Low Tonicity Mediates a Downregulation of Cyclooxygenase-1 Expression by Furosemide in the Rat Renal Papilla Diuretic Resistance Clarified—A Role for Prostaglandins.
Oral furosemide, even when takendutifully by the patient at home, often becomes progressivelyless effective, requiring higher doses or intravenous administration.Studies by Craig Brater and others have shown that resistanceresults from alterations both in gastrointestinal absorptionand in upregulation of NaCl transporters in the distal convolutedtubule and cortical collecting duct. In this issue, Castropand co-workers propose yet another mechanism. Furosemide reducedthe medullary interstitial tonicity of rats which, in turn,decreased medullary cyclooxygenase-1 and -2 expression. SincePGE2 in the inner medulla decreases NaCl resorption by the medullarythick ascending limb and the medullary collecting duct, antagonizesthe hydroosmotic action of vasopressin, and increases vasa rectablood flow, furosemide-induced reduction in PGE2 synthesis wouldreduce natriuresis and diuresis. This is furosemide resistance.It remains to be seen whether free water restriction, by raisingmedullary tonicity, would permit furosemide once again to benefitthe edematous patient.
Immunology and Pathology
Transcription Factor IRF-1 in Kidney Transplants Mediates Resistance to Graft Necrosis during Rejection A Transcription Factor Protects from Allograft Rejection.
Interferon-gamma is an importantcytokine that plays key functions in innate and antigen-specificimmunity. However, recent evidence clearly suggests that interferon-gammamay have a dual function. It has been demonstrated that IFN-gammais important in limiting T cell proliferation and promotingT cell apoptosis. In experimental kidney transplantation, IFN-gammahas been shown to be important in resistance to host effectormechanisms that result in ultimate graft destruction. The manuscriptby Afrouzian et al. is an extension of those studies and highlightsthe important role of the transcription factor IRF-1 in donortissue resistance to injury. Similar to IFN-gamma, IFR-1 confersprotection during acute renal allograft rejection mainly byprotecting the microcirculation and preventing epithelial cellnecrosis. The exact mechanisms of how these effects are mediatedremain unclear and require further investigations. The studieshave important clinical implications for understanding the mechanismsof graft rejection and for potentially developing novel therapeuticstrategies to prevent graft rejection.
Molecular Medicine, Genetics and Development
A Novel Approach to the Pathogenesis of Active Minimal Change Nephrotic Syndrome Using Subtracted cDNA Library Screening T Cells and Minimal Change Nephrotic Syndrome—Another Piece of the Puzzle.
Despite its frequency as a causeof idiopathic nephrotic syndrome, the pathogenesis of minimalchange nephrotic syndrome continues to defy elucidation. Overa quarter of a century ago Shalhoub proposed that it representeda disorder of T-cell function. Several investigators have sincedescribed circulating permeability factors of uncertain originand identity in patients with a related disorder, idiopathicfocal glomerulosclerosis, and even in some cases of minimalchange. However, the results have been inconsistent. In thispaper by Sahali advantage is taken of the techniques of subtractivecloning and differential screening to compare gene expressionin T-cell-enriched peripheral blood mononuclear cells in a singlepatient during both relapse and remission. Of 42 known transcriptswhich differed, 18 were related to T-cell signaling. While subjectto the obvious reservations of any study in one patient, theresults provide yet another piece of evidence linking T-cellsand the TH2 phenotype to minimal change nephrotic syndrome (Seealso editorial by Cunard and Kelley on pp 1409–1411).
Pathophysiology of Renal Disease
Selective Cyclooxygenase-2 Inhibition Impairs Glomerular Capillary Healing in Experimental Glomerulonephritis Another Role for Cox-2 in Kidney Diseases—A Link to Angiogenesis.
The topic of angiogenesis is gettingconsiderable press in the biomedical world with central rolesproposed in diseases from cancer to resolving acute glomerulonephritis.The rapidly expanding understanding of the effects of COX-2inhibitors is here linked to angiogenesis in the kidney by Kitahara,et al., who demonstrate that administration of two differentselective cyclooxygenase-2 (COX-2) inhibitors each impairs thecapillary healing response in the rat anti-Thy 1 model of glomerularinjury. This observation adds to recent evidence that COX-2inhibition may have an anti-angiogenic effect. COX-2 inhibitionhas also been shown to reduce inflammation. These complex andapparently non-complementary activities of COX-2 inhibitors(i.e., suppression of inflammation and impairment of angiogenesis,a key component of the healing response to wounds), if substantiatedin humans, are likely to have significant, but not yet predictable,consequences in inflammatory renal injuries occurring in patientstaking these widely prescribed pharmaceutical agents.
Dialysis
Riboflavin Is a Determinant of Total Homocysteine Plasma Concentrations in End-Stage Renal Disease Patients Riboflavin, Homocysteine and Atherogenesis—A New Therapeutic Insight?
