to assess temporal changes in the incidence of human immunodeficiency virus-1-associated nephropathy (HIVAN), and the association with use of highly active antiretroviral therapy (HAART).
HIVAN ...incidence and risk factors were assessed in 3976 HIV-1-infected individuals followed in clinical cohort in Baltimore, Maryland, USA from 1989 to 2001. The incidence of HIVAN, defined by biopsy or a conservative uniformly applied clinical coding protocol, was expressed in terms of person-years, and Poisson regression was used for multivariate analysis.
Ninety-four patients developed HIVAN over the course of the study for an incidence of 8.0 per 1000 person-years 95% confidence interval (CI), 6.5 to 9.8. African American race and advanced immunosuppression were strongly associated with HIVAN risk. HIVAN incidence declined significantly in 1998-2001 compared with 1995-1997. Among patients with a prior diagnosis of AIDS, HIVAN incidence was 26.4, 14.4, and 6.8 per 1000 person-years in patients not receiving antiretroviral therapy, treated with nucleoside analogue therapy only, or treated with HAART, respectively (P < 0.001 for trend). In multivariate analysis, HIVAN risk was reduced 60% (95% CI, -30 to -80%) by use of HAART, and no patient developed HIVAN when HAART had been initiated prior to the development of AIDS.
HAART was associated with a substantial reduction in HIVAN incidence. Additional follow-up will be needed to determine if renal damage in susceptible individuals is halted or merely slowed by HAART, particularly when control of viremia is incomplete or intermittent.
Clostridium difficile has been reported to occur in the gastrointestinal tract of 50% of Cystic Fibrosis (CF) subjects, however, clinical C. difficile infection (CDI) is a rare occurrence in this ...cohort despite the presence of toxigenic and hypervirulent ribotypes. Here, we present the first longitudinal, multicentre analysis of C. difficile prevalence among adult CF subjects.
Faecal samples were collected from adults with CF (selected based on confirmed Pseudomonas aeruginosa pulmonary colonisation) from Ireland, UK and Belgium as part of the CFMATTERS clinical research trial (grant No. 603038) and from non-CF controls. Faecal samples were collected on enrolment, at three monthly intervals, during pulmonary exacerbation and three months post exacerbation. C. difficile was isolated from faecal samples by ethanol shocking followed by culturing on cycloserine cefoxitin egg yolk agar. Isolates were characterised in terms of ribotype, toxin type and antibiotic susceptibility to antibiotics routinely used in the treatment of CDI (metronidazole and vancomycin) and those implicated in induction of CDI (ciprofloxacin and moxifloxacin).
Prevalence of C. difficile among CF subjects in the three sites was similar ranging from 47% to 50% at baseline, while the healthy control cohort had a carriage rate of 7.1%. Including subjects who were positive for C. difficile at any time point there was a higher carriage rate of 71.4%, 66.7% and 63.2% in Ireland, UK, and Belgium, respectively. Ribotyping of 80 isolates from 45 CF persons, over multiple time points revealed 23 distinct ribotypes with two ribotypes (046 and 078) shared by all centres. The proportion of toxigenic isolates varied across the sites, ranging from 66.7% in Ireland to 52.9% in Belgium and 100% in the UK. Antibiotic susceptibility rates to vancomycin, metronidazole, ciprofloxacin and moxifloxacin was 100%, 97.5%, 1.3% and 63.8%, respectively.
This study demonstrates the highest carriage rate of C. difficile to date in a CF cohort. Longitudinal data show that C. difficile can be a transient inhabitant of the CF gut, changing both in terms of strain and excretion rates.
