Evidence for attenuation of hypothalamic gonadotropin-releasing hormone (GnRH) impulse strength with preservation of GnRH pulse frequency in men with chronic renal failure.

To investigate the nature of putative disturbances in pulsatile gonadotropin (LH) secretion in men with chronic renal failure, we undertook blood sampling at 10-min intervals for 24 h in 9 hemodialysis-dependent uremic men and 16 community- and age-matched controls. Serum LH concentrations were measured in a 2-site immunoradiometric assay, which does not cross-react with free alpha or LH beta-subunit and correlates well with an in vitro Leydig cell bioassay. Deconvolution analysis was applied to calculate the number, amplitude, mass, and duration of spontaneous LH release episodes and simultaneously estimate the half-life of endogenous LH in each subject. We observed that: 1) the estimated half-life of immunoradiometric LH removal from plasma averaged 103 +/- 11 min in normal and 207 +/- 29 min in uremic men (P < 0.01); 2) the number of LH secretory bursts was slightly higher in uremic than healthy men (e.g. 20 +/- 2.2 vs. 15 +/- 1.0 secretory bursts/24 h, respectively; P = 0.05); 3) the mass of LH secreted per burst was approximately 50% lower in chronic renal failure than in health, namely 1.4 +/- 0.18 vs. 2.8 +/- 0.42 IU/L (P < 0.01); 4) the decrease in the mass of LH secreted per burst was not due to a decline in LH secretory burst amplitude, but rather an attenuation of LH secretory burst duration (4.8 +/- 0.35 min in uremic vs. 11 +/- 1.3 min in normal men; P < 0.001); 5) the mean 24-h serum immunoradiometric LH concentration was significantly higher in uremia at 5.7 +/- 0.68 vs. 3.6 +/- 0.41 IU/L in controls (P = 0.017); and 6) serum estradiol concentrations were increased in uremia, but total and free testosterone concentrations did not differ significantly between the two subject groups. In response to synthetic GnRH (10 micrograms, administered iv after the 24-h basal sampling period), the mean mass of immunoradiometric LH released within each calculated LH secretory burst was similar in uremic (n = 8) and normal (n = 21) individuals. We conclude that uremia is accompanied by a specific defect in the pulsatile mode of LH secretion, which is marked by an abbreviation of LH secretory burst duration and a consequent fall in the mass of LH secreted per spontaneous release episode. There is no overall decline in LH secretory pulse frequency or gonadotroph responsiveness to a submaximally effective dose of exogenous GnRH. Such findings are consistent with diminished hypothalamic GnRH impulse strength.(ABSTRACT TRUNCATED AT 400 WORDS)

Improved urea reduction ratio and Kt/V in large hemodialysis patients using two dialyzers in parallel.

Delivered dose of hemodialysis (HD) in large patients with end-stage renal disease is often less than adequate. Fourteen chronic HD patients with weights greater than 80 kg participated in a prospective, cross-over study comparing urea reduction ratio (URR +/- SEM) and the fractional clearance index for urea (eKt/V(urea) +/- SEM) on a single polysulfone dialyzer for a control (HDC) period of 4 weeks versus clearances obtained with two dialyzers in parallel during an intervention (HDP) period of 4 weeks. Clearance of the surrogate middle molecule iohexol (C(Io)) was also measured. Health status was assessed with the SF-36. Blood and dialysate flow rates and duration of HD sessions were constant. URR increased from 0.67 +/- 0.006 during HDC to 0.72 +/- 0.006 with HDP (P < 0.0001). eKt/V(urea) increased from 1.16 +/- 0.021 to 1.34 +/- 0.021 (P < 0.0001). Increased URR and eKt/V(urea) occurred in all 14 during HDP (P < 0.05). C(Io) during HDP averaged 182 +/- 7.7 mL/min compared with 131 +/- 5.4 mL/min in HDC sessions (P < 0.00001). Health status improved in six of eight categories. Expense increased approximately $14.27 per dialysis with HDP. In 11 of 14 patients continued on two dialyzers in parallel for 1 year, monthly eKt/V averaged 1.46 +/- 0.066, and health status further improved in five of eight categories. In large patients, two dialyzers in parallel increased urea and iohexol clearance. Increased urea clearance was maintained for 1 year, and health status improved.

Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men.