Elevated homocysteine levels areobserved in more than 90% of ESRD patients and are associatedwith increased risk of arteriosclerotic cardiovascular disease.Determinants of plasma homocysteine levels include plasma levelsof folate, cobalamin, vitamin B-12, pyridoxal phosphate andvitamin B(6), as well as methylenetetrahydrofolate reductase(MTHFR) polymorphisms. While folate, vitamin B(6) and vitaminB(12) supplementation normalize plasma homocysteine levels amongpatients with normal renal function, supraphysiological dosesof these vitamins usually fail to do so among ESRD patients.The reasons for this folate-resistance are poorly understood.The cross-sectional study of the association between riboflavin,a cofactor for MTHFR, and homocysteine levels in 54 peritonealdialysis patients provides additional insight into this problem.They report for the first time that riboflavin, measured asred blood cell availability, is independently associated withplasma homocysteine levels in an ESRD population. If these observationswere supported in other ESRD populations, it would be reasonableto conduct clinical trials to examine the role of riboflavinsupplementation as a means of lowering homocysteine levels infolate-replete ESRD patients.
Epidemiology and Outcomes
Prevalence of Low Glomerular Filtration Rate in Nondiabetic Americans: Third National Health and Nutrition Examination Survey Measuring GFR—Don’t Throw away Those 24-Hour Jugs Yet!
Efforts to delay the progressionof kidney disease depend on the ability of clinicians to identifymild degrees of impaired renal function and to apply effectiveinterventions during the early phases of renal injury. It hasbeen recognized for some time that measurement of serum creatinine,particularly in older individuals, is often not elevated inthe presence of mild-to-moderate decreases in GFR. Further,direct measurement of GFR is expensive and technically beyondthe capacity of clinical practice, while measurement of creatinineclearance is often inaccurate and difficult to complete in day-to-daypractice. These limitations have led to the development of estimatingequations that use serum creatinine and other patient characteristicsto estimate the GFR, and there are recommendations that oneor more of these equations be used to identify individuals withearly renal disease. The article by Clase et al. has importantramifications for the appropriateness of these recommendations.They used NHANES III data to apply four different GFR estimatingequations to determine the prevalence of chronic kidney diseasein the US population. Their main result is that strikingly differentestimates of impaired renal function are obtained dependingon the equation employed and that the MDRD and Crockcoft-Gaultequations result in estimates of 58% and 39% of the adult USpopulation with abnormal renal function. These results raisean important issue as to the appropriateness of derived estimatesof GFR as a guide to public policy or clinical algorithms forscreening for kidney disease in the general population. Theresults also suggest that it may be premature to abandon quantitativeurine collection as a means of estimating renal function inclinical practice. Clearly additional investigation is neededbefore we can unconditionally rely on one or more estimatingequation to identify individuals who would benefit from aggressiveinterventions to preserve renal function. This caveat is nota call for therapeutic nihilism. Individuals at risk for kidneydisease, including those with hypertension and family membersof patients with ESRD, should be periodically screened for impairedrenal function using serum creatinine, appropriate estimatingequations and 24-hr creatinine clearance, and evidence of impairedrenal function should lead to appropriate interventions. Incontrast, the response to a low GFR observed in a low-risk individualremains to be determined, and watchful waiting may be appropriate.
Refining Predictive Models in Critically Ill Patients with Acute Renal Failure A New Way to Predict Outcome of Acute Renal Failure in the ICU.
Developing and using decision supporttools is a key component of evidence-based renal medicine. Thestudy by Ravi Mehta and his colleagues from the Project to ImproveCare in Acute Renal Disease (PICARD) reports the developmentof a new tool to predict risk of death among ICU patients withacute renal failure. Risk stratification equations help cliniciansdevelop a prognosis by combining clinical and laboratory informationinto information about the likelihood of a subsequent outcomesuch as survival. The scale described by the PICARD study groupprovides a summary score based on patient characteristics atthe time of onset of treatment, including age, sex, BUN andcreatinine levels, urine output, heart rate and measures ofhematologic, liver and pulmonary functions. The resulting scorewas highly predictive of mortality and predicted risk of deathbetter than did either generic severity-of-disease indices likeAPACHE III or previously reported acute renal failure severity-of-illnessscales. Before the PICARD score can be reliably used clinically,additional validation studies in other populations are needed.To this end the authors have provided us their full model tofacilitate the replication of their results.
Transplantation
Withdrawal of Cyclosporine or Prednisone 6 Months after Kidney Transplantation in Patients on Triple Drug Therapy Can We Safely Take Patients off Some Transplant Drugs?
Minimizing the toxicity of calcineurininhibitors and/or steroids is the current trend in immunosuppressionin kidney transplantation. The approval of new potent immunosuppressiveagents, such as mycophenolate mofetil and rapamycin, allowstransplant professionals to test whether this trend is safeand effective. In this issue of the journal Gregoor et al. reportthe results of a multicenter randomized trial to compare cyclosporineversus steroid withdrawal under the cover of mycophenolate mofetil.The results highlight the risks and benefits of calcineurininhibitors withdrawal: higher incidence of rejection but betterrenal function. Steroid withdrawal was associated with bettercontrol of blood pressure and lipid abnormalities but withoutan increased risk of rejection. Interestingly, at two yearsall groups had similar graft survival. It is also importantto compare and contrast this study with the recently publishedreport by Johnson et al. (
Transplantation 2001; 72:777[Medline]) whererapamycin was used instead of mycophenolate mofetil followedby randomization to cyclosporine withdrawal. In that study therewas a slightly increased risk of rejection, but there was significantimprovement in blood pressure control and renal function inthe cyclosporine-withdrawal group.