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Hemodialysis is associated with an increased risk of neoplasms which may result, at least in part, from exposure to ionizing radiation associated with frequent radiographic procedures. In order to ...estimate the average radiation exposure of those on hemodialysis, we conducted a retrospective study of 100 patients in a university-based dialysis unit followed for a median of 3.4 years. The number and type of radiological procedures were obtained from a central radiology database, and the cumulative effective radiation dose was calculated using standardized, procedure-specific radiation levels. The median annual radiation dose was 6.9 millisieverts (mSv) per patient-year. However, 14 patients had an annual cumulative effective radiation dose over 20mSv, the upper averaged annual limit for occupational exposure. The median total cumulative effective radiation dose per patient over the study period was 21.7mSv, in which 13 patients had a total cumulative effective radiation dose over 75mSv, a value reported to be associated with a 7% increased risk of cancer-related mortality. Two-thirds of the total cumulative effective radiation dose was due to CT scanning. The average radiation exposure was significantly associated with the cause of end-stage renal disease, history of ischemic heart disease, transplant waitlist status, number of in-patient hospital days over follow-up, and death during the study period. These results highlight the substantial exposure to ionizing radiation in hemodialysis patients.
Residual and significant postinfarction left ventricular (LV) dysfunction, despite technically successful percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), ...remains an important clinical issue. In preclinical models, low-dose insulin-like growth factor 1 (IGF1) has potent cytoprotective and positive cardiac remodeling effects. We studied the safety and efficacy of immediate post-PCI low-dose intracoronary IGF1 infusion in STEMI patients.
Using a double-blind, placebo-controlled, multidose study design, we randomized 47 STEMI patients with significantly reduced (≤40%) LV ejection fraction (LVEF) after successful PCI to single intracoronary infusion of placebo (n = 15), 1.5 ng IGF1 (n = 16), or 15 ng IGF1 (n = 16). All received optimal medical therapy. Safety end points were freedom from hypoglycemia, hypotension, or significant arrhythmias within 1 hour of therapy. The primary efficacy end point was LVEF, and secondary end points were LV volumes, mass, stroke volume, and infarct size at 2-month follow-up, all assessed by magnetic resonance imaging. Treatment effects were estimated by analysis of covariance adjusted for baseline (24 hours) outcome.
No significant differences in safety end points occurred between treatment groups out to 30 days (χ2 test, P value = .77). There were no statistically significant differences in baseline (24 hours post STEMI) clinical characteristics or LVEF among groups. LVEF at 2 months, compared to baseline, increased in all groups, with no statistically significant differences related to treatment assignment. However, compared with placebo or 1.5 ng IGF1, treatment with 15 ng IGF1 was associated with a significant improvement in indexed LV end-diastolic volume (P = .018), LV mass (P = .004), and stroke volume (P = .016). Late gadolinium enhancement (±SD) at 2 months was lower in 15 ng IGF1 (34.5 ± 29.6 g) compared to placebo (49.1 ± 19.3 g) or 1.5 ng IGF1 (47.4 ± 22.4 g) treated patients, although the result was not statistically significant (P = .095).
In this pilot trial, low-dose IGF1, given after optimal mechanical reperfusion in STEMI, is safe but does not improve LVEF. However, there is a signal for a dose-dependent benefit on post-MI remodeling that may warrant further study.
Vitamin D insufficiency is highly prevalent among renal transplant recipients and in observational studies is associated with adverse outcomes. Hypercalcemia, usually due to persistent ...hyperparathyroidism, also commonly occurs in this population and often coexists with vitamin D insufficiency. However, concern that vitamin D supplementation might exacerbate the pre-existing hypercalcemia often leads clinicians to avoid vitamin D supplementation in such patients. This feasibility study aimed to quantify the effect on serum calcium of short-term low-dose cholecalciferol supplementation in a group of renal transplant recipients with a recent history of serum calcium levels >10 mg/dL.
A 2-week, single arm, open-label trial.
Renal transplant follow-up clinic in an Irish University Hospital.
Eighteen vitamin D-insufficient adult patients with a functioning renal allograft (estimated glomerular filtration rate > 30 mL/minute/1.73 m
) and a recent history of serum calcium >10 mg/dL.
Two weeks of treatment with 1,000 IU cholecalciferol/day.
Change in ionized calcium and urine calcium:creatinine ratio at follow-up compared with baseline.
