Polly A. Bittle

Alterations in soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in hemodialysis patients

Hemodialysis (HD) patients can develop acute reactions during treatment as well as increased long-term susceptibility to infections and malignancies. Abnormalities in leukocyte adhesion may contribute to these processes. Recently, serum levels of soluble adhesion molecules have been detected in circulating blood of normal subjects and in patients with chronic renal failure. We studied the effects of a single dialysis session with new cuprophane membrane on the soluble (s) form of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), two adhesion molecules with a variety of immunologic roles. Significant elevations in both sICAM-1 (523 +/- 61 v 304 +/- 45 [SEM] ng/mL, P < 0.05) and sVCAM-1 (2,055 +/- 270 v 1,189 +/- 149 ng/mL, P < 0.05) were observed in HD patients at baseline compared with controls. Both sICAM-1 and sVCAM-1 levels decreased after a 3-hour HD session (P < 0.001). Early in HD, sICAM-1 levels, though lower than predialysis, were elevated in the exit line of the dialyzer compared with entrance (339 +/- 64 v 259 +/- 53 ng/mL, P < 0.001), whereas sVCAM-1 was decreased on the exit line compared with entrance (639 +/- 90 v 932 +/- 92 ng/mL, P < 0.001). Because ICAM-1 and VCAM-1 are important for many leukocyte functions, alterations in serum levels of sICAM-1 and sVCAM-1 may play a role in the immunologic consequences of uremia and HD treatment.

Cyclosporine-Induced Alterations in the Hypothalamic Hypophyseal Gonadal Axis in Transplant Patients

We evaluated the response of 20 male patients, 13 cadaveric kidney and 7 heart transplant recipients, to the administration of 100 micrograms GnRH (gonadotropin-releasing hormone) and 500 micrograms TRH (thyrotropic-releasing hormone). All of the heart transplant recipients and 7 of the kidney transplant patients were receiving a combination of cyclosporine, azathioprine and prednisone; while the 6 remaining kidney transplant patients received azathioprine and prednisone. The patients receiving cyclosporine had decreased plasma levels of prolactin, and manifested a blunted response to TRH administration for prolactin and TSH. The heart transplant patients had a blunted response of LH and FSH to the administration of GnRH. The levels of testosterone were found to be low in all patients regardless of the immunosuppressant therapy. Despite the low testosterone levels, no increment in the concentration of LH or FSH was present. Intramuscular administration of HCG (human chorionic gonadotropin) (Ayerst Laboratories, New York, N.Y.) failed to increase the testosterone concentration in 5 of 6 patients with renal transplants, 3 taking cyclosporine and 3 taking azathioprine. This study suggests that cyclosporine has a selective effect on the hypothalamus and/or hypophysis, resulting in lower baseline levels of plasma prolactin and a pituitary insensitivity to TRH administration. In addition, FSH and LH were low or normal in the presence of low testosterone levels, suggesting that the hypothalamic pituitary gonadal axis is impaired. Furthermore, there may be a direct toxic effect of the immunosuppressant medications on the gonads, manifested as lower testosterone levels and inability to respond to the administration of HCG.

Clinical practice considerations and review of the literature for the Use of DPP-4 inhibitors in patients with type 2 diabetes and chronic kidney disease.

OBJECTIVE Many commonly prescribed agents for the treatment of type 2 diabetes (T2DM) have important restrictions on use in patients with renal impairment. Prescribing information and published data on dipeptidyl peptidase-4 (DPP-4) inhibitors indicate that these agents are suitable for use in this patient population. However, a recent database analysis indicated prevalent underrecognition of renal impairment and limited awareness of prescription considerations associated with DPP-4 inhibitor use in patients with renal impairment. Thus, this article reviews recent literature on the safety, efficacy, pharmacokinetics, and clinical use of DPP-4 inhibitors in patients with renal impairment and T2DM. METHODS PubMed searches were conducted for literature describing the use of DPP-4 inhibitors in patients with renal impairment. RESULTS Most DPP-4 inhibitors are characterized by significant renal clearance. As a result, pharmacokinetics are measurably affected by the presence of renal impairment; plasma exposure of DPP-4 inhibitors and their metabolites may increase by up to sevenfold in severe impairment/end-stage renal disease. The exception in this case is linagliptin, which is eliminated predominantly via the hepatobiliary system. Our search identified several studies that evaluated specific doses of DPP-4 inhibitors in patients with renal impairment and reported positive safety and efficacy results. CONCLUSIONS Overall, DPP-4 inhibitors are an effective means of controlling blood glucose in patients with T2DM and renal impairment. Considering the restrictions associated with many other antihyperglycemic agents when used in patients with renal impairment, DPP-4 inhibitors should be a considered as a treatment option in this patient population.

