International Urology and Nephrology32: 203–210, 2000.© 2000Kluwer Academic Publishers. Printed in the Netherlands.

203

Literature reviews and opinion

Steven R. Gambert, MD, Section EditorDepartment of Medicine, Johns Hopkins University School of Medicine, andSinai Hospital of Baltimore, Baltimore, Maryland, USA

Alluru S. Reddi, Associate Section EditorDivision of Nephrology, UMDNJ – New Jersey Medical School, Newark, New Jersey, USA

Contributors:

Steven R. Gambert,John Hopkins University School of Medicine, and Sinai Hospital, Baltimore, Maryland, USAAlluru S. Reddi,UMDNJ – New Jersey Medical School, Newark, New Jersey, USALisa Rosenberg,Division of Geriatric Medicine, Johns Hopkins Bayview Medical Center and Johns HopkinsUniversity School of Medicine, Baltimore, Maryland, USAJoselito T. Cabacar, Padmaja Kodali and Robert Czyzewski,UMDNJ – New Jersey Medical School, Newark, NewJersey, USA

Nephrotic-range proteinuria in patients withrenovascular disease

Halimi, J.M., Ribstein, J., Du Cailar, G. andMimran, A.Department of Medicine and Hypertension, HôpitalLapeyronie, Centre Hôpitalier Universitaire, Montpel-lier, France

Am J Med 108: 120–126, 2000

This study describes the characteristics of patientswith nephrotic-range proteinuria resulting from ren-ovascular disease compared to those with glomer-ulonephritis. Fourteen patients were chosen from eachcategory. Glomerulonephritis was biopsy-proven in allsubjects and there was matching for sex, age, andglomerular filtration rate. Patients with renovasculardisease were more likely to have known atheroscler-otic vascular disease (93% vs 21%,p < 0.0001) andwere smokers (85% vs 21%,p < 0.0001). They alsohad a greater mean difference between the lengths oftheir kidneys (29± 10 vs 5± 5 mm, p < 0.001);greater systolic blood pressure (203± 22 vs 174±25 mmHg,p < 0.005), plasma renin activity (17±19 vs 2± 2 ng/dl/h,p = 0.005), and plasma aldos-terone concentration (40± 23 vs 11± 10 ng/dl,p

= 0.0001); and lower serum potassium levels (3.3±0.5 vs 3.8± 0.5, p < 0.05). Effective renal plasmaflow was lower (139± 68 vs 307± 185 ml/min/1.73m3) and filtration fraction was markedly greater (0.28± 0.04 vs 0.15± 0.07, p = 0.0001) in the patientswith renovascular disease. After oral administration ofcaptopril, blood pressure, effective renal plasma flowand glomerular filtration rate decreased only amongpatients with renovascular disease. Of the 14 patientswith renovascular disease, 13 had evidence of renalartery thrombosis seen at the time of angiography; 2patients required dialysis, and 2 others died duringfollow-up. Ten of the 14 patients with renovasculardisease were treated medically, whereas the remaining4 underwent surgery. Patients with glomerulonephritiswere treated medically. Patients were re-evaluated at5 and 24 months with blood pressure, serum creat-inine levels, and measurements of proteinuria. Theauthors conclude that the patients with nephrotic-range proteinuria resulting from renovascular diseasehave distinct characteristics and a poor prognosis.

CommentaryRenovascular disease is a common cause of treatablehypertension in the elderly and may be an importantcause of reversible renal failure. Clinically, this entitymay present with hypertension refractory to treatment,

204

abdominal bruits, differences in renal morphology andsize, pulmonary edema, and decreases in renal func-tion after the use of an angiotensin-converting enzymeinhibitor. As our population continues to age, it isimportant to be aware that renovascular disease isamenable to treatment and if caught sufficiently earlyin its course, may be completely reversible. This studyis the first to describe the disease, however, once ithas progressed and is associated nephrotic-range pro-teinuria. The authors suggest that renovascular diseasemay result in significant proteinuria more than pre-viously suspected and that it be considered as partof the differential diagnosis of nephrotic syndrome,especially in the elderly. While the authors describedifferences between the two groups that were studied,an individualized evaluation plan can be developed.In this study, percutaneous biopsy of the kidney wasnot possible in 10 of the 14 patients with renovasculardisease due to severe hypertension. Clearly this wouldhave been helpful in defining the extent of disease andwhether there were other diseases effecting the renalparenchyma that perhaps influenced the study find-ings. Older persons may have more than one cause ofa specific problem and the kidney is no exception.