Mean (standard deviation SD) baseline 25 (OH) vitamin D (25 (OH) D) concentration was 15.9 (5.97) ng/mL and mean (SD) baseline serum calcium was 10.50 (0.6) mg/dL. Following the 2-week intervention, median (interquartile range IQR) change in serum calcium from baseline was -0.08 (-3.6 to 0.08) mg/dL, P = .3. Mean (SD) ionized calcium decreased from 5.24 (0.32) mg/dL at baseline to 5.16 (0.28) mg/dL, P = .05. Median (IQR) change in the urinary calcium:creatinine ratio was 0.001 (-0.026 to 0.299) mg/mg, P = .88. Median (IQR) change in 25 (OH) D was 3.6 (2.9-6.2) ng/mL, P < .05.
In vitamin D-insufficient renal transplant recipients at risk of hypercalcemia, low-dose short-term oral cholecalciferol supplementation improves 25 (OH) D concentrations without exacerbating hypercalcemia or increasing the urinary calcium:creatinine ratio.
Abnormalities in mineral homeostasis are ubiquitous in patients on dialysis, and influenced by race. In this study, we determine the race-specific relationship between mineral parameters and ...mortality in patients initiating hemodialysis.
We measured the levels of fibroblast growth factor 23 (FGF23) and 25-hydroxyvitamin D (25 D) in 184 African American and 327 non-African American hemodialysis patients who enrolled between 1995 and 1998 in the Choices for Healthy Outcomes in Caring for ESRD Study. Serum calcium, phosphorus, parathyroid hormone (PTH) and total alkaline phosphatase levels were averaged from clinical measurements during the first 4.5 months of dialysis. We evaluated the associated prospective risk of mortality using multivariable Cox proportional hazards models stratified by race.
PTH and total alkaline phosphatase levels were higher, whereas calcium, phosphorus, FGF23 and 25 D levels were lower in African Americans compared to those of non-African Americans. Higher serum phosphorus and FGF23 levels were associated with greater mortality risk overall; however, phosphorus was only associated with risk among African Americans (HR 5.38, 95% CI 2.14-13.55 for quartile 4 vs. 1), but not among non-African Americans (p-interaction = 0.04). FGF23 was associated with mortality in both groups, but more strongly in African Americans (HR 3.91, 95% CI 1.74-8.82 for quartiles 4 vs. 1; p-interaction = 0.09). Serum calcium, PTH, and 25 D levels were not consistently associated with mortality. The lowest and highest quartiles of total alkaline phosphatase were associated with higher mortality risk, but this did not differ by race (p-interaction = 0.97).
Aberrant phosphorus homeostasis, reflected by higher phosphorus and FGF23, may be a risk factor for mortality in patients initiating hemodialysis, particularly among African Americans.
Sirolimus (Rapamune; Wyeth-Ayerst, Philadelphia, PA) is a newer immunosuppressive drug with no known acute or chronic nephrotoxic effects; however, limited data are available in liver transplant ...recipients. We prospectively evaluated changes in renal function in liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus monotherapy. We measured serial serum creatinine levels in liver transplant recipients with chronic nephrotoxicity caused by calcineurin inhibitors before and after conversion to sirolimus therapy. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease formula. Change in eGFR over time, incidence of acute hepatocellular rejection, and adverse events while being administered sirolimus monotherapy were recorded. Mean interval between liver transplantation and initiation of sirolimus therapy was 310 weeks (range, 9 to 780 weeks). Of 21 patients included in our study, 18 patients were converted to sirolimus monotherapy and 3 patients were switched to sirolimus and low-dose steroid therapy. Patients were followed up for a mean of 66.8 ± 38.9 (SD) weeks after conversion. Renal function improved in 71% of patients (15 of 21 patients). Median eGFR improved significantly from 34 mL/min/1.73 m2 at the time of conversion to 43 mL/min/1.73 m2 at the last follow-up (27% increase in eGFR; P = 001). Median monthly change in eGFR was from −0.25 mL/min/1.73 m2 pre-sirolimus therapy to +1.28 mL/min/1.73 m2 post-sirolimus therapy (P = .09). Adverse events were mostly mild and self-limited. Only 1 patient developed biopsy-proven acute cellular rejection, which was treated with sirolimus and mycophenolate mofetil. Two patients discontinued sirolimus therapy because of toxicity (oral ulceration, 1 patient; interstitial pneumonitis, 1 patient). Renal function improved significantly in the majority of liver transplant recipients with renal insufficiency caused by calcineurin inhibitors when converted to sirolimus therapy. Sirolimus monotherapy provided adequate immunosuppression with a low incidence of acute cellular rejection and minimal adverse events. (Liver Transpl 2003;9:1079-1085.)
