Management of Glomerular Proteinuria: A Commentary
William A. Wilmer*,
Brad H. Rovin*,
Christopher J. Hebert,
Sunil V. Rao,
Karen Kumor and
Lee A. Hebert*
*Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio; Case Western Reserve University, Louis Stokes VA Medical Center, Cleveland, Ohio; Department of Medicine, Duke University, Durham, North Carolina; and Alexion Pharmaceuticals, Inc., Cheshire, Connecticut.
Correspondence to Dr. Lee A. Hebert, The Ohio State University Medical Center, 1654 Upham Drive, Columbus, OH 43210-1250. Phone: 614-293-4997; Fax: 614-293-3073; E-mail: hebert.1{at}osu.edu
ABSTRACT. It is widely accepted that proteinuria reduction isan appropriate therapeutic goal in chronic proteinuric kidneydisease. Based on large randomized controlled clinical trials(RCT), ACE inhibitor (ACEI) and angiotensin receptor blocker(ARB) therapy have emerged as the most important antiproteinuricand renal protective interventions. However, there are numerousother interventions that have been shown to be antiproteinuricand, therefore, likely to be renoprotective. Unfortunately testingeach of these antiproteinuric therapies in RCT is not feasible.The nephrologist has two choices: restrict antiproteinuric therapiesto those shown to be effective in RCT or expand the use of antiproteinurictherapies to include those that, although unproven, are plausiblyeffective and prudent to use. The goal of this work is to providethe documentation needed for the nephrologist to choose betweenthese strategies. This work describes 25 separate interventionsthat are either antiproteinuric or may block injurious mechanismsof proteinuria. Each intervention is assigned a level of recommendation(Level 1 is the highest; Level 3 is the lowest) according tothe strength of the evidence supporting its antiproteinuricand renoprotective efficacy. Pathophysiologic mechanisms possiblyinvolved are also discussed. The number of interventions ateach level of recommendation are: Level 1, n = 7; Level 2, n= 9; Level 3, n = 9. Our experience indicates that we can achievein most patients the majority of Level 1 and many of the Level2 and 3 recommendations. We suggest that, until better informationbecomes available, a broad-based, multiple-risk factor interventionto reduce proteinuria can be justified in those with progressivenephropathies. This work is intended primarily for clinicalnephrologists; therefore, each antiproteinuria interventionis described in practical detail.
This work focuses on therapies that can be expected to be antiproteinuricin all forms of glomerulopathy. Not considered are disease-specifictherapies such as insulin for diabetic nephropathy. In chronicglomerular diseases, the greater the proteinuria the greateris the risk of "progression" (irreversible and progressive GFRdecline) (1,2) (Table 1). The exceptions are glomerulopathiesthat manifest highly selective proteinuria such as minimal changedisease and certain forms of hereditary glomerulopathy (3).In these conditions, heavy proteinuria can be present for yearswithout evidence of kidney damage.
The historic explanation is that greater proteinuria indicatesa more severe glomerulopathy, and this accounts for the fasterGFR decline (1). Recently, it has become clear that proteinuria,particularly when heavy and nonselective, can be nephrotoxicthrough a variety of mechanisms (reviewed in references 4–6).Thus, there is strong evidence that proteinuria is both a markerfor and a mechanism of kidney disease progression. Consistentwith this hypothesis are the clinical studies showing that proteinuriareduction is associated with slower subsequent GFR decline (7–9),whereas maintained or worsened proteinuria is associated withfaster GFR decline (10,11). Nevertheless, to critically testthe hypothesis that proteinuria causes progression requiresstudies in which proteinuria, or a damaging mechanism attributedto proteinuria, is changed independent of all other progressionmechanisms. Presently the only possible approach is to blocka mechanism by which proteinuria could cause kidney damage.This has recently been accomplished in experimental nephropathiesin which complement activation in the tubular compartment waseither attenuated by complement inhibitors (12,13) or abrogatedby genetic deficiency of the sixth component of complement (14).The rationale is that nonselective proteinuria contains theentire alternative and terminal complement pathways, which activateand deposit the membrane attack complex (C5b-9) on tubular epithelium(12–15). Furthermore, activated renal tubular epitheliumcan synthesize and secrete C3 (6). Studies in the C6 geneticallydeficient rat (14) provide particularly compelling evidencethat proteinuria itself is nephrotoxic. In these studies, thenormal PVG rats subjected to 5/6 nephrectomy manifested proteinuria,tubular C5b-9 deposition, and progressive kidney damage. Bycontrast, the C6 genetically deficient rats with 5/6 nephrectomymanifest only the proteinuria (14).
If Proteinuria Is Reduced, How Much Slowing of GFR Decline Can Be Expected?
Of the studies examining this question (7–9,16,17), StudyA of the Modification of Diet in Renal Disease (MDRD) studyis among the largest (585 patients) and most detailed (adjustmentfor 11 relevant baseline and 6 relevant follow-up co-variates).The MDRD study showed that for each 1-g/d reduction in proteinuriaobserved at 4 mo of the antiproteinuria therapies (the BP anddietary interventions), subsequent GFR decline was slowed byabout 1 ml/min per year (7). The REIN study showed that foreach 1-g/d reduction in proteinuria observed at 3 mo of ACEItherapy, subsequent GFR decline adjusted for baseline GFR wasslowed by about 2.0 ml/min per year (18). In most proteinurickidney diseases, GFR loss occurs at about 4 to 10 ml/min peryear (7). Thus proteinuria reductions of 1.0 g/d or more shouldprolong time to ESRD (Figure 1) and may reduce cardiovasculardeaths because chronic kidney disease (CKD) is independentlyrelated to cardiovascular death rate (19).