Improved graft survival after renaltransplantation in the United States, 1988 to 1996

Hariharan, S., Johnson, C.P., Bresnahan, B.A.,Taranto, S.E., McIntosh, M.J. and Stablein, D.

N Engl J Med 342: 605–612, 2000

These authors analyzed the influence of demographiccharacteristics, transplant-related variables, and post-transplantation factors on graft survival for all 93,934renal transplant recipients in the United Sates between1988 and 1996. A regression analysis using a Kaplan-Meier Estimate of Graft Survival was done to adjustfor these variables and to estimate the risk of graftfailure within the first year and then after one year fol-lowing transplantation. Between 1988 and 1996 therewas an increase in the one-year survival rate for graftsfor living donors from 88.8 to 93.9% and for cadavericgrafts from 75.7 to 87.7%. The half-life for grafts fromliving donors increased steadily from 12.7 to 21.6years and for cadaveric grafts from 7.9 to 13.8 years.The half-life for grafts from living donors increasedfrom 16.8 to 35.9 years and that for cadaveric graftsincreased from 11.0 to 19.5 years. The average yearly

reduction in the relative hazard of graft failure afterone year was 4.2% for all recipients (p < 0.001), 0.4percent for those who had acute rejection (p = 0.57),and 6.3 percent for those who did not have acute rejec-tion (p < 0.001). In summary, the authors concludethat there has been a substantial increase in short-term and long-term survival of kidney grafts fromboth living and cadaveric donors. The authors alsoreport that clinical acute rejection within the first yearafter transplantation had a detrimental effect on long-term graft survival and that more black individuals hadchronic graft rejection with the projected half-life fortransplants lasting 5.1 years in 1988 and 7.2 years in1995 for blacks versus 9.1 and 13.3 years, respectively,for whites.

CommentaryThe number of patients with end-stage renal disease isincreasing at the rate of 7 to 8% per year with renaltransplantation the treatment of choice for most. Since1988, there has been a growing shortage of donor kid-neys and thus the need to maximize graft survival.Medications such as cyclosporine for the preventionof acute and chronic rejection has increased the rate ofsurvival and new medications such as mycophenolatemofetil and tacrolimus have further reduced episodesof acute rejection. Chronic rejection remains a realrisk. While acute rejection is a powerful predictor ofwho will go on to develop chronic rejection, no studieshave demonstrated that a reduction in the incidence ofacute rejection also reduces chronic rejection and thusincreased long term graft survival. Additional studiesare warranted. As our population continues to ageand renal transplants last longer, we will undoubtedlybe dealing with many more older persons obtainingrenal transplantations and many more persons livingto old age with transplants that they had earlier inlife. Exactly how increasing age, use of immunosup-pressive agents, and other host-versus graft issueseffect quality of life and functioning deserve furtherstudy.

The effect of spironolactone on morbidity andmortality in patients with severe heart failure

Pitt, B., Zannad, F., Remme, W.J., Cody, R., Cost-aigne, A., Perez, A., Palensky, J. and Wittes, J. Forthe Randomized Aldactone Evaluation Study Investi-gators

205

Department of Internal Medicine, Division of Cardi-ology, University of Michigan, Ann Arbor, Michigan,USA; Centre d’Investigation, Clinique de Nancy,Nancy, France; Sticares, Cardiovascular ResearchFoundation, Rotterdam, the Netherlands; Service deCardiologic, Hôpital Henri Mondor, Creteil, France;Global Medical Operations, Searle, Skokie, IL, USA;Statistics Collaborative, Washington, DC, USA

N Engl J Med 1999; 341: 709

Aldosterone plays an important role in the patho-physiology of heart failure because this hormonepromotes sodium retention, loss of potassium andmagnesium in the urine, sympathetic activation,parasympathetic inhibition, myocardial and vascularfibrosis and impairs arterial compliance. Althoughangiotensin converting enzyme-inhibitors (ACE-Is)suppress aldosterone, this suppression is transient.Therefore, aldosterone antagonists, such as spirono-lactone may be therapeutically efficacious in patientswith congestive heart failure. This study was designedto examine whether addition of spironolactone wouldimprove survival in patients with severe heart failureand left ventricular ejection fraction <35%.

