Faculty Bibliography

The purpose of this study was to evaluate in an animal model the safety and efficacy of dietary supplementation with high doses of selenium for the mitigation of the type of radiation injury that might be sustained during a nuclear accident or an act of radiological terrorism. Age-matched male rats were exposed to 10 Gy (single dose) of total-body irradiation (TBI) followed by a syngeneic bone marrow transplant, then randomized to standard drinking water or drinking water supplemented with sodium selenite or seleno-l-methionine. At 21 weeks after TBI, most rats on standard drinking water had severe renal failure with a mean blood urea nitrogen (BUN) level of 124 +/- 29 mg/dl (geometric mean +/- SE) whereas rats on selenium-supplemented drinking water (100 microg/day) had a mean BUN level of 67 +/- 12 mg/dl. The mitigating effect of selenium was confirmed by histopathological analyses. None of the animals on high-dose selenium showed signs of selenium toxicity. Our results suggest that dietary supplementation with high-dose selenium may provide a safe, effective and practical way to mitigate radiation injury to kidneys.

Suppression of the renin-angiotensin system has proven efficacy for mitigation and treatment of radiation nephropathy, and it has been hypothesized that this efficacy is due to suppression of radiation-induced chronic oxidative stress. It is known that radiation exposure leads to acute oxidative stress, but direct evidence for radiation-induced chronic renal oxidative stress is sparse. We looked for evidence of oxidative stress after total-body irradiation in a rat model, focusing on the period before there is physiologically significant renal damage. No statistically significant increase in urinary 8-isoprostane (a marker of lipid peroxidation) or carbonylated proteins (a marker of protein oxidation) was found over the first 42 days after irradiation, while a small but statistically significant increase in urinary 8-hydroxydeoxy-guanosine (a marker of DNA oxidation) was detected at 35-55 days. When we examined renal tissue from these animals, we found no significant increase in either DNA or protein oxidation products over the first 89 days after irradiation. Using five different standard methods for detecting oxidative stress in vivo, we found no definitive evidence for radiation-induced renal chronic oxidative stress. If chronic oxidative stress is part of the pathogenesis of radiation nephropathy, it does not leave widespread or easily detectable evidence behind.

BACKGROUND:The burden of chronic kidney disease (CKD) in sub-Saharan Africa is unknown. The aim of this study was to investigate the prevalence and the risk factors associated with CKD in Kinshasa, the capital of the Democratic Republic of Congo (DRC). METHODS:In a cross-sectional study, 503 adult residents in 10 of the 35 health zones of Kinshasa were studied in a randomly selected sample. Glomerular filtration rate was estimated using the simplified Modification of Diet in Renal Disease Study equation (eGFR) and compared with the Cockcroft-Gault equation for creatinine clearance. The associations between health characteristics, indicators of kidney damage (proteinuria) and kidney function (<60 ml/min/1.73 m(2)) were examined. RESULTS:The prevalence of all stages of CKD according to K/DOQI guidelines was 12.4% [95% confidence interval (CI), 11.0-15.1%]. By stage, 2% had stage 1 (proteinuria with normal eGFR), 2.4% had stage 2 (proteinuria with an eGFR of 60-89 ml/min/1.73 m(2)), 7.8% had stage 3 (eGFR, 30-59 ml/min/1.73 m(2)) and 0.2% had stage 5 (eGFR < 15 ml/min/1.73 m(2)). Hypertension and age were independently associated with CKD stage 3. The prevalences of major non-communicable diseases considered in this study were 27.6% (95% CI, 25.7-31.3%) for hypertension, 11.7% (95% CI, 10.3-14.4%) for diabetes mellitus and 14.9% (95% CI, 13.3-17.9%) for obesity. Hypertension was also independently associated with proteinuria. CONCLUSION/CONCLUSIONS:More than 10% of the Kinshasa population exhibits signs of CKD, which is affecting adults in their productive years. Risk factors for CKD, including hypertension, diabetes and obesity, are increasing. These alarming data must guide current and future healthcare policies to meet the challenge raised by CKD in this city and hopefully in the whole country.

Terrorist attacks or nuclear accidents could expose large numbers of people to ionizing radiation, and early biomarkers of radiation injury would be critical for triage, treatment and follow-up of such individuals. However, no such biomarkers have yet been proven to exist. We tested the potential of high throughput proteomics to identify protein biomarkers of radiation injury after total body X-ray irradiation in a rat model. Subtle functional changes in the kidney are suggested by an increased glomerular permeability for macromolecules measured within 24 hours after TBI. Ultrastructural changes in glomerular podocytes include partial loss of the interdigitating organization of foot processes. Analysis of urine by LC-MS/MS and 2D-GE showed significant changes in the urine proteome within 24 hours after TBI. Tissue kallikrein 1-related peptidase, cysteine proteinase inhibitor cystatin C and oxidized histidine were found to be increased while a number of proteinase inhibitors including kallikrein-binding protein and albumin were found to be decreased post-irradiation. Thus, TBI causes immediately detectable changes in renal structure and function and in the urinary protein profile. This suggests that both systemic and renal changes are induced by radiation and it may be possible to identify a set of biomarkers unique to radiation injury.