Figure 1. Rate of GFR decline in normals an in hypothetical patients with onset of progressive renal disease at age 25 yr. The course of GFR decline with normal aging (top curve) is based on a cross-sectional study of iothalamate clearance in 357 patients aged 17 to 70 years. Note also that small differences in rates of GFR decline can result in large differences in time to onset of ESRD. Reprinted with permission from Hebert et al. (4).
Spot versus 24-h Urine Collection to Assess Proteinuria
The Work Group of the Kidney Disease Outcome Quality Initiative(K-DOQI) of the National Kidney Foundation recommends firstmorning or random spot urine collections to monitor proteinuriain established kidney disease (20). Spot urine testing is aconvenient and acceptable practice; but we suggest that 24-hurine testing is a "best practice" for the following reasons.
Twenty-four-hour urine collections estimate proteinuria ratemore accurately than spot urine collections. In the typicalnephrotic patient, the urine protein/creatinine ratio (P/C ratio)at midday is about 1.7-fold greater than that in the morning(21,22). Thus, the closer the urine collection approaches 24h, the closer the urine P/C ratio approaches the 24-h proteinuriarate. The notion that the spot urine/creatinine ratio accuratelypredicts 24-h proteinuria is based on cross-sectional studiesin which the between-patient variation in proteinuria rate wasgreat, generally 600-fold or greater (20, 23). Thus, the highcorrelation coefficients do not apply to individual proteinuricpatients followed longitudinally (24).
The urine P/C ratioof even an inaccurately timed 24-h urinecollection is likelyto yield a better estimate of 24-h proteinuriarate than thatof a random spot urine. This follows from Point#1 (above).
Kidney disease progression attributable to proteinuria isprobablyrelated to the absolute 24-h proteinuria rate. Spotor overnighturine collections tend to overestimate or underestimatetheabsolute 24-h proteinuria rate. Morning spot or fractionalurinecollections usually represent nadir proteinuria rates.Middayspot or fractional urine collections usually representpeakproteinuria rates (21,22).
Large daily changes in urinarycreatinine excretion can occurindependently of urine proteinexcretion, causing the urineP/C ratio to be an inaccurate estimateof proteinuria rate.Spot urine testing cannot detect this confounder,but 24-h urinetesting can. In the average carnivorous NorthAmerican adult,about one third of urine creatinine is fromeating cooked meat(cooking converts meat creatine to creatinine)(25), particularlybeef (26). Sustained heavy exercise can increase24-h urinecreatinine by nearly twofold (27). Creatine, a nutritionalsupplementusually taken at 2 to 5 g daily is metabolized tocreatinine(28). Fenofibrate increases urinary creatinine excretionbyas much as 35% (29). Thus, creatinine excretion can be changedsubstantially depending on whether the 24-h urine was collectedin relation to vigorous exercise, high-meat or no-meat meal,a creatine supplement, or fenofibrate. Measuring the 24-h urinecreatinine content should detect these confounders; a spot urinecannot.
Twenty-four-hour urine testing provides relevant informationregarding nutrient and fluid intake that a spot urine cannot.Our practice in CKD management is to test 24-h urine collectionsat 2- to 6-mo intervals for volume, creatinine, protein, urea,sodium, and potassium if abnormalities of serum potassium arepresent (4). The relevance is discussed later.
To assist the patient in obtaining an accurate and informative24-h urine collection, we suggest that the patient should dothe following. (1) Pick a day that is convenient and typicalof their usual regimen. (2) Obtain the 24-h urine within 1 wkof the clinic visit. Store it in the cold. It is OK if individualvoidings must be held at room temperature for up to 12 h. (3)Avoid missed voidings by carrying in purse or duffle bag a leak-proof500-ml plastic wide-mouth container (e.g. Rubbermaid Sipp’nSport 590 ml). (4) Inform their physician if voidings are lost.It is better to submit an incomplete 24-h urine collection thannone at all.
Table 2 summarizes the advantages of 24-h versus spot urinetesting. Table 3 is an algorithm to interpret 24-h urine collectionsto assess proteinuria and nutrient intake.
Table 2. Advantages of 24-h urine versus "spot" urine testing in monitoring chronic kidney disease (the column containing the dot indicates the advantage)
Table 3. Interpretation of urine collections submitted as 24-h collections to estimate proteinuria and nutrient excretion rate
Urine Albumin Versus Urine Total Protein for Monitoring Proteinuria
The K-DOQI Work Group recommends urine albumin measurement tomonitor CKD (20). Certainly microalbuminuria measurement forthe early detection of CKD and cardiovascular risk (30) is appropriate.However, in established glomerulopathies (proteinuria >500mg/d) or to screen for tubular proteinuria (where albuminuriamay be at normal levels), we suggest measurement of total urineprotein (albumin + other proteins). The rationale is that inestablished glomerulopathies, there is no evidence that albuminuriarate is more informative than total proteinuria rate. Indeed,albuminuria and total proteinuria rates are generally highlycorrelated (20). Nevertheless, recent studies demonstrate differencesin the renal tubular reclamation and degradation of filteredalbumin compared with IgG and transferrin (31,32). Thus, measurementof albuminuria alone might provide spurious information regardingthe status of glomerular and tubular function. Furthermore,urine albumin measurement is more costly. In a survey of fourOhio hospitals and one commercial laboratory, median chargefor a urine albumin/creatinine ratio was $77 compared with $25for a P/C ratio.