In this multicenter, randomized, double-blind,placebo controlled study, 822 patients were assignedto receive either 25 mg of spironolactone daily or841 patients to receive a matching placebo. Prior torandomization, these patients were on ACE-I, a loopdiuretic and in most cases digoxin. The mean agein both groups was 65 years. The primary end pointwas death from all causes. The study was discon-tinued after a mean follow-up of 24 months becausean interim analysis showed that spironolactone wasefficacious in improving survival.

The analysis showed that there were 284 deathsin the spironolactone group (35%) and 386 deaths inthe placebo group (46%), suggesting a 30% reductionin death rate in the former group of patients. Thisreduction was attributed to a lower risk of both deathfrom progressive heart failure and sudden death fromcardiac causes. Also, the frequency of hospitalizationfor worsening heart failure was reduced by 35% inthe spironolactone group. The New York Heart Asso-ciation functional classification was also improved.Serious hyperkalemia was not a problem in the spiro-nolactone group. Overall, the study emphasizes thataddition of spironolactone to standard therapy is bene-ficial in improving survival of patients with severeheart failure.

CommentaryThis study clearly demonstrates that blockade ofaldosterone-receptors by spironolactone in patientswith sever heart failure is additive to those of ACE-Is. Although gynecomastia and breast tenderness wereobserved only in 10% of men, clinical experiencesuggests that higher dosages of spironolactone mayincrease these side effects, particularly in men. Serioushyperkalemia may not be a problem in those patientswith serum creatinine levels <2.5 mg/dl; however,hyperkalemia may be potentially dangerous in patientswith a defect in potassium secretion or concomitantuse of certain drugs that impair potassium secretion.

Spironolactone increases nitric oxide bioactivity,improves endothelial vasodilator dysfunction, andsuppresses vascular angiotensin I / angiotensin IIconversion in patients with chronic heart failure

Farquharson, C.A.J. and Struthers, A.D.University Department of Clinical Pharmacology andTherapeutics, Ninewells Hospital and Medical School,Dundee, UK

Circulation 2000; 101: 594–597

The previously described Randomized AldactoneEvaluation Study trial was discontinued prematurelybecause of a 30% survival advantage in patientsreceiving spironolactone. However, this trial did notevaluate the mechanisms responsible for such a bene-ficial effect of spironolactone on survival. The cur-rent study tested the hypothesis that the beneficialeffect of spironolactone was due to improvement inendothelial function and/or to amplified suppressionof the vascular renin-angiotensin axis.

In this randomized, placebo-controlled, double-blind, crossover trial, 10 male patients with stable mildto moderate heart failure were treated with spirono-lactone for one month with a switchover to placeboafter a 2-week washout period. The mean age was68.9 years. Spironolactone (50 mg/day) was added toa standard regimen that included an ACE-I, a diur-etic and aβ-blocker in 6 patients. Other medicationsincluded nitrates in 5 patients and calcium antagonistsin 4 patients. Mean serum creatinine was 116 mmol/l(1.13 mg/dl). Forearm vasculature endothelial func-tion was assessed by bilateral forearm venous occlu-sion plethysmography using acetylcholine (Ach) andN-monomethyl-L-arginine (L-NMMA) with sodium

206

nitroprusside as a control vasodilator. Also vascularACE activity was assessed by use of angiotensin (Ang)I, with Ang II as a control vasoconstrictor.

Ach is an endothelium-dependent vasodilator, andL-NMMA is a competitive inhibitor of nitric oxide(NO) synthase. Ang I exerts vasoconstriction in thisforearm model through conversion in vasculature toAng II. Spironolactone caused a significant increasein Ach-mediated vasodilation. Similarly, the vaso-constrictive response to L-NMMA was augmentedby spironolactone. In contrast, spironolactone hadno effect on sodium nitroprusside responses. Thevasoconstriction produced by Ang I was significantlyreduced by spironolactone therapy, but this therapyhad no effect on Ang II-induced vasoconstriction.Serum potassium was slightly increased after spirono-lactone therapy. The data suggest that spironolactoneimproves endothelial dysfunction, increases NO bio-activity, and inhibits vascular conversion of Ang I toAng II in patients with congestive heart failure.