The effects of high altitude on hypothalamic‐pituitary secretory dynamics in men

OBJECTIVE Individuals adapted to high altitude (HA) have abnormalities In endocrine function and specifically In the pituitary‐thyroid axis and aldosterone regulation. In this study we assessed hypothalamic‐pituitary function In men adapted to high altitude living using exogenous administration of synthetic hypothalamic hormones

Response to growth hormone-releasing hormone in adult renal failure patients on hemodialysis☆☆☆

Exogenous synthetic growth hormone-releasing hormone (GHRH [hpGRF-40]), 1 microgram/kg body weight, was administered intravenously (IV) to eight men with chronic renal failure on chronic hemodialysis and to seven men matched for age (control group). Basal and stimulated growth hormone (GH) concentrations following GHRH (hpGRF-40) in renal failure patients were significantly higher than in controls. Basal prolactin and somatomedin C/insulin-like growth factor-1 (SmC/IGF-1) concentrations were significantly higher in the renal failure patients compared with controls. Following GHRH there was no further increase in serum concentration of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, SmC/IGF-1, or cortisol. GH appears to be the only pituitary hormone where there is an exaggerated response to its specific releasing hormone in adults with renal failure.

Low-dose captopril scintigraphy in the evaluation of renovascular hypertension.

This study compared the results of renal scintigraphy with simultaneous administration of Tc-99m DTPA and 1–131 Hippuran (before and after 25 mg of oral captopril) with the results of the renal arteriogram and renal vein renins (before and after the administration of 25 mg of oral captopril) to evaluate the sensitivity and specificity of renal scintigraphy in the diagnosis of renovascular hypertension. The results of 21 consecutive patients suspected of having renovascular hypertension who under-went scintigraphy and renal arteriography were analyzed. Renal scintigraphy postcaptopril detected all the cases of renovascular hypertension (eight patients) plus two additional patients who had significant renovascular stenosis but no renin overproduction. The results indicate that the renal scintigram, before and after the administration of captopril, is an accurate and sensitive test for the detection of renovascular hypertension and should be used as a screening procedure before arteriography is considered.

Effect of haemoglobin and endogenous erythropoietin on hypothalamic‐pituitary thyroidal and gonadal secretion: an analysis of anaemic (high EPO) and polycythaemic (low EPO) patients

OBJECTIVE Correction of anaemia with recombinant human erythropoietin (rHu‐EPO) Improves the responsiveness of thyroidal and gonadal axes to exogenous TRH and GnRH In chronic haemodialysis patients, but the mechanisms remain to be fully elucidated. In order to assess the Influences of endogenous erythropoietin on the hypothalamo‐hypophyseal thyroidal and gonadal axes, we studied the response of polycythaemic and anaemic patients, In comparison to normal controls, after the administration of exogenous TRH and GnRH.

Nutritional implications of recombinant human erythropoietin therapy in renal disease

The treatment of anemia in patients with renal failure has been dramatically changed with the development of recombinant human erythropoietin (r-HuEPO). This review discusses the pathogenesis of the anemia renal failure and the biology of erythropoietin. Causes of poor response to r-HuEPO therapy are outlined, and the importance of adequate available iron is highlighted. Parameters used to measure iron adequacy include serum iron levels, transferrin saturation, and ferritin levels. Other nutritional deficiencies, such as folic acid and vitamin B-12, can also impair r-HuEPO response. Clearly, the advent of r-HuEPO treatment for patients with renal failure and anemia has brought another dimension to the care of these patients. Optimal nutrition management is critical for the success of this new agent.