Antiproteinuric therapies of proven effectiveness, or plausiblyeffective and prudent to use, are listed in Table 4 accordingto level of recommendation. Level 1 (highest) recommendationis based on one or more large high-quality controlled clinicaltrials. Level 2 (intermediate) recommendation is based on asecondary analysis of the high-quality trials or randomizedcontrolled trials. Level 3 (lowest) recommendation is basedon observational or experimental kidney disease studies.
Table 4. Antiproteinuric strategies ranked according to level of recommendation
The goal of antiproteinuric therapy is to reduce proteinuriaas much as possible, ideally to <500 mg daily, which appearsto approach the maximum benefit of proteinuria reduction (33,34).The antiproteinuric therapies listed in Table 4 are discussedbelow.
1. Control BP (Level 1)
Three large trials have randomized kidney disease patients totwo different levels of BP control, a usual goal (approximately140/85 mmHg) or a low goal (approximately 125/75 mmHg), andobserved the effects on proteinuria. The studies are the MDRDstudy (7), the Appropriate Blood Pressure Control in Diabetes(ABCD) study (35), and the African American Study of KidneyDisease and Hypertension (AASK) (11). The low BP goal eitherreduced proteinuria by 50% (7) or prevented the twofold to threefoldincrease in proteinuria observed in the usual BP goal patients(11,35). In the MDRD study, the greater the baseline proteinuria,the greater was the percent reduction in proteinuria in thelow goal group (7). The low BP goal was well tolerated in thelarge randomized trials (7,11,35) and in the smaller studiesof the effect of the low BP goal (36,37). Compared with theusual BP goal, the low BP goal reduced stroke rate (35) andleft ventricular mass index (38). A recent meta-analysis showedthat the higher mortality rates associated with lower BP (theJ-curve phenomenon) is explained by association of low BP withpoor health, not the low BP itself (39). Benefits of the lowgoal have also been confirmed in hypertensive non-kidney diseasepatients (40,41). Thus, the low BP goal, sitting systolic BPin the 120s or less if tolerated, is recommended. The systolicBP is specified because it correlates better than diastolicpressure with kidney disease progression (7,10).
BP should be taken in the sitting position and after takingthe antihypertensive medications at the usual times. However,if the antihypertensive medication has rapid onset (clonidinetablets, labetalol, captopril, hydralazine), this needs to betaken into account. At the first evaluation, BP is taken inboth arms. The arm with the higher BP is used for future BPmeasurement (42). We recommend home BP monitoring using propertechnique and calibrated equipment, particularly if office BPis not at goal (4). Ambulatory BP monitoring (ABPM) may be usefulto assess cardiovascular risk if the clinic BP is not at goal(43). Also ABPM tests for increased nocturnal BP, which maypromote proteinuria progression (44). Thus, consider ABPM ifthe proteinuria goal is not met (discussed later). ABPM mayalso be useful in identifying whether BP control is better thanthat estimated by clinic BP. A striking example is that observedin the HOPE trial, where ABPM results showed much better BPcontrol than suggested by the clinic BP (45).
Recommended Antihypertensive Regimens. Nonpharmacologic Therapy.
Restrict salt intake and lose excess weight (discussed later).Avoid alcohol more than 2 drinks daily, vasoconstrictor nosedrops and eye drops, decongestants, amphetamines, anabolic steroids,high-dose estrogen therapy, cocaine, and nonsteroidal antiinflammatoryagents (NSAIDs) (4).
Pharmacologic Therapy.
This is shown in Figures 2 and 3. The strategy is to achievethe BP goal using drugs that are antiproteinuric and attenuateangiotensin II (AngII) and aldosterone. The recommended startingpoint is ACEI or ARB, not diuretics. ALLHAT (Antihypertensiveand Lipid-Lowering Treatment to Prevent Heart Attack) showedthat chlorthalidone reduced certain cardiovascular risks betterthan ACEI, dihydropyridine calcium channel blocker (DH CCB),or doxazosin (46). On this basis, diuretics are recommendedas first-line therapy in hypertension (47). However, diureticsstimulate the renin-angiotensin system, which is probably undesirablein CKD (discussed later). Furthermore, in ALLHAT, the main benefitof diuretics was reduction in congestive heart failure and strokein African Americans (48). Both are salt-sensitive states. Thus,unless heart failure or another edema-forming state is present,the preferred initial antihypertensive/antiproteinuric therapyin CKD is ACEI or ARB because they attenuate AngII effects.This should not compromise BP control in CKD. Note that about60% of MDRD Study A patients and about 40% of the AASK patientsreceived no diuretics, and most achieved their BP goal (11,49).Consistent with our recommendation of ACEI rather than diureticas initial therapy of hypertension is the outcome of the secondAustralian National Blood Pressure Study (50), and the May 5,2003, nationally promulgated joint statement of the AmericanSociety of Nephrology and the National Kidney Foundation recommendingthat ACEI, ARB, or both is the preferred initial therapy ofhypertension in CKD. If diuretic therapy is needed in CKD, furosemideis recommended (4,51).