CommentaryAldosterone has an adverse effect on vasculature. Ina tissue culture study, aldosterone has been shownto inhibit NO release. Also, aldosterone seems toamplify tissue ACE and Ang II responses. Spirono-lactone counteracts these effects of aldosterone, andthus improves endothelial dysfunction in patients withheart failure. Indeed improving endothelial dysfunc-tion has been suggested as a new therapeutic targetin congestive heart failure, and spironolactone therapynot only achieves that target but also improves survivalin patients with heart failure.

Hemodialysis impairs endothelial function viaoxidative stress: Effects of vitamin E-coateddialyzer

Miyazaki, H., Matsuoka, H., Itabe, H., Usui, M.,Ueda, S., Okuda, S. and Imaizumi, T.Department of Internal Medicine III and Cardiovas-cular Research Institute, Kurume University School ofMedicine, Kurume, the Department of Microbiologyand Molecular Pathology, Faculty of PharmaceuticalSciences, Teikyo University, Kanagawa, Japan

Circulation 2000; 101: 1002–1006

Oxidative stress plays an important role in the patho-genesis of vascular injury and in the progression of

atherosclerosis. Inhibition of NO synthase activity andinactivation of NO by reactive oxygen species hasbeen proposed as one of the mechanisms for vascularinjury. It has been demonstrated that NO-dependentflow-mediated vasodilation is blunted in patientsundergoing hemodialysis, suggesting that impairedNO bioactivity may contribute to the progression ofatherosclerosis in these patients. It is also possiblethat hemodialysis per se may contribute to endothelialdysfunction. In this study, the authors hypothesizethat hemodialysis per se may impair endothelial func-tion by oxidative stress, and that hemodialysis usinga vitamin E-coated dialyzer may improve endothelialdysfunction.

Twelve hemodialysis-dependent patients (6 menand 6 women) with a mean age of 40.5 years (20to 64 years) were included in the study. Endothelialfunction was assessed by flow-mediated vasodilationof the branchial artery using reactive hyperemia usinghigh resolution ultrasound Doppler echocardiography.A noncoated cellulose dialyzer or a cellulose dialyzercoated with vitamin E of the same membrane size wasused. Plasma oxidized LDL level, an index of lipidperoxidation, was measured before and after a singlehemodialysis treatment.

The results showed that a single dialysis treat-ment with noncoated dialyzer was associated withimpaired flow-mediated vasodilation and increasedplasma levels of oxidized LDL. In contrast, hemodia-lysis with vitamin E-coated dialyzer prevented theseabnormalities. The data suggest that hemodialysis perse impairs endothelial function by increasing oxidativestress.

CommentaryPatients on maintenance hemodialysis experienceaccelerated atherosclerosis and premature death.Increased oxidative stress seems to play an importantrole in the progression of atherosclerosis and associ-ated mortality. Antioxidants such as vitamins E and Cand also selenium may prevent oxidative stress, andthus premature death by preserving endothelial func-tion. Studies using vitamin E-coated dialyzers andendothelial function in patients undergoing chronichemodialysis are clearly warranted.

207

Kidney biopsy as a predictor for renal outcome inANCA-associated necrotizing glomerulonephritis

Bajema, I.M., Hagen, E.C., Hermans, J., Noel, L.H.,Waldherr, R., Ferrario, F., van der Woude, F.J.,Bruijn, J. For the EC/BCR project for ANCA-assayStandardisationDepartment of Pathology, Nephrology and MedicalStatistics, Leiden University Medical Center, Leiden;Department of Internal Medicine, Eemland Hospital,Amersfoort, the Netherlands; Department of Nephro-logy, Hospital Necker, Paris, France; Department ofPathology, University of Heidelberg, Heidelberg, Ger-many; Ospedale San Carlo Borromeo, Milan, Italy;Medical Faculty Mannheim, University of Heidelberg,Heidelberg, Germany

Kidney Int 1999; 56: 1751–1758

In kidney biopsies of patient with anti-neutrophil cyto-plasmic antibody (ANCA)-associated systemic vas-culitis a broad spectrum of histopathologic lesionscan be found and their relationship to renal outcomeis practically unknown. Previous research addressingthe relationship in systemic vasculitis between histo-pathologic findings and renal outcome has producedcontradictory results. In addition, the comparisonamong studies is difficult because of large differencesin entrance criteria, the type of lesions evaluated andthe way renal outcome was measured.