Mycophenolate mofetil treatment for primary glomerular diseases.
Treatment of primary glomerular diseases may be unsuccessful or have potential toxicities. Therefore, we evaluated the use of ...mycophenolate mofetil (MMF) for empirical treatment of primary glomerulopathies.
Forty-six patients with biopsy-proven primary glomerulopathies received MMF for ≥3 months as adjunctive or primary treatment. Median (range) 24-hour urine protein to creatinine ratio (Up/c) and serum creatinine at the start and end of MMF therapy were compared using the Wilcoxon signed-ranks test.
Overall, the median Up/c decreased from 4.7 (range <0.1, 20.3) to 1.1 (<0.1, 14.3; P < 0.001) at the end of MMF treatment with no significant change in median serum creatinine 1.3 (0.6 to 6.1) to 1.2 (0.5 to 6.5) mg/dL. Median serum albumin increased from 3.4 (1.4, 4.6) to 4.1 (1.7, 48) g/dL (P < 0.001) and the median serum cholesterol decreased from 270 (148, 795) to 220 (140, 309) mg/dL (P < 0.001) post-treatment. For those with minimal change disease, a complete steroid withdrawal was accomplished in 5/6 steroid dependent patients. Focal segmental glomerulosclerosis (FSGS) patients had a median Up/c that decreased from 2.7 (0.1, 20.3) to 0.8 (<0.1, 8.2; P = 0.001) in 18 patients. In membranous nephropathy (MN) patients, the median Up/c decreased from 7.3 (0.1, 18.5) to 1.5 (<0.1, 14.3) (P = 0.001) in 17 patients. No significant change in median serum creatinine was detected in FSGS or MN patient groups during treatment.
Empirical MMF therapy in the majority of patients with primary glomerulopathies was well tolerated and achieved the goals of steroid withdrawal, improvement of nephrotic syndrome, and stabilization of renal function.
Background. There has been controversy about the utility of new third-generation parathyroid hormone (PTH) assays measuring only 1–84 PTH, with few large studies comparing second- and ...third-generation PTH measurements in patients with ESRD. Methods. We measured 1–84 PTH (‘biointact’ or ‘whole’ PTH) and total PTH (‘intact’ PTH) in a national cohort of 515 incident dialysis patients from banked frozen EDTA plasma (median follow-up, 35 months) and examined the accuracy of estimating 1–84 PTH from total PTH and the associations of these levels with patient characteristics and mortality. Results. The 1–84 PTH and total PTH levels were closely correlated. Higher 1–84 PTH was associated with African-American race and higher serum phosphate and lower calcium levels. The percentage of total PTH represented by 1–84 PTH was, on average, 53%, but with a wide range (25–89%). Calculating 1–84 PTH from total PTH using a proposed standard conversion factor (54%) led to misclassification of 8% of the population compared with measured 1–84 PTH. In a multivariate Cox proportional hazards model for all-cause mortality, a 1–84 PTH value >160 pg/ml was associated with increased risk of mortality (HR = 1.62, 95% CI, 1.03–2.54) compared to a level of 80–160 pg/ml. Elevated total PTH, 7–84 PTH and the 1–84 PTH/7–84 PTH ratio were not significantly associated with mortality. Conclusions. The 1–84 PTH and total PTH are highly correlated. Elevated 1–84 PTH was significantly associated with increased mortality, whereas total PTH did not reach statistical significance. Thus, although in other respect they are similar, there may be utility in measuring 1–84 PTH for its associations with mortality.
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