Figure 2. Algorithm 1: Initial Pharmacologic Blood Pressure Management in Kidney Disease. Assumes nonpharmacologic therapy to control BP is in place (see text) and that the patient does not have renovascular hypertension, congestive heart failure, ischemic heart disease, or hypertensive urgency. The above approach focuses on BP control in proteinuric nephropathies, but it may also be appropriate for nephrosclerosis, polycystic kidney disease, and interstitial nephropathies. *The suggestion to add diuretic before ARB is arbitrary but can be justified by the evidence that diuretic increases the antihypertensive effect of angiotensin-converting enzyme inhibitor (ACEI), is often needed in chronic kidney disease (CKD) to control fluid retention, is inexpensive, and may increase the renoprotective effects of ACEI, angiotensin receptor blocker (ARB), or the combination (93). Emphasize salt restriction in autosomal dominant polycystic kidney disease (ADPKD) rather than diuretic therapy, which may promote cyst growth (4). Details of diuretic therapy are discussed previously (4) and in the text.
Figure 3. Algorithm 2: BP Management in Kidney Disease if Initial Therapy (Algorithm 1) Fails. (a) Diltiazem and verapamil sustained release preparations are recommended. (b) Clonidine recommended for individuals receiving insulin, because it does not importantly affect glucoregulation, and for those who have difficulty with beta-blocker (e.g., bronchospasm, cardiac conduction). (c) Beta-blocker/clonidine combination is usually well tolerated, but may cause bradycardia.
2. ACEI Therapy (Level 1)
ACEI, rather than ARB, is the initial choice because, althoughboth ACEI (4,5,33,52) and ARB (16,17,53) are antiproteinuricand renal protective, it is unclear whether ARB are cardioprotectiveto the level of ACEI. A detailed discussion of this issue isbeyond the scope of this work; however, we cite the two largestcontrolled cardiovascular trials involving ACEI or ARB. TheHOPE trial (n > 9000 patients) showed that ramipril significantlyreduced the composite endpoint of death, stroke, and myocardialinfarction, and each component of the composite endpoint (54).In the LIFE trial (n > 9000 patients), the composite endpointof death, stroke, and myocardial infarction was reduced significantlyby losartan but of the individual components of the compositeendpoint, only stroke was significantly reduced (55). Furthermore,in the recent OPTIMAAL trial (n = 5477 patients), which comparedlosartan to captopril in patients with acute myocardial infarctionand heart failure (56), captopril was numerically better thanlosartan in reducing death, the primary endpoint (P = 0.069),and in reducing each of the twelve secondary cardiac and non-cardiacendpoints, although statistical significance was reached onlyfor cardiovascular death, P = 0.032. In the captopril trial(57), the combined endpoint of death or ESRD was reduced significantly.By contrast, such benefit was not observed in RENAAL or theIDNT study (16,17,58). Further insight into ACE and ARB cardiovascularprotection may be provided by the VALIANT, which is currentlyunderway and much larger than HOPE or LIFE, and will comparevalsartan, captopril, and the combination in patients post-myocardialinfarction with evidence of heart failure, left ventriculardysfunction, or both.
Theoretical advantages of ACEI over ARB include the increasedbradykinin levels during ACEI therapy, which can be additionallyvasodilatory and antifibrotic (59,60). ACEI also decrease elevatedplasminogen activation inhibitor-1 (PAI-1) levels. Lower PAI-1levels are antifibrotic by promoting higher plasmin levels,which degrade matrix proteins (61). ACEI also suppresses profibroticaldosterone (62) better than ARB (63). Both ACEI and ARB appearto reduce the rate of new-onset diabetes mellitus: ACEI, 34%reduction in HOPE (54); ARB, 25% reduction in LIFE (55). Somesuggest that the lower rates of new-onset diabetes in the ACEIor ARB groups in these trials are not truly protection againstdiabetes but rather reflect induction of diabetes by the beta-blockeror diuretic therapy of the control group. The ALLHAT results,however, suggest true protection against diabetes by ACEI becausethe chlorthalidone group had more new cases of diabetes mellitusand the ACEI group had fewer new cases of diabetes mellitusthan the group receiving DH CCB (46), which does not affectglucose metabolism (64). A further ACEI advantage is that captopril,enalapril, and lisinopril are available as generics. There areno generic ARB.
Benefits of ACEI are believed to be a property of the drug class.Nevertheless, there are differences among ACEI with respectto binding to plasma proteins, tissue penetration, lipid solubility,ACE affinity, and off rate (65,66), each of which could influenceefficacy. Most ACEI have relatively low plasma protein binding.Benazepril and fosinopril have higher protein binding (67).ACEI with the highest affinity for tissue ACE are benazepril,quinapril, and ramipril (67). In heart tissue, ACE is expressedmainly on endothelial cells with its catalytic site toward thevessel lumen (68). In kidney, tissue ACE is expressed mainlyon the apical portion of the proximal tubular epithelial cell(69). ACEI block both plasma and tissue ACE. Tissue ACE primarilyregulates BP (70). Indeed, ACE knockout mice, which lack tissueACE but have abundant plasma ACE, are hypotensive (70).
ACEI therapy reduces proteinuria by about one third (33,52,71).At maximum recommended doses, ACEI may be more antiproteinuricthan ARB (72). Concomitant use of low-salt and reduced-proteindiet enhances ACEI antiproteinuria (4,73) as does diuretic therapy(74), the low BP goal (11), and statin therapy (75). The greaterthe proteinuria, the greater the benefits of ACEI therapy inslowing CKD progression (33). ACEI are antiproteinuric and renoprotectiveeven in inflammatory glomerulopathies (76). ACEI is generallywell tolerated in renal insufficiency (serum creatinine >3mg/dl, reviewed in reference 4). However, greater caution isadvised. Hyperkalemia can usually be controlled by restrictingpotassium intake, increasing diuretic therapy, and adding sodiumbicarbonate therapy (4). Serum creatinine increases of up to50% can occur with ACEI therapy. There is no need to discontinueACEI therapy if it is a stable increase (4,11,77); however,awareness to possible renal artery stenosis is indicated.