PURPOSE/OBJECTIVE:To test whether the angiotensin-converting enzyme inhibitor captopril was effective in mitigating chronic renal failure after hematopoietic stem cell transplantation (HSCT). METHODS AND MATERIALS/METHODS:A total of 55 subjects undergoing total body irradiation (TBI)-HSCT were enrolled in this randomized controlled trial. Captopril or identical placebo was started at engraftment and continued as tolerated until 1 year after HSCT. RESULTS:The baseline serum creatinine and calculated glomerular filtration rate (GFR) did not differ between groups. The 1-year serum creatinine level was lower and the GFR higher in the captopril compared with the placebo group (p = 0.07 for GFR). Patient survival was higher in the captopril compared with the placebo group, but this was also not statistically significant (p = 0.09). In study subjects who received the study drug for more than 2 months, the 1-year calculated GFRs were 92 mL/min and 80 mL/min, for the captopril and placebo groups, respectively (p = 0.1). There was no adverse effect on hematologic outcome. CONCLUSIONS:There is a trend in favor of captopril in mitigation of chronic renal failure after radiation-based HSCT.

BACKGROUND:Treatment of BK virus (BKV) infection in renal transplant recipients remains controversial. This retrospective analysis evaluated efficacy and safety of reducing immunosuppression without antiviral therapy. METHODS:This single center analysis included 24 patients diagnosed with BK viremia between September 2001 and December 2003. Sixteen patients (66%) presented with BKV nephritis and eight patients (34%) presented with viremia without evidence of nephritis on renal biopsy. RESULTS:At time of diagnosis, mean plasma BKV DNA (copies/mL) was 460,409 (range 10,205-1,920,691). Mean doses reduction of mycophenolate mofetil and tacrolimus were 44% and 41%, respectively, from time of diagnosis of BKV infection to complete resolution of viremia. A decline in BK viral load was noticed within 15 to 30 days, with successful elimination of viremia over a mean period of 5.8 months (range, 1-9.5). Mean serum creatinine at time of diagnosis of BK viremia was 1.8 mg/dL (range, 1.2-2.8). Mean follow-up period is 30.9 months postdiagnosis. At the most recent visit, serum creatinine was 2.0 mg/dL (range, 1.0-3.6) (P=0.14). With reduction in immunosuppressive therapy, three patients (13%) developed acute cellular rejection and were treated successfully with intravenous bolus steroids. During follow-up, one patient had a relapse of BKV nephritis during pregnancy and lost her graft. After mean follow-up period of 43.5 months posttransplantation, all 24 patients are alive and 23 have a functioning graft. Seventeen patients (71%) have stable or improved graft function. CONCLUSION/CONCLUSIONS:Our analysis shows that reduction in immunosuppression therapy alone results in clearance of the BK viremia with good long-term outcome.

BACKGROUND:BK virus (BKV) infection of kidney transplant patients is an increasing problem and is thought to be secondary to potent immunosuppressive therapy. BKV infection progresses to BKV nephritis (BKVN) in approximately 8% of transplants and in half of these cases the graft is lost. METHODS:We used an interferon-gamma enzyme-linked immunosorbent spot (ELISPOT) assay to measure the cellular immune response to peptides encoding BKV large T antigen. Eight kidney transplant patients with BKVN were tested at the time of diagnosis of BKVN and then after resolution of active BKV infection. RESULTS:When total spot counts from all peptide pools were combined, the mean ELISPOT signal per 10,000 cells at the time of BKVN diagnosis was 23.1 (range 3.4-59.7), with a median of 21.8. This increased to 70.2 (range 5.4-189.4) with a median of 37.0 (P=0.1216) after resolution of active BKV infection. To further increase specificity of response, we counted the number of peptide pools with ELISPOT activity of greater than 10 spots per well after subtraction of background. The mean number of pools fitting this criteria at the time of BKVN diagnosis was 2.1 (range 0-8) with a median of 1.5; this increased to 8 (range 1-18) and a median of 6.5 after recovery (P=0.0338). CONCLUSION/CONCLUSIONS:This demonstrates that recovery of cellular immune response to large T antigen corresponds with resolution of active BKV infection. This may prove useful in monitoring patients' cellular immunity and recovery from active BKV infection when treated with reduction in immunosuppressive therapy.

Regarding the prevalence of chronic kidney disease in the population, estimation of glomerular filtration rate is of importance. Creatinine-based formulas are thus useful as the first step of a prevention strategy. Several creatinine-based formulas have been published. Among these, the Cockcroft-Gault formula and the Modification of Diet in Renal Disease (MDRD) study equation are the most used by physicians. The latter may be automatically reported by laboratories and has thus great success. However, these formulas have limitations. First, the MDRD formulas are not applicable to all populations, notably the healthy one and the patients with abnormal weight (anorectic or obese). Second, we evoke the limitations in the precision of the formulas linked to analytical aspects. Indeed, these analytical limitations remain significant even if they are improved by creatinine standardization. Lastly, we briefly mention the potential impact of these limitations on the epidemiology and the staging of chronic kidney disease.