Evaluation of the effect of acetazolamide versus mannitol on cisplatin-induced nephrotoxicity,a pilot study

Background Cisplatin-induced nephrotoxicity still occurs despite the intensive hydration approach adapted to prevent its occurrence. Objective Evaluation of the effect of acetazolamide (ACTZ) on minimizing cisplatin-induced nephrotoxicity compared to mannitol when added to hydration regimen. Setting Nasser Institute Cancer Center (NICC), Cairo, Egypt. Method A total of 35 patients planned to receive cisplatin were divided into two groups: 20 patients received mannitol and 15 patients received ACTZ. Both groups received standard hydration measures as well for prevention of cisplatin-induced nephrotoxicity. Main outcome measure Patients’ kidney function was assessed using serum creatinine, creatinine clearance and blood urea nitrogen. Kidney injury was assessed using RIFLE criteria. Patients’ liver function tests and hematological parameters were also monitored. Results Patients in the mannitol group showed higher risk of developing kidney injury (30%) whereas those in the ACTZ group showed lower risk (8.9%), relative risk (RR) 0.269, 95% CI 0.108–0.815. No statistically significant difference occurred between the two groups concerning liver function tests or hematological parameters. Conclusion Use of ACTZ in addition to intensive hydration may have more beneficial effect on minimizing cisplatin-induced nephrotoxicity compared to mannitol plus intensive hydration approach. A large multicenter randomized clinical trials is recommended to confirm study results and to assess effect of ACTZ on tumor response.     

Köbberling type of familial partial lipodystrophy: an underrecognized syndrome

OBJECTIVE: The phenotypic expression of partial lipodystrophy is present in two familial syndromes: familial partial lipodystrophy type 1 (FPLD1), with fat loss from the extremities, and central obesity and FPLD type 2, with fat loss from the extremities, abdomen, and thorax. The latter disorder is associated with mutations in the LMNA gene. FPLD1 is thought to be rare. Here, we report 13 subjects with FPLD1, suggesting that this syndrome is more common than previously thought. RESEARCH DESIGN AND METHODS: Fasting glucose, plasma lipids, leptin, HbA(1c), and anthropomorphic measurements were evaluated in 13 subjects with clinical features of FPLD1 and are compared with two age-matched control groups, with and without diabetes. RESULTS: Only women with clinical features of FPLD1 have been identified. Although they lack extremity and gluteal subcutaneous fat, they do have truncal obesity. Skinfold thickness on the arm and leg was significantly less than that in control subjects. The ratio of skinfold thickness from abdomen to thigh was significantly higher in subjects, suggesting an easy method for identifying affected patients. FPLD1 subjects also had components of the metabolic syndrome, including hypertension, insulin resistance, and severe hypertriglyceridemia resulting in pancreatitis. Premature coronary artery disease was present in 31% of subjects. None of the subjects had coding mutations in the LMNA gene or in the gene coding for peroxisome proliferator-activated receptor (PPAR)-gamma. CONCLUSIONS: FPLD1 is more common than previously described, but the diagnosis is often missed. Early recognition and intensive treatment of hyperlipidemia and diabetes in FPLD1 is important for prevention of pancreatitis and early cardiovascular disease.     

Plasma Apolipoprotein L1 Levels Do Not Correlate with CKD

Polymorphisms in APOL1 are associated with CKD, including HIV-related CKD, in individuals of African ancestry. The apolipoprotein L1 (APOL1) protein circulates and is localized in kidney cells, but the contribution of APOL1 location to CKD pathogenesis is unclear. We examined associations of plasma APOL1 levels with plasma cytokine levels, dyslipidemia, and APOL1 genotype in a nested case-control study (n=270) of HIV-infected African Americans enrolled in a multicenter prospective observational study. Patients were designated as having CKD when estimated GFR (eGFR) decreased to <60 ml/min per 1.73 m² (eGFR<60 cohort) or protein-to-creatinine ratios became >3.5 g/g (nephrotic proteinuria cohort). Circulating APOL1 levels did not associate with APOL1 genotype, CKD status, or levels of proinflammatory cytokines, but did correlate with fasting cholesterol, LDL cholesterol, and triglyceride levels. At ascertainment, CKD-associated polymorphisms (risk variants) in APOL1 associated with the eGFR<60 cohort, but not the nephrotic-range proteinuria cohort. Of note, in both the eGFR<60 and nephrotic proteinuria cohorts, CKD cases with two APOL1 risk variants had significant declines in eGFR over a median of 4 years compared with individuals with one or no risk variants. APOL1 risk genotype was not associated with changes in proteinuria. Higher circulating proinflammatory cytokine levels were independently associated with CKD but not APOL1 genotype. In conclusion, the function of variant APOL1 proteins derived from circulation or synthesized in the kidney, but not the level of circulating APOL1, probably mediates APOL1-associated kidney disease in HIV-infected African Americans.Nondiabetic CKD in individuals of African ancestry have been linked to polymorphisms in the gene for apolipoprotein L1 (APOL1),^1–5 a protein component of HDL particles with a known function in the immune clearance of Trypanosoma brucei infections.⁶ CKD is associated with two coding variants of the APOL1 gene known as G1 and G2, both of higher allele frequency in African and African descendent populations compared with white populations where they are almost absent. Evidence suggests that the prevalence of the G1 and G2 variants may have increased in African populations because of a selective advantage from their ability to kill a broader range of Trypanosoma species.^1,2,7 Individuals carrying at least one G1 or G2 allele have additional protection from trypanosomiasis; however, individuals with two G1 or G2 alleles are at increased risk for nondiabetic CKD.^2,4,5The pathogenic mechanisms responsible for CKD associated with APOL1 risk variants are unknown. We recently showed that, in addition to being secreted and circulated in the blood,⁸ APOL1 is localized in podocytes, proximal tubular epithelial cells, and small-artery endothelium in normal kidney.⁹ Thus, the contribution of circulating versus kidney-localized variant APOL1s to CKD pathogenesis is unknown. In kidney transplantation, two studies suggest that graft loss is associated with the APOL1 genotype of the allograft, not the recipient.^10,11 However, the association of APOL1 plasma levels with CKD phenotypes or APOL1 genotype has not been studied.To address these issues, we examined circulating APOL1 levels with APOL1 genotype and renal function in HIV-infected African Americans in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort because the occurrence of HIV-associated nephropathy (HIVAN) and renal outcomes in HIV-infected patients are strongly associated with APOL1 risk alleles.^12–14 In addition, we examined the relationship between circulating APOL1 levels and proinflammatory cytokines known to induce APOL1 expression and previously associated with CKD and HIV/AIDS progression.^15,16 Additional analyses examined associations of APOL1 levels with dyslipidemia and the role of APOL1 genotype on CKD progression using longitudinal data.