The current study is so far the largest study of sys-temic vasculitis described to date. Renal biopsy resultsfrom 157 patients with systemic vasculitis from 14European centers were assembled together with theirclinical data, and their renal histopathology was corre-lated to renal function both at the time of biopsy andduring follow-up period. The biopsies were evaluatedaccording to previously standardized scoring protocol.Serum creatinine level during follow-up period wastaken into account as the optimum level of renal func-tion recovery. The percentage of normal glomerulicorrelated most significantly with the outcome at allpoints of measurement. Other lesions predicting forrenal outcome were glomerular sclerosis at one yearafter biopsy, diffuse interstitial infiltrates at entry andone year, tubular necrosis at entry and tubular atrophyat entry and one year.

CommentaryAttention is focused on the extent of active lesions inthe renal biopsy in order to determine the severity of

the renal disease and its implication for renal outcome.This study clearly shows that both at the time of biopsyand during follow-up, the percentage of normal glom-eruli in the initial biopsy turned out to be the mostreliable predictor for renal outcome in patients withsystemic vasculitis. In contrast, extracapillary prolif-eration and fibrinoid necrosis, the active lesions thatserve to establish the diagnosis of systemic vasculitis,proved not to be indicative for renal function, both atentry and follow-up period.

Renoprotective effects of angiotensin II receptorblockade in type 1 diabetic patients with diabeticnephropathy

Andersen, S., Tarnow, L., Rossing, P., Hansen, B.V.and Parving, H.H.Steno Diabetes Center, Copenhagen, Denmark

Kidney Int 2000; 57: 601–606

It is well known that Ang I converting enzyme-inhibitors (ACE-I) reduce Ang II formation and causeaccumulation of bradykinin. Bradykinin is a potentvasodilator acting through the release of prostacyclin,nitric oxide and endothelial-derived factors. Recentstudies have suggested that bradykinin may play a rolein the effects of ACE inhibition on blood pressure andkidney function. In addition, Ang II is produced viaalternative pathways which are not affected by ACE.Ang II receptor blockade has no effect on bradykininaccumulation but antagonised Ang II generated by anypathway. Therefore, the authors compared the renalfunction and hemodynamic effects of Ang II subtypeI receptor blocker (losartan) to the effect of an ACE-I(enalapril). This randomized, double-blind, cross-overtrial, included 16 type 1 diabetic patients (10 male and6 female) with a mean age of 42 years, and consistedof five periods each lasting 2 months. The patientsreceived losartan 50 mg, losartan 100 mg, enalapril10 mg, enalarapril 20 mg, and placebo in randomorder during these time periods. Both losartan andenalapril reduced albuminuria and mean arterial bloodpressure, whereas GFR remained stable. HbAlc andsodium intake remained stable throughout the study,whereas a significant rise in serum potassium occurredduring ACE inhibition. The decreases in albuminuriawere 33% on losartan 50 mg, 44% on losartan 100 mg,45% on enalapril 10 mg, and 50% on enalapril 20 mg.

208

CommentaryThe Ang II subtype 1 receptor antagonist reduces albu-minuria and mean arterial blood pressure similar tothat of ACE-I. These results suggest that the reductionin albuminuria and blood pressure during ACE inhibi-tion is primarily caused by interference in the renin-angiotensin system. On the other hand, bradykininantagonists have not been shown to have renopro-tective effect in animal studies. Again this indicatesthat the renoprotective effect of ACE inhibition ismediated by the interference in the renin-angiotensinsystem.

Retinopathy and nephropathy in patients withtype 1 diabetes four years after trial of intensivetherapy

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Compli-cations Research Group

N Engl J M 2000; 342: 381–389

Patients with type 1 diabetes mellitus with intensivetherapy (three daily injections of insulin or treat-ment with an insulin pump, diet and exercise) andnear-normal blood glucose and glycosylated hemo-globin concentration have markedly reduced risk ofmicrovascular complications as compared with thoseon conventional therapy (one or two insulin injectionsper day). To assess whether there are long-term bene-fits of tight glucose control, the authors reported theeffects of former intensive and conventional therapyon the occurrence and severity of retinopathy andnephropathy for four years after the end of the Dia-betes Control and Complications Trial (DCCT).