ACEI Dose.
Antiproteinuric and renoprotective effects of ACEI have beenshown with four different ACEI (captopril, enalapril, benazepril,and ramipril) used in relatively low doses (78). High-dose ACEItherapy may be more antiproteinuric and more renoprotectivethan usual doses (4,72,79–81), although mild anemia hasbeen reported with ramipril at 20 mg daily (82). Current trendsare to use the maximum recommended dose of ACEI, if tolerated(4,11,72,79–81). Tolerance to ACEI occurs on lower-doseACEI, which can be overcome by increased ACEI dose (83). Thus,preemptively increasing ACEI dose to tolerance may avoid undertreatment.
Choosing an ACEI.
Based on reported efficacy and safety in achieving both cardiovascularand renoprotection in large patient populations, ramipril wouldbe the ACEI of choice (11,54,84). Also to be considered is thatin the nephropathy of type 1 diabetes, captopril reduced therisk of death or ESRD (57). Nevertheless, as discussed above,ACEI benefits may be a drug class effect.
3. ARB Therapy (Level 1)
ARB are recommended in ACEI-intolerant patients (cough, angioedema,or allergy [4]). Also, ARB may raise serum potassium less thanACEI (63). ARB are antiproteinuric and renoprotective in thenephropathy of type II diabetes (16,17). The American DiabetesAssociation recommends ARB as first-line therapy in type IIdiabetic patients with nephropathy (85) because no large-scaletrials demonstrate efficacy of ACEI in this group (4,5). However,we and others recommend ACEI as initial therapy in the nephropathyof type II diabetes (4,53,79) because ARB may not be cardioprotectiveto the level of ACEI (discussed above) and may be less antiproteinuric(72). Theoretically, ARB might be more cardioprotective thanACEI therapy (86) in part because most myocardial AngII is formedby chymase, not ACE (87), and ACEI do not inhibit chymase. Myocardialchymase is in interstitial cells, mast cells, and bound to extracellularmatrix (87). If ARB can efficiently penetrate myocardial interstitium,they should be more effective than ACEI in attenuating myocardialAngII effects such as myocardial hypertrophy and fibrosis. However,ARB are highly protein bound, which could affect tissue penetration.A reduced salt intake increases the antiproteinuric effectsof ARB (4).
Choosing an ARB.
Both losartan and inrbesartan have been shown to be both antiproteinuricand renoprotective in the nephropathy of type II diabetes mellitus(16,17). There are no generic ARB.
ARB Dose.
The maximum recommended ARB dose, if tolerated, is recommendedbecause it is more antiproteinuric (72,88) and more likely toregress left ventricular hypertrophy (89) than the usual ARBdose.
4. Combination ACEI and ARB (Level 1).
There is now clear evidence that combination ACEI/ARB therapyis more antiproteinuric than ACEI or ARB alone (72,90–94).Also combination ACEI/ARB may be more renoprotective than eitherdrug alone as demonstrated in a recent large-scale trial innondiabetic kidney disease (93). Therefore, early deploymentof combination ACEI/ARB therapy can be recommended. The optimumantiproteinuric strategy appears to be addition of ARB to maximumACEI in those who fail to achieve their proteinuria goal onACEI alone (72). The theoretical benefits of combination therapyinclude those of ACEI therapy (increased bradykinin, decreasedaldosterone, decreased AngII levels) and those of ARB therapy(blockade of AngII produced by chymase, and increased AT2 receptoractivation, which may be vasodilatory, antiproliferative, andantifibrotic) (5,90,95). The VAL-HEFT study results suggestedthat in patients with systolic dysfunction and heart failure,addition of an ARB to beta-blocker and ACEI increases mortality.However, the longer CHARM study showed no adverse effect ofcombinations of ACEI, ARB, and -blocker therapies (96). Diuretictherapy may increase the renoprotective effects of combinationtherapy (93). Combination ACEI/ARB therapy might be particularlyeffective in those with the ACE gene DD genotype where resistanceto ACEI may be present. The D allele encodes for high ACE, bothcirculating and tissue, and might contribute to kidney diseaseprogression and resistance to ACEI therapy (71,97–101).A low salt intake may restore responsiveness to ACEI in theDD genotype (71). Not all studies show resistance to ACEI inDD genotypes, particularly in males (99). The reason for thisdifference is not clear. The incidence of hyperkalemia in combinationACEI/ARB therapy in CKD is similar to that of ACEI alone (93),even when ACEI and ARB are given in maximum recommended doses(72,92).