To investigate the pathophysiology of altered growth hormone (GH) and prolactin secretion in endstage renal disease, we sampled blood at 10-min intervals for 24 h and applied deconvolution analysis to calculate hormone half-lives and pulsatile secretion rates. Two-site immunoradiometric assays were employed to quantitate presumptively intact GH and prolactin in nine middle-aged men with chronic renal failure and 14 gender-, age-, body weight- and community-matched controls. We observed that the half-lives of endogenous GH and prolactin were prolonged significantly in uremia: for GH, control 17 +/- 1.4 versus uremia 21 +/- 1.3 min (p < 0.05); for prolactin, control 66 +/- 9.3 versus uremia 112 +/- 10 min (p < 0.01). Daily GH secretion rates exceeded sex-, age- and weight-predicted values in eight of nine uremic individuals, while values for prolactin were variable but on average twofold higher in uremia. In both the somatotropic and lactotropic axes, the frequency of secretory bursts was increased significantly (for GH, control 11 +/- 1.1 versus uremia 15 +/- 0.84 secretory events/24 h: for prolactin, control 20 +/- 0.90 versus uremia 27 +/- 1.3 pulses/24 h, p < 0.05). Although there were no significant alterations in the mean amplitude, duration or mass of GH secretory bursts, prolactin secretory burst amplitudes were elevated threefold in uremia (p < 0.01). These distinctive mechanisms brought about higher 24-h mean serum concentrations of GH (0.70 +/- 0.17 control versus 1.22 +/- 0.32 micrograms/l uremia) and prolactin (7.3 +/- 2.4 control versus 26 +/- 6.1 micrograms/l uremia, p < 0.05). Lastly, serum concentrations of estradiol were increased but those of unconjugated estriol decreased in uremia. We conclude that hypersomatotropinemia and hyperprolactinemia in uremic men result from prolonged hormone half-lives combined with increased frequencies of secretory events driven by unknown stimuli within the respective axes, and/or by defects in their negative-feedback regulation. We postulate that the latter may arise from partial tissue resistance to hormone action in hemodialyzed men.

Flurbiprofen-associated acute tubulointerstitial nephritis.

We report a case of biopsy-proven acute tubulointerstitial nephritis associated with a second course of flurbiprofen, a nonsteroidal anti-inflammatory drug of the propionic acid class. The clinical presentation and course was consistent with acute tubulointerstitial nephritis due to these agents.

Neuroendocrine alterations in the somatotrophic axis in chronic renal failure.

Both secretion and metabolic clearance of GH in health and disease are subject to regulation by an array of metabolic, nutritional, physical activity, age, and body composition cues. Moreover, both GH and its mediators (e.g. IGF-I) are bound in plasma by one or more high-affinity binding proteins. Accordingly, carefully designed clinical and basic investigations are required to examine and clarify the diverse alterations in the dynamics of the somatotrophic axis that accompany the syndrome of CRF with its attendant attenuation of normal anabolism, growth and development.

Hemodialysis access stenosis: early detection with color Doppler US.

PURPOSE: To evaluate color Doppler ultrasound (US) in detection of subclinical stenosis of hemodialysis access grafts and fistulas. MATERIALS AND METHODS: Doppler US was performed in 40 consecutive patients with no clinical or laboratory findings of hemodialysis access dysfunction. To assess the presence and percentage of stenosis, the maximum systolic blood velocity and velocity ratios were measured and the US images were assessed visually. Fistulography was recommended in patients who demonstrated stenosis greater than 50% at US. RESULTS: At US, 32 of the 40 patients had evidence of stenosis greater than 50%. In 23 of the 32 patients, a follow-up fistulogram was obtained. Hemodynamically significant stenosis was confirmed in 19 of the 23 patients at fistulography. Percutaneous transluminal angioplasty was then performed in 18 of the 19 patients and was successful. CONCLUSION: Color Doppler US is more sensitive than clinical or laboratory methods for detection of hemodialysis access stenosis. Screening with US appears to enable earlier detection and therapy.

Risk factors in idiopathic renal vasculitis and glomerulonephritis.

In this retrospective study, we analyzed clinical laboratory, and pathologic variables to determine their value in predicting survival and survival free of renal failure for 170 consecutive patients with idiopathic renal vasculitis and glomerulonephritis evaluated during a 15 year period. Of the 170 patients, 108 had focal segmental necrotizing glomerulonephritis alone (FSNGN), 33 had FSNGN and small-artery vasculitis, and 29 had FSNGN and medium-sized artery vasculitis. Considerable overlap of clinical, laboratory, and pathologic findings existed among the three groups. Overall patient survival was 81% at one year, 61% at five years, and 44% at ten years, significantly less than expected survival. Overall survival free of renal failure, by definition, was lower than patient survival. There were no differences among these three groups in patient survival or survival free of renal failure. Multivariate analysis identified leukocytosis and serum creatinine level as independent predictors of patient survival and survival free of renal failure. In addition, univariate analysis identified age and hypertension as significant risk factors but did not add independent predictive value for these two end points. In patients with serum creatinine levels less than 4 mg/dl, the effect of increasing levels of leukocyte count was significantly associated with poorer outcomes for both patient survival (P = 0.006) and survival free of renal failure (P = 0.024). Outcomes for these two end points were worse for patients with lower serum creatinine levels (less than 4.0 mg/dl) and high leukocyte counts (greater than 16,000/mm3) than for those with serum creatinine levels greater than or equal to 4.0 mg/dl.