Cell and Transport Physiology Differential Regulation of Collecting Duct Na+/K+-ATPase and K+Excretion by Furosemide and Piretanide: Role of Bradykinin Are All Loop Diuretics the Same?
In this issue, Buffin-Meyer et al.demonstrate differences in the responses to furosemide and piretanide.Both inhibit the NaKCl2 cotransporter in the thick ascendinglimb of Henle’s loop, but there is a clear differencein their kaliuretic effect, which reflects a differential increasein bradykinin production with piretanide. The fact that bradykininproduction is increased by piretanide and may have a directeffect on the apical membrane Na+ and/or K+ transport in thedistal nephron is intriguing and demonstrates that not all loopdiuretics can be lumped together. There may be an importantclinical implication of these findings. Inhibition of the rennin/angiotensin/aldosteronesystem plays a critical role in slowing the progression of proteinuricrenal diseases, but hyperkalemia can limit aggressive therapy,especially in patients who have stage IV or V CKD. In this setting,the more robust kaliuretic response to furosemide could be advantageouscompared with piretanide, but the utility of this approach needsto be established in humans. Page 876.
Hemodynamics and Vascular Regulation Atorvastatin Improves the Course of Ischemic Acute Renal Failure in Aging Rats Statins for Acute Renal Failure?
Nephrology has evolved into anever-more-geriatric specialty. Among the many unpleasant aspectsof aging is diminished endothelial cell NO, predictably increasingthe susceptibility to ischemic acute renal failure (ARF), whichis known to be associated with, and presumably causally relatedto, reduced bioavailability of NO. Pursuing this line of thought,Sabbatini et al. examined whether statins increase bioavailabilityof NO and severity of ischemic ARF. Short-term treatment withAtorvastatin attenuated ischemic ARF in old rats. The expressionof endothelial NO was improved on both the mRNA and proteinlevels. These findings do not provide new therapeutic strategiesfor prevention or intervention in ARF, but — to the extentthat animal data can be extrapolated to humans — theysuggest that the susceptibility to ARF may be diminished inelderly patients with a high atherosclerotic burden when theyare on a statin, which would be a benefit not to be neglected.Page 901.
Immunology and Pathology Gene Therapy via Blockade of MCP-1 for Renal Fibrosis Gene Therapy for Renal Fibrosis.
Interstitial fibrosis representsa common final pathway in many renal diseases and is positivelyassociated with prognosis. Recent studies have implicated thechemokine monocyte chemoattractant protein-1 (MCP-1) and itsreceptor, CC chemokine receptor 2 (CCR2), in the pathogenesisof organ fibrosis. For example, knockout mice that lack CCR2are resistant to bleomycin-induced pulmonary fibrosis. In thisissue, Wada et al. examined the role of MCP-1/CCR2 in experimentalrenal fibrosis induced by unilateral ureteral obstruction (UUO)in mice. They injected DNA encoding a dominant-negative MCP-1mutant into limb skeletal muscle and observed that this pretreatmentameliorated renal fibrosis. The mechanism appeared to involvediminished infiltration of CCR2-positive macrophages as wellas decreased synthesis of the profibrotic cytokine, TGF, andtype I collagen. Although the impact on preservation of renalfunction was not measured, this study suggests that inhibitionof MCP-1/CCR2 signaling may represent an effective strategyfor reducing renal fibrosis. Page 940.
CLINICAL SCIENCE
Clinical Nephrology Environmental Exposure to Lead and Progression of Chronic Renal Diseases: A 4-yr Prospective Longitudinal Study Lead and Chronic Kidney Disease.
The search for modifiable risk factorsfor renal insufficiency is partially predicated on the substantialheterogeneity in the loss of renal function noted among individualswith otherwise similar causes and degrees of chronic kidneydisease (CKD). The study by Yu et al. suggests that low-levelenvironmental lead exposure is associated with progressive CKD.While the lead exposure they studied fell within levels generallyaccepted as safe, they noted that each increase of 1 µg/dLin blood lead level was associated with a decrease in 24-hourclearance rates of 4.0 ml/min (P = 0.01) during follow-up. Environmentallead exposure is a common hazard for the urban poor, resultingfrom pica consumption of leaded paint by infants and, priorto removal of lead from gasoline, air pollution. It is interestingto speculate that some of the difference in risk associatedwith increased poverty noted in earlier studies might be a resultof exposure to these and other sources of environmental lead.Page 1016.
Epidemiology and Outcomes Renal Insufficiency and the Risk of Lower Extremity Peripheral Arterial Disease: Results from the Heart and Estrogen/progestin Replacement Study (HERS) Renal Insufficiency and PVD in HERS.
It is not uncommon to encounterseveral patients during dialysis rounds with a lower extremityamputation and leave with the impression that the prevalenceof diabetic foot disease and peripheral vascular disease complicationsis increasing in the ESRD population. Previous work by O’Hareet al. and several other groups has clearly established thatdiabetic foot disease and peripheral vascular disease constitutea major burden for the ESRD patient. The current report extendsthese observations to individuals with chronic kidney diseaseby comparing the risk of developing peripheral vascular diseaseamong participants in the Heart and Estrogen/Progestin ReplacementStudy (HERS) trial. They report that the risk of peripheralvascular disease was 60% greater among women with a clearancebetween 30 and 59 ml/min per 1.73 m2 and over threefold forwomen with a clearance <30 ml/min per 1.73 m2 when comparedwith women with an estimated clearance >60 ml/min per 1.73m2. Perhaps the greatest clinical application of these data,beyond recognizing that the lower extremity disease encounteredin the patient with ESRD may well have been present at the startof renal replacement therapy, is that lower extremity amputationis a potentially preventable complication and that at-risk patients,including patients with chronic kidney disease at any stage,should have a periodic foot examination and referral to a footspecialist when disease is detected. Further, as noted by theauthors, we need to develop evidence based on carefully designedand conducted clinical trials, to support our care of this importantclinical problem. Page 1046.
Dialysis The Relative Contribution of Residual Renal Function and Different Measures of Adequacy to Survival in Hemodialysis Patients: An Analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2 Kt/V Is Associated with Survival in Incident Hemodialysis Patients who Become Anuric.
The failure of the HEMO study todemonstrate improved survival with increased dialysis dose hasraised many questions. In an observational study of 740 incidenthemodialysis patients in the Netherlands, Termorshuizen et al.explore the interrelations among residual renal function, dialysisurea clearance, and net ultrafiltration. For patients with residualfunction, the findings are consistent with the HEMO study; foranuric patients, there is marked increase in mortality withdecreased dialysis Kt/V. In addition, there is higher mortalityassociated with the lowest quintile of net ultrafiltration comparedwith the referent quintile. Whether this is confounded by nutritionalstatus or is a reflection of inappropriate ultrafiltration isaddressed in the discussion. Page 1061.
, and type I collagen. Although the impact on preservation of renal function was not measured, this study suggests that inhibition of MCP-1/CCR2 signaling may represent an effective strategy for reducing renal fibrosis. Page 940. 