Commentary: ENDOCRINE DYSFUNCTION

We will address the physiology as well as some clinical observations regarding the secretion of prolactin (PRL), cortisol andb-endorphin in patients with ESRD. In order to understand the effects of high circulating prolactin levels in renal failure patients, we must understand its normal physiologic effects. PRL is produced in the anterior pituitary (lactotropic cells) and secreted normally in a pulsatile fashion in a bimodal pattern. The highest production of prolactin is between 4 and 10 AM and the lowest between 3 and 11 PM. During sleep the peak secretory heights and amplitude are enhanced (1). Normally, this pulsatile secretion is independent from the functional gonadal state, gender or concentration of steroid hormones (2). The secretion of PRL is predominantly under inhibitory hypothalamic control (3). Dopamine inhibits prolactin mRNA levels (4) at the level of prolactin gene transcription (5) and regulates lactotroph proliferation as well (6). A specific dopamine receptor (DRD2) is present in the anterior pituitary. Endogenous opiods of the gamma-aminobutyric acid (GABAergic) type also have an inhibitory action on PRL secretion (7). Thyrotropin releasing hormone (TRH) stimulates PRL gene expression but its physiological control of PRL release is still in question (8). Alpha 1-adrenergic receptors located in the central nervous system have a PRL stimulatory action. Normally, infusion of the alpha 1-adrenergic agonist methoxamine stimulates the secretion of PRL, thyroid stimulating hormone (TSH) and adrenocorticotropin (ACTH) and this effect can be abolished by the administration of the alpha 1-antagonist prazosin. The fact that norepinephrine does not produce the same effect indicates that the stimulant alpha 1-adrenergic receptors are located in the central nervous system and not in the pituitary itself since norepinephrine cannot cross the blood-brain barrier (9). Circulating estrogen is the most important peripheral regulator for an increase in PRL gene expression (8). Also, PRL acts on the gonadotropin-releasing hormone (GnRH) neurons either directly or indirectly through an inhibitory afferent neuronal system, decreasing their responsiveness to stimuli (10). Clinically, excessive secretion of PRL may interfere with the cyclic release of gonadotropin and may inhibit the peripheral activity of gonadotropin on the gonads (8). In the rat, its high concentration provokes a premature release of germ cells in the testes, the number of spermatozoa decreases and the sperm cells have morphological abnormalities in the head and tail (11). In men, low sperm counts have been correlated with hyperprolactinemia (12) and in women hyperprolactinemia is frequently diagnosed in patients with infertility and menstrual cycle irregularities (13). Premenopausal anovulatory bleeding has also been associated with hyperprolactinemia (14). Osteopenia is an important clinical manifestation of hyperprolactinemia and has been attributed to deficiencies of the gonadal hormones (15). However, an increase in parathyroid hormone related peptide (PTHrP) expressed in human mammary tissue has been described in lactation and in patients with prolactinomas (16, 17). Patients with renal failure have basal PRL levels higher than normal and do not respond to the exogenous administration of TRH (18) or to vasoactive intestinal peptide (VIP), another stimulant of PRL secretion (8, 19). Investigation of the secretory pattern of the lactotropic axis in patients with chronic renal failure revealed that the frequency of secretory bursts is increased threefold, producing a prolonged half-life of the hormones. The stimuli that drive this increment in secretory activity are not currently known (20) but it may be caused by a lactotroph which is unresponsive to the inhibitory effects of dopamine (21). In addition to the increased production of PRL, there also appears to be a 33% decrease in the metabolic clearance rate (MCR) of PRL due to chronic renal failure (22). Erectile dysfunction, a common finding in dialysis patients, does not improve by normalization of PRL concentration through the administration of bromocriptine (23). Therefore, it is difficult to attribute impotency to excessive circulating PRL levels in renal failure patients. However, low sperm counts and abnormally low testosterone levels in men and abnormal menstruation in women may be the result of excessive PRL production. Erythropoietin (EPO) therapy of anemia has been associated with decreased basal elevations in serum PRL levels in patients with end stage renal disease (24). Some authors, without detailed studies, have equated normalization of PRL levels with improvement in sexual function in men and normalization of menstruation in women (24). The fall in PRL was not associated with an improvement in the low testosterone concentrations in these patients, indicating that any improvement in sexual function is not mediated by an increase in serum testosterone. Also, the response of PRL to exogenous TRH is not normalized by EPO (25). At this point it is difficult to attribute all the sexual dysfunction present in renal failure patients to only abnormally high circulating PRL levels. Thorough studies of the diurnal production of PRL before and after the correction of the anemia are needed. These may shed light on the still mysterious source of the sexual dysfunction in patients on dialysis.

Effect of potassium concentration in dialysate on total body potassium

OBJECTIVE To investigate the effects of the presence/absence of potassium in the dialysate on total body potassium content in stable hemodialysis patients. DESIGN Randomized selection. SETTING Outpatient chronic hemodialysis unit at the James A. Haley VA Hospital in Tampa, Florida. PATIENTS Six adult hemodialysis patients (mean age 48 +/- 11.61 years, range 32-65 years) participated in this study. They were all males, four African-Americans and two Caucasians. INTERVENTION Subjects in a random order received dialysis using a dialysate containing no potassium for 3 months, followed by a 2 mEq/L of potassium for another 3 months. Total body potassium measurements and routine blood analysis were taken at baseline and after each three month period. All subjects received diet instruction pre and monthly on a 3 g/day potassium dietary restriction. MAIN OUTCOME MEASURED There were no significant differences in the amount of total body potassium concentration between the two different dialysates containing 0 or 2 mEq/L potassium. Mean values of serum albumin were significantly higher when the subjects were dialyzed on a 0 potassium bath. CONCLUSION The use of dialysate containing 0 or 2 mEq/L potassium concentration does not make a significant difference with regard to total body potassium concentration and maybe advantageous for the patients in terms of more freedom in nutritional intake as demonstrated by a significant increase in serum albumin when they were dialyzed on a 0 potassium bath.