review of the Issues

Hormone replacement is an integral part of therapies to prevent osteoporosis in postmenopausal women and may be considered a component in the treatment of dyslipidemia, cardiovascular disease, and possibly cognitive function. The indications for, and efficacy and prescription of, hormone replacement therapy in postmenopausal women with ESRD have been infrequently studied and less than 10% of postmenopausal women on dialysis are receiving hormone replacement. Small studies suggest that hormone replacement therapy is valuable in treating the dyslipidemia of women on dialysis, but indicate that a reduction in the dosage of hormone replacement may be needed. A potential role for hormone replacement therapy in the treatment and/or prevention of osteoporosis and sexual dysfunction in postmenopausal women on dialysis exists as well.