5. Avoid Dihydropyridine Calcium Channel Blocker (DH CCB) Therapy Unless Needed for BP Control (Level 1)
DH CCB are excellent antihypertensive agents, and a nonrandomizedintervention suggested that DH CCB may be antiproteinuric ifgood BP control is achieved (102). However, the randomized trialsdo not support this suggestion. In the ABCD trial, despite goodBP control, nisoldipine resulted in threefold greater albuminuriarate compared with enalapril (103). In the IDNT, despite substantialBP reduction in the amlodipine group, proteinuria remained atbaseline. By contrast, at the same BP level as the amlodipinegroup, the irbesartan group achieved a 33% reduction in proteinuria(17). In the AASK, although amlodipine achieved better BP controlthan ramipril or metoprolol, proteinuria increased about twofoldon amlodipine therapy but generally remained at or below baselinelevels on ramipril or metoprolol therapy (11). These resultsconfirm previous observational studies suggesting that DH CCBare not antiproteinuric and may actually promote proteinuriaand more rapid CKD progression (10). Also, the AASK showed that,compared with ACEI and beta-blocker therapy, DH CCB increasedthe risk of the composite endpoint of doubling of serum creatinine,ESRD, or death, compared with ACEI or beta-blocker (10). IfDH CCB is needed for BP control, concomitant use of ARB (16),ACE (102), combination ACEI/ARB (93), or beta-blocker may mitigatethe vasodilatory effects of DH CCB to cause glomerular hypertension(11) and, apparently, promote proteinuria. This strategy mayalso limit RAS stimulation by DH CCB.
6. Beta-Blocker Therapy (Level 1)
The AASK showed that sustained-release metoprolol had antiproteinuriceffects nearly equal that of ramipril and better than that ofamlodipine (11). Sympathicoplegic effects may be involved (104).
7. Control Protein Intake (Level 1)
In proteinuric renal diseases, reducing protein intake fromusual levels (about 1.0 to 1.5 g/kg ideal body weight per d)to about 0.7 g/kg ideal body weight per d decreases proteinuriaabout 50% (4), even with nephrotic-range proteinuria (105).Reduced protein intake lowers fibrinogen levels (105), possiblyreducing cardiovascular risk (4), and inhibits glomerular hypertrophy(106), possibly contributing to renoprotection (4). In patientswith proteinuria < 250 mg/d, the low-protein diet does notreduce proteinuria; however, it does slow the progression fromminor to major proteinuria, which is a strong risk factor forCKD progression (4). Thus, the low-protein diet is recommendedeven in low-level proteinuria (4). Substituting soy proteinsfor animal proteins is antiproteinuric and inhibits glomerulosclerosis(107,108). Soy proteins are high in antioxidants (isoflavones)and L-arginine, a nitric oxide donor, which may be renoprotective.A reduced protein diet is recommended in both diabetic and nondiabeticCKD (4,109). However, malnutrition must be avoided (110). Tomonitor dietary protein intake, we recommend measurement of24-h urine urea excretion (4).
8. Restrict NaCl Intake (Level 2)
High salt intake (e.g., 200 mmol NaCl/d or 4.6 g sodium/d) cancompletely override the antiproteinuric effects of ACEI or NDHCCB (4). The average adult North American daily dietary NaClintake is 170 mmol or 3.9 g of sodium, or 10 g of NaCl. Counselingthe patient in dietary salt restriction is usually necessary.We recommend in CKD that dietary salt intake be monitored with24-h urine collection at 2- to 6-mo intervals, particularlyif hypertension, edema, or heart failure are present. Sodiumbicarbonate usually does not contribute importantly to sodiumretention and should not be included in the estimates of saltintake. Because virtually all dietary chloride is as NaCl, urinechloride rather than urine sodium should be measured to estimateNaCl intake for patients receiving sodium bicarbonate therapy(4). Urine chloride of 88 mEq/d corresponds to a 2.0-g sodiumdiet. Concomitant KCl therapy must be taken into account wheninterpreting urine chloride levels.
9. Control Fluid Intake (Level 2)
A retrospective analysis of the MDRD Study A showed that each1% greater urine volume was associated with a 1% greater urineP/C ratio (111). Higher urine volume was associated with higherBP, lower serum sodium, and frankly hypotonic urine, suggestingexcessive fluid intake, not renal sodium and water wasting,as the mechanism of the increased urine volume. Also, higherfluid intake was associated with faster GFR decline (111). Wefound no benefit of a high fluid intake in CKD (111).
10. NDH CCB Therapy (Level 2)
This class includes diltiazem and verapamil. NDH CCB are antiproteinuricand may be renoprotective (4,10). Sustained release forms arerecommended. Verapamil is available as a generic. CombinationNDH CCB and DH CCB is potent antihypertensive therapy (112,113),which should be considered when quadruple therapy is required(Figure 3).
11. Control Blood Lipids (Level 2)
Controlled clinical trials show an antiproteinuric effect oflipid-lowering therapy, particularly statins (75,114–117)and niceritrol, a nicotinic acid derivative (118). The mechanismsmay include decreasing oxidative stress and prevention of lipid-inducedpodocyte damage from decreased nitric oxide production (119).The maximum recommended statin dose may be the appropriate startingdose, based on the remarkable benefits and safety of 40 mg/dsimvastatin in the MRC/BHF study (120). This study also suggestedthat there may not be a blood lipid threshold for cardiovascularbenefit of statin therapy (121). Combining ACEI and statinsmay further reduce proteinuria (122). Note that fenofibrateincreases serum creatinine by as much as 35% because of increasedcreatinine production (29). Lisinopril therapy may contributeto lipid control by effects independent of proteinuria reduction(123).
12. Aldosterone Antagonists (Level 2)
In stroke-prone hypertensive rats, spironolactone prevents theprogressive proteinuria independent of BP control (124). InCKD, 25 mg/d spironolactone added to ACEI therapy for 4 wk reducedmean proteinuria from 3.8 g/d to 1.8 g/d (125), perhaps by blockingthe profibrotic effects of aldosterone (126). Combination spironolactoneand ACEI therapy can cause serious hyperkalemia (127). Eplerenone(currently under study) is similar to that of spironolactone,but with fewer side effects (128), and is antiproteinuric (129,130).