After the end of the DCCT, the patients in theconventional-therapy group were offered intensivetherapy, and the care of all patients was transferredto their own physicians. Most of these patients wereenrolled in the Epidemiology of Diabetes Interven-tions and Complications study. Retinopathy was eval-uated on the basis of centrally graded fundus photo-graphs in 1,208 patients during the fourth year after theDCCT ended, and nephropathy was evaluated on thebasis of urine specimens obtained from 1,302 patientsduring the third or fourth year, approximately half ofwhom were from each treatment group. The differ-ence in the median glycosylated hemoglobin valuesbetween the conventional and intensive therapy groups

during the 6.5 years of the DCCT (average 9.1%and 7.2% respectively) narrowed during the follow-upperiod (median 8.2 and 7.9%, respectively). Never-theless, the proportion of patients who had worseningretinopathy, including proliferative retinopathy, mac-ular edema, and the need for laser therapy, was lowerin the intensive therapy group. Also, intensive therapysignificantly blunted the increase in urinary albuminexcretion.

CommentaryThis study demonstrated marked reduction in therisk of retinopathy and nephropathy in the intensivetherapy group during the DCCT persisted for at leastfour years despite rising glycosylated hemoglobinlevels. The findings strongly suggest that intensivetherapy has beneficial effect on the long-term com-plications of diabetes that persists long after the actualperiod of such therapy. It should be noted that theresults of the DCCT and a follow-up period shouldnot be interpreted that intensive therapy needs to beadministered for only a limited period of time.

Urinary albumin excretion in families with type 2diabetes is heritable and genetically correlated toblood pressure

Fogarty, D.G., Rich, S.S., Hanne, L., Warram, J.H.and Krolewski, S.Research Division, Joslin Diabetes Center, andDepartment of Medicine, Harward Medical School,Boston, Massachusetts, and Wake Forest UniversitySchool of Medicine, Winstom-Salem, North Carolina,USA

Kidney Int 2000; 57: 250–257

In this study, the investigators estimated the her-itabilities of urinary albumin excretion (UAE) andblood pressure (BP) and their correlation attributableto genetic effects using 96 large families ascertainedfor type 2 diabetes. They determined the extent towhich UAE measured as the albumin:creatinine ratio(ACR) is heritable in large families with type 2 dia-betes, and also assessed the proportion of variationin BP measurements that is attributable to geneticeffects. The genetic correlation between ACR and BPmeasurements was estimated to test the hypothesis thatdiabetic nephropathy and hypertension in type 2 dia-betes share a common genetic susceptibility. A total

209

of 1,365 members of 96 large families were examined.A random urine sample for determination of ACR wasprovided by 1,269 of whom 630 had type 2 diabetes,and 639 were normoglycemic. In all 96 families, thetotal number of usable pairs of relatives were 6481.Estimates of the familial correlations for each type ofrelationship (ACR, SBP and DBP) were determined bythe FCOR program within S.A.G.E. software package.The heritability for ACR was similar to that for BP.Heritabilities were estimated separately for diabeticsas they have different distribution of ACR than non-diabetics (normoglycemics). The estimates of herit-ability for the traits were higher in the diabetics thanin the total group. It was concluded that in familieswith type 2 diabetes, UAE is a heritable trait, with aheritability similar to that for BP. A significant geneticcorrelation between UAE and BP, particularly in thepresence of diabetes, indicates that these traits sharecommon genetic determinants.

CommentaryThis is a large study assessing familial aggregation ofUAE, measured as ACR in Caucasian families withtype 2 diabetes mellitus. Variance components ana-lysis used in this study allowed the estimation ofgenetic and environmental correlations between traitsand also was able to link relationship between albuminexcretion and BP. As the study is done in Caucasianfamilies, it cannot be generalized to the whole popula-tion, particularly the African Americans. Even thoughthe study is done in a large group of 1,365 members,BP was taken only once and a single urinary samplewas taken for determination of ACR, which couldcause a sampling error.

Nitric oxide synthase isoforms and glomerularhyperfiltration in early diabetic nephropathy

Veelken, R., Hilgers, Karl F., Hartner, A., Haas, A.,Bohmer, Kirsten P. and Sterzel, R. BerndMedizinische Klinik IV, Universitat Erlangen-Nurnberg, Germany

J Am Soc Nephrol 2000; 11: 71–79

Evidence of diabetic nephropathy is present early inthe course of diabetes, in the form of hyperfiltration.This study investigated whether it is the activity ofthe inducible (i) rather than the constitutive (ec) formof nitric oxide synthase (NOS) that is responsible for

this early change. Diabetes mellitus was induced inSprague Dawley rats via intraperitioneal streptozocininjection, and healthy rats were used as controls. Twoweeks following induction, glomerular filtration rate(GFR) and renal plasma flow (RPF) were measuredand found to be significantly higher in diabetic ratsthan in controls. L-NIL, an inhibitor of iNOS, wasadministered in doses of 0.1, 1.0 and 10 mg to diabeticrats, and only those receiving the highest dose hada decrease in RPF. L-NAME, a nonselective blockerof all NOS isoforms, was also administered, and alldoses significantly reversed the diabetic nephropathicchanges.