13. Smoking Cessation (Level 2)
Cigarette smoking is associated with proteinuria and fasterprogression of CKD of all types (131,132). Cigarette smoke condensateworsened experimental renal injury and increases proteinuria(133).
14. Avoid Hormone Replacement Therapy in Postmenopausal Women (Level 2 for Kidney Protection, Level 1 for General Benefit)
CKD occurs less frequently and progresses more slowly in premenopausalwomen compared to men (4). However, estrogen replacement therapyor estrogens contained in oral contraceptives are associatedwith microalbuminuria (134). Combination estrogen and progestintherapy also is not recommended because it increased cancerand cardiovascular disease in the Women’s Health Initiativestudy (135). Whether estrogen therapy alone can be justifiedin younger menopausal women, particularly those with hysterectomy,has not been determined (136).
15. In Heavy Proteinuria, Supine or Recumbent Posture Is Encouraged, Severe Exertion Is Discouraged (Level 2)
Exercise and erect posture increase proteinuria. In experimentalnephritis, severe exercise worsens proteinuria (137). Nephrotic-rangeproteinuria decreases by as much as 50% during recumbency (138).In severely nephrotic patients, encouraging recumbent posturemay decrease proteinuria and raises serum albumin. This couldimprove edema, hyperlipidemia, nutrition, and Ig depletion.However, there should be sufficient exercise (for example, 100min per week of walking at a moderate pace [2–3 miles/h][139]), and measures to avoid thrombosis such as low-dose aspirintherapy (4).
16. Reduce Obesity (Level 2)
Obesity is associated with glomerulomegaly, focal and segmentalglomerulosclerosis (FSGS), and proteinuria that can be progressive(140). Reducing obesity can reduce proteinuria (140–142)but may not affect progression of primary glomerulopathies (143).
17. Decrease Elevated Homocysteine (Level 3)
Elevated plasma homocysteine is associated with microalbuminuria(4) and increased cardiovascular risk (144). We recommend 5mg of folic acid, 50 mg of Vitamin B6, and 1 mg of Vitamin B12daily, which is the vitamin intervention of the NIH multicentertrial in kidney transplant patients (FAVORIT). During folicacid therapy, B12 levels must be normal to avoid neurologicdamage (4).
18. Antioxidant Therapies (Level 3)
Antioxidants, d--tocopherol (145), Vitamin C (146), -lipoicacid (147), and selenium (148) decrease proteinuria in experimentalkidney disease, and a 50% reduction of proteinuria was notedin diabetic nephropathy after 3 mo of -lipoic acid therapy (147).However, Vitamin E does not decrease cardiovascular risks (149).
19. Sodium Bicarbonate (NaHCO3) to Correct Metabolic Acidosis (Level 3)
NaHCO3 is not antiproteinuric, but it may block alternativecomplement pathway in the renal tubules in nonselective proteinuria.Oral bicarbonate therapy sufficient to raise urine pH to >5.0,the optimum pH for alternative pathway activation, decreasescomplement activation in the tubular compartment in proteinurichumans (150) and rats (151). Metabolic acidosis correction alsodecreases protein catabolism, which may benefit proteinuricrenal disease (152).
20. NSAIDs in Severe Untreatable Nephrotic Syndrome (Level 3)
NSAIDs, both COX 2 and nonspecific COX inhibitors, are antiproteinuricbut nephrotoxic in humans (153) and should be avoided in kidneydisease (4,77). However in untreatable severe nephrotic syndrome,NSAIDs can substantially reduce proteinuria and provide symptomaticrelief (154).
21. Other Therapies Based on Animal Studies (Level 3)
(1) Avoid excessive caffeine consumption. Obese diabetic ratsdevelop heavy proteinuria if fed caffeine, equivalent to 3 cupsof coffee daily in humans (155). (2) Avoid iron overload. Inexperimental proteinuric renal disease, iron depletion reducesproteinuria and kidney injury (156). Thus, iron overload mightworsen proteinuria. Iron catalyzes formation of free oxygenradicals and reactive iron-oxygen complexes (156). Low plasmatransferrin, which favors iron glomerular filtration, is anindependent risk factor for CKD progression (157). Transferrininduces C3 biosynthesis by human proximal tubular epithelialcells in culture (158). In proteinuric CKD, filtration of iron-bearingtransferrin could contribute to tubular injury. (3) Allopurinoltherapy to reduce elevated serum uric acid levels (Level 3).Hyperuricemia in the rat induces proteinuria and CKD, perhapsby activation of the renin-angiotensin system and inductionof COX-2 (159). Allopurinol or a uricosuric agent attenuatesthese changes (160). Also, allopurinol may improve endothelialcell dysfunction in humans (161). (4) Pentoxifylline. In ratswith 5/6 nephrectomy, this drug prevented progression of proteinuriaand renal disease. The mechanism may involve suppression ofmitogenic and profibrotic genes (162). (5) Mycophenolate mofetil(MMF). This widely used immunosuppressive drug is antiproteinuricand renoprotective in the 5/6 nephrectomy model (163). The benefitof MMF may be related to suppression of nonspecific trappingby the kidney of circulating inflammatory cells (4, 163)
Kidney Conditions for which Antiproteinuria Therapy Is Usually Indicated
Any patient with a CKD is a candidate for antiproteinuric therapy,even in those with low-level proteinuria. CKD with low-levelproteinuria generally manifests slow GFR decline, but progressionof proteinuria during follow-up is the rule (7,11,35). Thus,those with low level proteinuria and slow GFR decline tend tobecome those with greater proteinuria and greater GFR decline.
The ability of antiproteinuric therapy to slow GFR decline hasbeen documented at proteinuria levels starting as low as 500mg/d (33). A plausible explanation for the benefit of antiproteinurictherapy, even at low-level proteinuria, is that current methodsunderestimate the actual protein load to the proximal tubuleby about 2.0 g/d (31,32). The underestimate occurs because filteredplasma proteins are extensively absorbed, degraded, and thenlargely excreted in urine in forms not measured by clinicalmethods (31,32). Thus interventions that reduce only microalbuminuria(Table 4) may have greater benefit than would be inferred fromthe magnitude of microalbuminuria reduction. Microalbuminuriais a risk factor for progression of autosomal-dominant polycystickidney disease (ADPKD) (38). However, there is no clear rationalefor suggesting that reducing microalbuminuria in ADPKD wouldslow progression. Nevertheless, because microalbuminuria isalso a cardiovascular risk factor (164), we suggest that itis appropriate to use antiproteinuric therapies in ADPKD, especiallyLevel 1 therapies. Patients with directly treatable forms ofnephropathy such as lupus nephritis should also be managed withconcomitant antiproteinuric therapies to hasten resolution ofproteinuria and thereby lessen kidney damage (165). Those withcongenital solitary kidney or solitary kidney that was acquiredin childhood should be considered at least for Level 1 antiproteinurictherapies (166) because the only renal diagnosis in 27 patientsin the MDRD Study A was solitary kidney (7).
Chronic Kidney Diseases for which Antiproteinuric Therapies Usually Are Not Indicated
Aggressive use of kidney protective therapies are not recommendedin CKD at low risk for ESRD (4). These include steroid-responsiveminimal change disease, a solitary kidney that is normal andacquired in adulthood (e.g., a kidney donor), hereditary nephritis,or thin GBM disease in the normotensive adult whose only renalmanifestation is microscopic hematuria, and in elderly patientswith idiopathic and moderately elevated serum creatinine (1.3to 2.0 mg/dl) and minor proteinuria (<1 g/d) that have beenstable for a least 1 yr.
Practicality of a Multiple Risk Factor Intervention for Proteinuria
Our experience suggests that most of the Level 1 and Level 2interventions are achievable in the majority of patients withchronic proteinuria. A strategy that appears to help our patientsachieve compliance is to provide written documentation for ourrecommendations (4). We suggest that the current work couldserve this purpose, especially Table 4. With regard to druginteractions, there is no a priori reason to believe that anyof the antiproteinuria interventions antagonize any of the others.Indeed, there is already evidence that specific combinationshave at least additive effects (see discussion of BP, ACEI,ARB, statins, diet, aldosterone antagonists and NDH CCB). Giventhe benefits of even modest proteinuria reductions in CKD progression(4), Figure 1, a broad therapeutic approach to antiproteinurictherapy seems prudent.
Acknowledgments
Supported in part by NIH grants U01 DK 39485, U01 DK 48621,PO1 DK 55546, MO1 RR 00034.
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Top
Abstract
Introduction
. The strategy is to achieve the BP goal using drugs that are antiproteinuric and attenuate angiotensin II (AngII) and aldosterone. The recommended starting point is ACEI or ARB, not diuretics. ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) showed that chlorthalidone reduced certain cardiovascular risks better than ACEI, dihydropyridine calcium channel blocker (DH CCB), or doxazosin (46). On this basis, diuretics are recommended as first-line therapy in hypertension (47). However, diuretics stimulate the renin-angiotensin system, which is probably undesirable in CKD (discussed later). Furthermore, in ALLHAT, the main benefit of diuretics was reduction in congestive heart failure and stroke in African Americans (48). Both are salt-sensitive states. Thus, unless heart failure or another edema-forming state is present, the preferred initial antihypertensive/antiproteinuric therapy in CKD is ACEI or ARB because they attenuate AngII effects. This should not compromise BP control in CKD. Note that about 60% of MDRD Study A patients and about 40% of the AASK patients received no diuretics, and most achieved their BP goal (11,49). Consistent with our recommendation of ACEI rather than diuretic as initial therapy of hypertension is the outcome of the second Australian National Blood Pressure Study (50), and the May 5, 2003, nationally promulgated joint statement of the American Society of Nephrology and the National Kidney Foundation recommending that ACEI, ARB, or both is the preferred initial therapy of hypertension in CKD. If diuretic therapy is needed in CKD, furosemide is recommended (4,51). 
-blocker therapies (96). Diuretic therapy may increase the renoprotective effects of combination therapy (93). Combination ACEI/ARB therapy might be particularly effective in those with the ACE gene DD genotype where resistance to ACEI may be present. The D allele encodes for high ACE, both circulating and tissue, and might contribute to kidney disease progression and resistance to ACEI therapy (71,97–101). A low salt intake may restore responsiveness to ACEI in the DD genotype (71). Not all studies show resistance to ACEI in DD genotypes, particularly in males (99). The reason for this difference is not clear. The incidence of hyperkalemia in combination ACEI/ARB therapy in CKD is similar to that of ACEI alone (93), even when ACEI and ARB are given in maximum recommended doses (72,92). 
-tocopherol (145), Vitamin C (146), 