In addition, nine diabetic and six control rats weresacrificed for the detection of glomerular NOS RNAand protein, using Northern Blot, Western Blot andreverse transcriptase-PCR methods. ecNOS proteinwas significantly elevated in diabetic rat glomeruli;immunohistochemical staining for iNOS was negativein both diabetic and control rats but was positive in ratspretreated with L-NAME and in those pretreated withlipopolysaccharides (which induce iNOS expressionin the kidney).

CommentaryThis article demonstrates the importance of NO inthe development of early diabetic nephropathy, anddelineates which form of NOS is important in itsproduction. The article also underscores the growingimportance of molecular biology’s role in the study ofclinical phenomena and their treatment. This is one ofa large group of articles, not just in nephrology but inall fields, which will be useful to pharmacologists indetermining drug targets (i.e. in this case, iNOS wouldnot be a viable target because it has essentially no rolein the development of early diabetic nephropathy).

Urinary tract infection prophylaxis usingEscherichia coli 83972 in spinal cord injuredpatients

Hull, R., Rudy, D., Donovan, W., Svanborg, C.,Wieser, I., Stewart, C. and Darouiche, R.Department of Physical Medicine and Rehabilitation,and Microbiology and Immunology, Center for Pros-theses Infections, Baylor College of Medicine; Depart-ment of Physical Medicine and Rehabilitation, Divi-sion of Urology, University of Texas Health ScienceCenter; The Institute for Rehabilitation and Research,and Department of Medicine, Infectious Disease Sec-

210

tion, Veterans Administration Medical Center, Hou-ston, Texas; and Department of Medical Microbiology,Section of Clinical Immunology, Lund University,Lund, Sweden

Journal of Urology 2000; 163: 872–877

Urinary tract infection continues to be a significantcause of morbidity and mortality among spinal cordinjury patients. This study is a non-randomized studyin which the ‘controls’ are the twenty-one studysubjects before their entry into the study. Adultswith spinal cord injury and history and at least onesymptomatic urinary tract infection within 12 monthsprior to the study were eligible, and individuals wereexcluded if they had a reversible cause for infectionsor if they had hardware associated with their urinarytracts. Three attempts were made on each of threeconsecutive days to inoculate the bladder of eachsubject, using a sterile bladder catheter to infuse 30ml of normal saline with a bacterial concentrationof 105 to 106 per ml. Persistent colonization wasachieved in 13 subjects, who had an average of3.1 UTI’s per year prior to participation in thestudy. During the follow-period (total 18.4 patientyears), there were no UTI’s in participants whoremained colonized. The subjects who experiencedUTI’s following successful colonization wereshown to have lost colonization spontaneously. Inaddition to this clinical parameter, nine of the tensubjects who remained colonized for at least three

months completed a quality of life questionnaire bytelephone; scores were significantly higher (better)during colonization than just before colonization. Allsubjects interviewed reported that they would seekrecolonization if they were to lose it. Scores fellwith spontaneous loss of colonization secondary torecurrence of symptomatic UTI.

CommentaryUrinary tract infection remains problematic for spinalcord injured patients, and the use of nonpatho-genic bacteria for ‘interference’ is a novel approachaddressing it. The numbers in this study are not highenough to recommend bacterial colonization for allpeople at risk, although enough evidence is presentedto justify further study. The complete absence of UTI’sduring colonization does appear convincing. Improve-ments in quality of life scores in the participants arejust as appealing, although the authors do acknowl-edge that this may be related to the frequency orvigilance of medical follow-up over a subject’s usualcare.

There is a high incidence of UTI in the elderly,secondary to risk factors which are frequently com-pounded in this population, i.e., prior CVA, neuro-genic bladder and dementing disorders. This higherfrequency of UTI raises the question of whether thepractice of bacterial colonization of the urinary tractshould be considered for the elderly as well, possiblyreducing their number of infections and their exposureto antibiotic medications.